Safety, Tolerability and Efficacy Assessment of Dynacirc CR in Parkinson Disease

A Pilot Phase II Double-Blind, Placebo-Controlled, Tolerability and Dosage Finding Study of Isradipine CR as a Disease Modifying Agent in Patients With Early Parkinson Disease

The primary purpose of this study is to establish a dosage of isradipine CR that is tolerable and demonstrates preliminary efficacy for utilization in future pivotal efficacy studies.

There is solid scientific rational and preclinical data supporting a clinical trial of isradipine CR as a potential disease modifying agent in early PD. Human pharmacokinetic data demonstrate that it is feasible to achieve the serum concentrations in humans that were neuroprotective in preclinical models with the FDA approved dosage range. Pilot data demonstrate acceptable tolerability of isradipine CR in the PD population. Tolerability is inversely proportional to the dosage dependent. Considering that tolerability of isradipine CR is inversely proportional to the dosage exposure, it is essential to proceed with the dose selection tolerability study in preparation for the future efficacy trials.

The tolerability, defined as the ability to complete the study, of three dosages of isradipine CR relative to placebo in subjects with early Parkinson's disease will be examined first. The dosage that is tolerable and demonstrates preliminary efficacy will be evaluated further in the future pivotal efficacy studies.

Inclusion Criteria:

• Subjects with early idiopathic PD. If tremor is not present, subjects must have unilateral onset and persistent asymmetry of the symptoms.
• Be over 30 years old at the time of diagnosis of PD.
• Hoehn & Yahr stage is less than or equal to 2.5.
• Currently not receiving dopaminergic therapy and not projected to require dopaminergic therapy for at least 6 months from enrollment.
• Use of MAO-B inhibitors (rasagiline, selegiline), amantadine, or anticholinergics will be allowed. The dosage has to be stable for 3 months prior to baseline visit and throughout the duration of the study.

Exclusion Criteria:

• Subjects with a diagnosis of an atypical Parkinsonism
• Subjects unwilling or unable to give informed consent
• Use of CoQ10 at a dosage >600mg daily or use of creatine >5 grams daily within the 60 days prior to randomization
• Exposure to dopaminergic PD therapy within 60 days prior to enrollment or for 3 months or more at any point in the past
• History of clinically significant orthostatic hypotension or presence of orthostatic hypotension at the screening visit defined as > 20 mmHg change in systolic BP and >10mm change in diastolic BP after 2 min of standing, or baseline BP <90/60
• History of congestive heart failure
• History of bradycardia defined as heart rate <55
• Presence of 2nd or 3rd degree atrioventricular block or other significant ECG abnormalities that in the investigator's opinion would compromise participation in study
• Clinically significant abnormalities in the Screening Visit laboratory studies or electrocardiogram.
• Presence of other known medical or psychiatric comorbidity that in the investigator's opinion would compromise participation in the study
• Prior exposure to isradipine or other calcium channel blockers within 6 months of baseline
• Subjects with history of hypertension treated with a maximum of 2 other antihypertensive agents will be allowed provided that the doses of concomitant anti HTN therapy can be reduced/adjusted during the study based on the BP readings in consultation with the subject's primary care physician or cardiologist.
• Use of grapefruit juice, Ginkgo biloba, St. John's wart and/or ginseng will be prohibited during the study (as they interfere with the metabolism of isradipine).
• Presence of cognitive dysfunction defined by a Mini Mental Status Exam ( MMSE) score < 26 at screening
• Subjects with clinically significant depression as determined by a Beck Depression Inventory (BDI) score >15 at screening
• History of exposure to typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to enrollment
• Subjects have to be on a stable regimen of central nervous system acting medications (benzodiazepines, antidepressants, hypnotics) for 30 days prior to enrollment
• Lactating women or women of childbearing potential who are not surgically sterilized have to use a reliable measure of contraception and have a negative serum pregnancy test at screening
• Participation in other investigational drug trials within 30 days prior to screening
• History of brain surgery for PD