Efficacy of Isradipine in Early Parkinson Disease

The study will enroll 336 participants in this multi-center study at approximately 56 sites
across the US and Canada. In this study, we are comparing 10 mg of Isradipine to Placebo for
treatment of newly diagnosed PD patients. Isradipine has been approved by the Food and Drug
Administration (FDA) to treat high blood pressure but is considered investigational in this
study, as it has not been approved for use in patients with PD.Isradipine can affect the
function of specialized channels that are present in the types of brain cells that are
affected in PD patient. These cells are usually responsible for making dopamine, which is
depleted in patients with PD. Isradipine may block the damage caused by the flow of certain
chemicals through these channels. Laboratory data has showed that Isradipine may prevent the
development of Parkinson-like symptoms in animal studies. Isradipine has been evaluated in
some patients with PD. The first study with isradipine controlled release (CR) in patients
with early PD and normal blood pressure found that the drug was reasonably well tolerated and
safe. The controlled release formulation of isradipine is not available for use and therefore
this study is using the immediate release formulation. Eligible participants will be followed
for up to 36 months and will be expected to complete 12 in-person visits and 4 telephone
visits. The study visits will include clinical assessment of motor, neuropsychiatric and
cognitive testing as well as collection of blood and urine samples. Study drug will taken
twice daily, in the morning and in the evening with or without food. Prior to taking study
drug, study participants will be required to take their blood pressure with a home blood
pressure device provided to them for use in this study.

Inclusion Criteria:

- Subjects with early idiopathic PD (presence of at least two out of three cardinal
manifestations of PD). If tremor is not present, subjects must have unilateral onset
and persistent asymmetry of the symptoms

- Age equal or greater than 30 years at the time of diagnosis of PD

- Hoehn and Yahr stage less than or equal to 2

- Diagnosis of PD less than 3 years.

- Currently NOT receiving dopaminergic therapy (levodopa, dopamine agonist or MAO-B
inhibitors) and NOT projected to require PD symptomatic therapy for at least 3 months
from the baseline visit

- Use of amantadine and/or anticholinergics will be allowed provided that the dose is
stable for 8 weeks prior to the baseline visit

- If subject is taking any central nervous system acting medications (e.g.,
benzodiazepines, antidepressants, hypnotics) regimen must be stable for 30 days prior
to the baseline visit

- Women of childbearing potential may enroll but must use a reliable measure of
contraception and have a negative serum pregnancy test at the screening visit

Exclusion Criteria:

- Subjects with a diagnosis of an atypical Parkinsonism

- Subjects unwilling or unable to give informed consent

- Exposure to dopaminergic PD therapy within 60 days prior to baseline visit or for
consecutive 3 months or more at any point in the past

- History of clinically significant orthostatic hypotension or presence of orthostatic
hypotension at the screening or baseline visit defined as greater than or equal to 20
mmHg change in systolic BP and greater than or equal to 10 mmHg change in diastolic BP
from sitting position to standing after 2 minutes, or baseline sitting BP less than
90/60

- History of congestive heart failure

- Clinically significant bradycardia

- 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 ECG

- 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 dihydropyridine calcium channel blockers within
6 months of the baseline visit

- Subjects on greater than 2 concomitant antihypertensive medications. If a history of
hypertension, then a maximum of 2 other antihypertensive agents will be allowed
provided that the dosages 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 provider or cardiologist. Use of any concomitant calcium channel blockers will
not be allowed from the baseline visit and for the duration of the study

- Use of grapefruit juice, ginkgo biloba, St. John's wort or ginseng will be prohibited
starting from the screening visit and for the duration of the study (as they interfere
with the metabolism of isradipine)

- Use of clarithromycin, telithromycin and erythromycin will be prohibited starting from
the screening visit and for the duration of the study as the combination of
clarithromycin, telithromycin or erythromycin and calcium channel blockers has been
reported to be associated with increased risk of kidney and heart injury

- Presence of cognitive dysfunction defined by a Montreal Cognitive assessment (MoCA)
score of less than 26 at screening

- Subjects with clinically significant depression as determined by a Beck Depression
Inventory II (BDI) score greater than 15 at the screening visit

- History of exposure to typical or atypical antipsychotics or other dopamine blocking
agents within 6 months prior to the baseline visit

- History of use of an investigational drug within 30 days prior to the screening visit

- History of brain surgery for PD

- Allergy/sensitivity to isradipine or its matching placebo or their formulations

- Pregnant or lactating woman