Clinical trial NCT02168842: Efficacy of Isradipine in Early Parkinson Disease
Official title: Phase 3 Double-blind Placebo-controlled Parallel Group Study of Isradipine as a Disease Modifying Agent in Subjects With Early Parkinson Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Parkinson Disease
Keywords: Parkinson
Parkinson Disease
Parkinson's Disease
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Michael J. Fox Foundation for Parkinson's Research
name: The Parkinson Study Group
First posted: 2014-06-20
Enrollment: 336
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to determine whether treatment with isradipine is effective in slowing the progression of Parkinson disease disability.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Adjusted Mean Change in Total Unified Parkinson Disease Rating Scale (UPDRS) Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Adjusted UPDRS Score
timeFrame: Baseline to 36 months of treatment
Secondary outcomes:
measure: Adjusted Mean Change in LED
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in LED Cumulative
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in UPDRS Part IV
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in MDS-UPDRS nmEDL
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in MDS-UPDRS mEDL
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in UPDRS Score to 1 Year
timeFrame: Baseline to 12 months of treatment
measure: Adjusted Mean Change in UPDRS Part II
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in UPDRS Part III OFF
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in SE/ADL
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Modified Rankin Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in MoCA Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in PDQ39 Total Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Ambulatory Capacity
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in BDI Total Score
timeFrame: Baseline to 36 months of treatment
measure: Risk of Need for Antiparkinsonian Therapy
timeFrame: Baseline to 36 months of treatment
measure: Risk of Need for Dyskinesia
timeFrame: Baseline to 36 months of treatment
measure: Risk of Need for Fluctuations
timeFrame: Baseline to 36 months of treatment
Other outcomes:
measure: Adjusted Mean Change in UPDRS PIGD Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in UPDRS Tremor Score
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in H/Y Stage
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Levodopa
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Levodopa Cumulative
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Systolic BP, Seated
timeFrame: Baseline to 36 months of treatment
measure: Adjusted Mean Change in Diastolic BP, Seated
timeFrame: Baseline to 36 months of treatment
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Fountain Valley
country: United States
facility: The Parkinsons & Movement Disorder Institute
state: California
city: Irvine
country: United States
facility: University of California
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center
state: Colorado
city: New Haven
country: United States
facility: Institute of Neurodegenerative Disorders
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Honolulu
country: United States
facility: Pacific Health Research & Education Institute
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Shreveport
country: United States
facility: LSU Health Science Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Golden Valley
country: United States
facility: Struthers Parkinson's Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: University of Nevada School of Medicine
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Summit
country: United States
facility: Atlantic Neuroscience Institute
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Kingston
country: United States
facility: Health Quest Kingston
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Neurology Specialists
state: Virginia
city: Kirkland
country: United States
facility: Booth Gardner Parkinson's Care Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital Civic Site
state: Ontario
city: Toronto
country: Canada
facility: The Centre for Addiction and Mental Health
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital, University Health Network
state: Ontario
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Affilie
state: Quebec
Study officials:
affiliation: Northwestern University
name: Tanya Simuni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Robert Holloway, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Venuto CS, Yang L, Javidnia M, Oakes D, James Surmeier D, Simuni T. Isradipine plasma pharmacokinetics and exposure-response in early Parkinson's disease. Ann Clin Transl Neurol. 2021 Mar;8(3):603-612. doi: 10.1002/acn3.51300. Epub 2021 Jan 18.
citation: Parkinson Study Group STEADY-PD III Investigators. Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial. Ann Intern Med. 2020 May 5;172(9):591-598. doi: 10.7326/M19-2534. Epub 2020 Mar 31.
citation: McFarthing K, Simuni T. Clinical Trial Highlights: Phase III Study in Spotlight. J Parkinsons Dis. 2019;9(1):3-4. doi: 10.3233/JPD-190002. No abstract available.