Objective/Rationale:
Isradipine, a drug approved by the FDA for treatment of high blood pressure, has been found to be neuroprotective in pre-clinical models of parkinsonism. The objective of this study is to determine the highest dose of isradipine that is safe in Parkinson's disease (PD) patients and shows relative efficacy to be used in the future definitive clinical trial. Three doses will be compared to placebo.
Project Description:
This study (called STEADY-PD) will recruit 100 patients with early PD who are not yet taking any medications to treat PD symptoms. Patients will be assigned to one of four treatment groups (5 mg, 10 mg, 20 mg or placebo). Patients will be followed for 12 months. Safety of each dose of isradipine will be evaluated first based on the number of patients able to complete the study on their original dosage assignment, and then on the rate and severity of side effects. If all doses are tolerable, then the dosage that is most effective will be selected based on the comparison of the rate of progression of PD symptoms in each group over 12 months of the study. The tolerable dosage that is most effective will be used in future studies to determine if isradipine slows progression of PD.
Relevance to Diagnosis/Treatment of Parkinson ’s Disease:
Currently, nothing has been proved to stop or slow the progression of PD. Having a drug that significantly slows the progression of the disease would broaden the therapeutic window for treatments aimed at lessening the symptoms in early-stage PD patients, improving their quality of life. This study is the first step toward determining whether isradipine, or drugs with a similar target, will fill this critical need.
Anticipated Outcome:
This study will provide information on the dosage of isradipine that is safe and has highest relative efficacy (compared to the other dosages) to be used in the future definitive study that will test if isradipine is neuroprotective in patients with PD.
Final Outcome
STEADY-PD successfully completed enrollment of 99 subjects at 21 sites over 13 months. The tolerability of isradipine was dose-dependent. Isradipine 10 mg daily dose was the maximally tolerable dosage. The most common adverse events were dosage-dependent peripheral edema and dizziness. While there was no difference in efficacy between treatment arms, the effect size compared to placebo did not rule out possible meaningful clinical benefit. Isradipine had no PD symptomatic effect based on the wash-in or washout analyses. The data supports the use of 10 mg dosage for the future efficacy trial.
Presentations & Publications
Chan, C.S., T.S. Gertler, and D.J. Surmeier, A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease. Mov Disord, 2010. 25 Suppl 1: p. S63-70.
Guzman, J.N., et al., Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 2010.
Ilijic, E., J.N. Guzman, and D.J. Surmeier, The L-type channel antagonist isradipine is neuroprotective in a [pre-clinical] model of Parkinson's disease. Neurobiol Dis, 2011. 43(2): p. 364-71.
Simuni T, Martel A, Zadikoff C, Videnovic A, Vainio L, Weaver F, Williams K, Surmeier DJ. Safety and tolerability of isradipine, a dihydropyridine calcium channel blocker, in patients with early Parkinson’s disease. Poster. 12th International Congress of Parkinson’s Disease and Movement Disorders, June 22-26, 2008, Chicago.
Simuni T, Martel A, Zadikoff C, Videnovic A, Vainio L, Weaver F, Williams K, Surmeier DJ. Safety and tolerability of isradipine, a dihydropyridine calcium channel blocker, in patients with early Parkinson’s disease. Poster. Platform presentation, 22nd Annual Symposium on Etiology, Pathogenesis and Treatment of Parkinson’s Disease and Other Movement Disorders, September 21, 2008, Salt Lake City. Award for the best poster in Parkinson’s disease category
Tanya Simuni, MD, Audrey Martel, BS, Michael Avram, PhD, Cindy Zadikoff, MD, Aleksandar Videnovic, MD and Dalton J Surmeier, PhD. (Chicago, IL, United States). Isradipine plasma concentrations in patients with early Parkinson's disease taking isradipine CR, a dihydropyridine Ca channel antagonist. Poster. 13th International Congress of Parkinson’s Disease and Movement Disorders, June, 2009, Paris.
Tanya Simuni MD (1), Kevin Biglan MD MPH (2), David Oakes PhD (2), D. James Surmeier PhD (1). Parkinson Study Group STEADY-PD: Safety, Tolerability, and Efficacy Assessment of Isradipine (Dynacirc CR) for PD. Poster. Accepted for the WPC, December 2009, Miami
Tanya Simuni MD (1), Kevin Biglan MD MPH (2), David Oakes PhD (2), D. James Surmeier PhD (1). Parkinson Study Group STEADY-PD: Safety, Tolerability, and Efficacy Assessment of Isradipine (Dynacirc CR) for PD. Poster. PSG symposium, October 2009, Baltimore.
STEADY-PD. Safety and tolerability of Isradipine CR in patients with early Parkinson’s disease. Baseline characteristics of the cohort. MDS meetings June 7 and 9, 2011
STEADY-PD: Safety, Tolerability, and Efficacy Assessment of Isradipine (DynacircCR) for PD Interim Tolerability Data Analysis (guided poster tour). MDS meetings June 7 and 9, 2011
Final data was presented as the late breaking news poster at the 15th International Congress of Parkinson’s Disease and Movement Disorders, June, 20012, Dublin. Blue ribbon award and included in the highlights session.
Parkinson Study Group STEADY-PD: Safety, Tolerability, and Efficacy Assessment of Isradipine (Dynacirc CR) for PD. Poster. 15th International Congress of Parkinson’s Disease and Movement Disorders, June, 20012, Dublin.
The draft manuscript is in preparation.
November 2012
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