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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Isradipine CR 5mg
* Drug: Isradipine CR 10mg
* Drug: Isradipine CR 20mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Parkinson disease