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

Condition(s) targeted: Parkinson Disease

Intervention: Isradipine CR 5mg (Drug); Isradipine CR 10mg (Drug); Isradipine CR 20mg (Drug); Placebo (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Northwestern University

Official(s) and/or principal investigator(s):
Tanya Simuni, MS, Study Chair, Affiliation: Northwestern University

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.

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Tolerability of the Three Dosages(5mg, 10mg and 20mg) of Isradipine CR.

Secondary outcome:

Efficacy: Change in Unified Parkinson's Disease Rating Scale (UPDRS)

Efficacy: Change in Mental Subscales of the Unified Parkinson's Disease Rating Scale

Efficacy: Change in Activities of Daily Living(ADL) Subscale of the Unified Parkinson's Disease Rating Scale

Efficacy: Change in Motor Subscale of the Unified Parkinson's Disease Rating Scale

Efficacy: Change in Modified Hoehn & Yahr Scale

Efficacy: Change in Modified Schwab & England Independence Scale

Efficacy: Change in Beck Depression Inventory II (BDI-II)

Efficacy: Change in Montreal Cognitive Assessment

Efficacy: Change in Parkinson Disease Quality of Life Questionnaire-39(PDQ-39)

Vital Signs: Change in Systolic Standing

Vital Signs: Change in Systolic Supine

Vital Signs: Change in Diastolic Standing

Vital Signs: Change in Diastolic Supine

Vital Signs: Change in Pulse Standing

Vital Signs: Change in Pulse Supine

Common Adverse Events: Oedema Peripheral

Common Adverse Events: Dizziness

Common Adverse Events: Nasopharyngitis

Common Adverse Events: Headache

Common Adverse Events: Constipation

Common Adverse Events: Fatigue

Common Adverse Events: Nausea

Common Adverse Events: Upper Respiratory Tract Infection

Common Adverse Events: Depression

Common Adverse Events: Somnolence

Common Adverse Events: Insomnia

Common Adverse Events: Dyspepsia

Common Adverse Events: Diarrhoea

Common Adverse Events: Sinusitis

Common Adverse Events: Back Pain

Common Adverse Events: Hypotension

Detailed description: 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.

Minimum age: 30 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Parkinson Institute, Sunnyvale, California 94805, United States

Institute for Neurodegenerative Disorders, New Haven, Connecticut 06510, United States

Mayo Clinic Jacksonville, Jacksonville, Florida 32224, United States

University of Miami, Miami, Florida 33136, United States

University of South Flordia, Tampa, Florida 33606, United States

Emory University School of Medicine, Atlanta, Georgia 30329, United States

Pacific Health Institute, Honolulu, Hawaii 96817, United States

Northwestern University, Chicago, Illinois 60611, United States

Rush University Medical Center, Chicago, Illinois 60612, United States

Boston University, Boston, Massachusetts 02118, United States

Michigan State University, East Lansing, Michigan 48824, United States

Park Nicolet Clinic, Golden Valley, Minnesota 55427, United States

University of Minnesota, Minneapolis, Minnesota 55455, United States

Washington University, St. Louis, Missouri 63110, United States

University of Rochester, Rochester, New York 14618, United States

University of Cincinnati, Cincinnati, Ohio 45219, United States

Ottowa Hospital Civic Site, Ottawa, Ontario K1Y 4E9, Canada

Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

University of Tennessee, Memphis, Tennessee 38104, United States

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Starting date: July 2009
Last updated: April 16, 2013