Safety, Tolerability and Efficacy Assessment of Dynacirc CR in Parkinson Disease (STEADY-PD)

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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Isradipine CR 5mg; Drug: Isradipine CR 10mg; Drug: Isradipine CR 20mg; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottowa Hospital Civic Site
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
• United States
  • California
    • Sunnyvale, California, United States, 94805
      • Parkinson Institute
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Institute for Neurodegenerative Disorders
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33606
      • University of South Flordia
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University School of Medicine
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Pacific Health Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University
  • Michigan
    • East Lansing, Michigan, United States, 48824
      • Michigan State University
  • Minnesota
    • Golden Valley, Minnesota, United States, 55427
      • Park Nicolet Clinic
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Rochester, New York, United States, 14618
      • University of Rochester
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • University of Tennessee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; 4 Placebo to Match (PTM) tablets once daily
Active Comparator: Isradipine CR 5mg; Isradipine CR 5mg/day	Drug: Isradipine CR 5mg; 5mg dose: 1 Dynacirc CR 5mg tablet, 3 tablets placebo once daily; Other Names: Isradipine CR; Dynacirc CR
Active Comparator: Isradipine CR 10mg; Isradipine CR 10mg/day	Drug: Isradipine CR 10mg; 10mg dose: 2 Dynacirc CR 5mg tablets, 2 tablets placebo once daily; Other Names: Isradipine CR; Dynacirc CR
Active Comparator: Isradipine CR 20mg; Isradipine CR 20mg/day	Drug: Isradipine CR 20mg; 20mg dose: 4 Dynacirc CR 5mg tablets once daily; Other Names: Isradipine CR; Dynacirc CR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of the Three Dosages(5mg, 10mg and 20mg) of Isradipine CR.	Tolerability will be judged by the proportion of subjects enrolled in a dosage group able to complete the 12 month study or to the time of initiation of dopaminergic therapy on their original assigned dosage. Tolerability of each active arm will be compared to placebo group.	Baseline to 12 months or the time to require dopaminergic therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Change in Unified Parkinson's Disease Rating Scale (UPDRS)	Outcome is defined as change in total Unified Parkinson's Disease Rating Scale (UPDRS) between the baseline visit and month 12 or the time to require dopaminergic therapy (last visit before subject goes on dopaminergic therapy), whichever occurs first. The UPDRS score has 4 components. Part I assesses mentation; Part II assesses activities of daily living; Part III assesses motor abilities; Part IV assesses complications of therapy. A total of 44 items are included in Parts I-III. Each item will receive a score ranging from 0 to 4 where 0 represents the absence of impairment and 4 represents the highest degree of impairment. Part IV contains 11 items, 4 of these items are scored 0-4 in the same manner, and 7 are scored 0-1, with 0 indicating the absence of impairment and 1 indicating the presence of impairment. Total UPDRS score represents the sum of these items in Parts I-IV. A total of 199 points are possible. 199 represents the worst (total) disability), 0--no disability.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Mental Subscales of the Unified Parkinson's Disease Rating Scale	The outcome is defined as change in Mental subscale of Unified Parkinson's Disease Rating Scale(UPDRS Part I) between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. UPDRS Part I: Mentation, behavior and mood, consisting of 4 questions answered on a 0-4 point scale where 0 represents the absence of impairment and 4 represents the highest degree of impairment. Total score represents the sum of these 4 questions. A greater increase in score indicates a greater increase in disability. A total of 16 points are possible. 16 represents the worst (total) disability), 0--no disability.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Activities of Daily Living(ADL) Subscale of the Unified Parkinson's Disease Rating Scale	The outcome is defined as change in ADL subscale of the Unified Parkinson's Disease Rating Scale(UPDRS Part II) between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. UPDRS Part II: Activities of Daily Living in the week prior to the designated visit, consisting of 13 questions answered on a 0-4 point scale where 0 represents the absence of impairment and 4 represents the highest degree of impairment. Total Part II score represents the sum of these 13 questions. A greater increase in score indicates a greater increase in disability. A total of 52 points are possible. 52 represents the worst (total) disability), 0--no disability	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Motor Subscale of the Unified Parkinson's Disease Rating Scale	The outcome is defined as change in Motor subscale of the Unified Parkinson's Disease Rating Scale(UPDRS Part III) between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. UPDRS Part III: motor abilities at the time of the visit, consisting of 27 items (including 13 general questions and 14 sub-questions) each answered on a 0-4 point scale where 0 represents the absence of impairment and 4 represents the highest degree of impairment. Total Part III score represents the sum of these 27 items. A total of 108 points are possible. 108 represents the worst (total) disability), 0--no disability.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Modified Hoehn & Yahr Scale	The Modified Hoehn & Yahr Scale is an 8-level Parkinson's disease staging instrument. The outcome is defined as change in Modified Hoehn & Yahr Scale between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. A greater increase in stage indicates a greater increase in disability. Stage ranges from 0-5 (also including 1.5 and 2.5) with 0 indicating no disability and 5 indicating maximum disability.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Modified Schwab & England Independence Scale	The Schwab & England scale is an investigator and subject assessment of the subject's level of independence at all scheduled study visits. The subject will be scored on a percentage scale reflective of his/her ability to perform acts of daily living in relation to what he/she did before Parkinson's disease appeared. The outcome is defined as change in Schwab & England Independence Scale between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. Higher decrease in score indicates higher disability. Score ranges from 100% (complete independence) to 0% (total disability).	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Beck Depression Inventory II (BDI-II)	The Beck Depression Inventory (BDI) is a validated self-reported 21-item depression scale that was tested and validated as a reliable instrument for screening for depression in PD. The outcome is defined as change in BDI-II between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. Total BDI score represents the sum of these 21-items. A higher change in score indicates a greater increase in disability. Total score of 0-13 is considered minimal, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Montreal Cognitive Assessment	The Montreal Cognitive Assessment(MoCA) is a brief 30-point screening instrument that was developed and validated to identify subjects with mild cognitive impairment. The outcome is defined as change in MoCA between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. Total MoCA score represents the sum of these 30-points, with a lower score indicating greater cognitive impairment. 30 is the maximum score, with a score of 26 or higher considered normal and below 26 indicative of Mild Cognitive Impairment.	Baseline to 12 months or the time to require dopaminergic therapy
Efficacy: Change in Parkinson Disease Quality of Life Questionnaire-39(PDQ-39)	The PD Quality of Life Scale(PDQ-39) asks the subject to evaluate how Parkinson disease has affected their health and overall quality of life at that point in time. The total quality of life scale includes subscales relating to social role, self-image/sexuality, sleep, outlook, physical function and urinary function. The outcome is defined as change in PDQ-39 between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy. It is scored on a scale of zero to 100, with lower scores indicating better health and higher scores more severe disability.	Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Systolic Standing		Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Systolic Supine		Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Diastolic Standing		Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Diastolic Supine		Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Pulse Standing		Baseline to 12 months or the time to require dopaminergic therapy
Vital Signs: Change in Pulse Supine		Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Oedema Peripheral	General disorders and administration site conditions. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Dizziness	Nervous system disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Nasopharyngitis	Infections and infestations. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Headache	Nervous System disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Constipation	Gastrointestinal Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Fatigue	General Disorders and Administration Site Conditions. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Nausea	Gastrointestinal Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Upper Respiratory Tract Infection	Infections and Infestations. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Depression	Psychiatric Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Somnolence	Nervous System Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Insomnia	Psychiatric Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Dyspepsia	Gastrointestinal Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Diarrhoea	Gastrointestinal Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Sinusitis	Infections and Infestations. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Back Pain	Musculoskeletal and Connective Tissue Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy
Common Adverse Events: Hypotension	Vascular Disorders. Common adverse experience/event is defined as AE occurs to 5(about 5%) or more subjects. They will also be tabulated by treatment groups.	Baseline to 12 months or the time to require dopaminergic therapy

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: Michael J. Fox Foundation for Parkinson's Research; The Parkinson Study Group; Northwestern University Dixon Fund
• Investigators: Study Chair: Tanya Simuni, MS, Northwestern University

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: May 26, 2009
• First Submitted That Met QC Criteria: May 26, 2009
• First Posted (Estimate): May 28, 2009

Study Record Updates

• Last Update Posted (Estimate): April 17, 2013
• Last Update Submitted That Met QC Criteria: April 16, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Early Parkinson disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Isradipine
• Other Study ID Numbers: CTCC Protocol #124