Protocol Number: 04-N-0258

Title:

Transcutaneous Lisuride Therapy for Parkinson's Disease

Number:

04-N-0258

Summary:

This study will evaluate the effectiveness of a skin patch formulation of the dopamine agonist Lisuride in controlling parkinsonian symptoms and dyskinesias (involuntary movements) caused by levodopa. Lisuride is currently available in tablet form; this study will test whether a patch formulation that provides continuous stimulation of the dopamine receptors will better control disease symptoms.

Patients between 40 and 80 years old with Parkinson's disease and dyskinesias may be eligible for this 4-month study. Participants undergo the following procedures:

Screening and baseline evaluation: Participants are evaluated with a medical history, physical examination, neurologic evaluation, blood tests, urinalysis, and electrocardiogram. A chest X-ray and MRI or CT scan of the brain are done, if needed. If possible, patients stop taking all antiparkinsonian medications except levodopa (Sinemet) for 1 month (2 months for Selegiline) before the study begins and throughout its duration.

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 levodopa 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. (Patients who have had dosing infusions in the last 3 months do not have to undergo this phase of the study.)

Active study phase: Patients are randomly assigned to one of two treatment groups. One group receives a placebo (a patch with no active drug) and a patch that contains Lisuride; the other group receives placebo throughout the entire study. Patients are instructed on how to apply the patches. During the first 2 weeks of this study phase, the number of patches containing active drug is gradually increased until the individual's optimum dose is reached. Patches are changed about every 2 days. During this time, intake of other antiparkinsonian medications is tapered down and patients are evaluated frequently. For the next 3 months, patients wear the patches continuously at the optimum dose. The patches are changed every 2 days or once a week, depending on the individual patient's need. Two levodopa infusion studies are done in the active study phase as they were in the dose-finding phase - at the beginning of the dose escalation phase and again at the end of the dose maintenance phase. In addition, patients are tested for their ability to perform different motor tasks.

Sleep studies: Because oral Lisuride can cause excessive sleepiness, some patients are asked to participate in a sleep study to evaluate sleep patterns during the night and daytime sleepiness. The subject's brain, muscles, and breathing are continuously monitored during sleep. Also, an electroencephalogram (EEG) is done to record brain waves while the subject lies quietly, breathes deeply, watches flashes of light, sleeps, or performs a task.

Safety checks: Patients are monitored closely for safety with a history of side effects, blood tests, and ECG each time a new supply of study drug is dispensed.

Follow-up: 2 weeks after completing the active phase of the study, patients are contacted by phone for a follow-up evaluation.

Sponsoring Institute:

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Individuals who meet all of the following inclusion criteria will be eligible to participate:

Patient has been diagnosed with idiopathic Parkinson's disease.

Patient has relatively advanced disease with levodopa-associated motor response complications, including, peak-dose dyskinesias and wearing-off fluctuations.

Patient can be optimized on oral levodopa, usually with an interdose interval of less than 3.0 hours.

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

Patient is between the ages of 40 and 80 years, inclusive.

EXCLUSION CRITERIA:

Individuals meeting any of the following exclusion criteria immediately before or during the study will not be enrolled or will be immediately excluded from the study, as appropriate:

Patient has a history of any medical condition that can reasonably be expected to subject them to unwarranted risk, such as history of significant cardiac (myocardial infarction within 12 months prior to study, dysrhythmia), cerebrovascular, convulsive, hepatic (enzyme elevation greater than twice the upper limit of normal), or renal (creatinine exceeding the upper limit of normal) disorder.

Patient is taking a prohibited medication.

Patient is unable to be treated with levodopa/carbidopa alone while a participant in this protocol.

Patient has unilateral or bilateral deep brain stimulating (DBS) devices who are unable or unwilling to turn them off during the period of protocol participation.

Patient has prior bilateral pallidotomy.

Patient has cognitive impairment as indicated by a Minimental status examination (MMSE) score less than 25.

Patient has not been using an adequate contraceptive method for the last 2 months, or (if female) is pregnant or breastfeeding, or not at lease one year post-menopausal or unwilling or unable to continue contraceptive use during the study.

Patient has participated in a clinical study with an investigational drug within the last 30 days.

Patient has dermatological problems, such as eczema or hirsutism, that would interfere with transcutaneous therapy.

Patients with known hypersensitivity to lisuride or to skin patch material.

Patients with slow lisuride metabolism due to CYP450 2D6 deficiency or requiring drugs also metabolized by CYP450 2D6, including B-blockers: S-metoprolol, propafenone, antidepressants: amitriptyline, clomipramine, desipramine, imipramine, antipsychotics: haloperidol, risperidone, thioridazine, other drug: codeine, dextromethorphan, flecainide, ondansetron, and tramadol.

CONCOMITANT MEDICATION EXCLUSION:

The following medications are prohibited for at least one month prior to randomization (except as noted below) and during the course of study:

Dopamine agonists of any kind (for 1 week, Cabergoline for 8 weeks).

Any investigational drug not specifically permitted in the protocol.

MAO inhibitors, such as selegiline (for 2 months).

Anticholinergics.

Drugs not used primarily to treat Parkinson's disease but which may modify parkinsonian symptoms, including neuroleptics, metoclopramide and alpha or beta adrenergic receptor antagonists.

Drugs considered to ameliorate dyskinesias including NMDA antagonists (such as amantadine, budipine, memantine, remacemide and dextromethorphan), alpha or beta adrenergic receptor antagonists, anxiolytics (such as fluoxetine and buspirone), antipsychotics (such as clozapine, quetiapine and olanzapine), cannabinoid receptor antagonists, and adenosine A2a antagonists, or to exacerbate dyskinesias (such as sodium valproate and CNS stimulants).

Drugs known to have 5HT receptor subtype affinity (such as ritanserin, sumatriptan).

Special Instructions: Currently Not Provided

Keywords:

Parkinson's Disease

Motor Fluctuations

Intravenous Levodopa

Antiparkinsonian Response

Lisuride Patch

Recruitment Keywords:

Parkinson Disease

PD

Conditions:

Parkinson Disease

Investigational Drug(s):

Intravenous Levodopa

Lisuride Patch

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001 May;16(3):448-58.

PMID: 11391738

Chase TN, Oh JD. Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications. Ann Neurol. 2000 Apr;47(4 Suppl 1):S122-9; discussion S129-30. Review.

PMID: 10762139

Grace AA, Bunney BS. The control of firing pattern in nigral dopamine neurons: single spike firing. J Neurosci. 1984 Nov;4(11):2866-76. PMID: 6150070

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