STEADY-PD III

Principal Investigator: Camila Aquino
Keywords: Parkinson's Disease , Isradipine , early idiopathic PD , motor disability , cognitive disability , global disability , quality of life Department: Neurology
IRB Number: 00074246 Co Investigator: Tyler Hohnholt
Specialty: Neurology, Neurology, Neurology, Neurology
Sub Specialties: Movement Disorders, Parkinson's Disease, Neurodegenerative Disorders
Recruitment Status: Not yet recruiting

Contact Information

Alissa Davis
alissa.davis@hsc.utah.edu
801-587-8581

Brief Summary

STUDY PURPOSE

The purpose of this study is to determine if an investigational drug called isradipine immediate release (Isradipine-IR) is safe and helpful in slowing the rate of PD decline.  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.

In this study we are comparing 10mg of isradipine to placebo (a pill that looks like the study drug but doesn’t have any active medication in it, like a sugar pill).  If a participant is eligible and choose to be in the study they will be randomized to take either:

  • Isradipine (5mg taken by mouth twice daily) OR
  • Placebo

Participants have an equal chance of receiving study drug or placebo.  Neither participant nor the researchers will know whether the participant is taking study drug or placebo.

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.

OBJECTIVES

Primary:

To establish efficacy of isradipine to slow progression of Parkinson disease (PD) disability as determined by the change in the total (Part I-III) Unified Parkinson Disease Rating Scale (UPDRS) score in the active treatment arm versus placebo between the baseline and 36 month visit.

Secondary:

To explore long-term efficacy of isradipine 5 mg twice daily to slow progression of disability between baseline and 36 months of treatment as measured by parameters that reflect long term disability in PD:
1) Motor function (characterized by UPDRS Part III in the medications OFF state, UPDRS ambulatory capacity subscore, time to initiation of symptomatic therapy, time to onset of motor complications, dosage and utilization of symptomatic therapy, MDS-UPDRS Motor score)
2) Cognitive function as measured by the Montreal Cognitive assessment Scale (MoCA)
3) Global measures of disability as measured by modified Rankin score
4) Measures of functional status and quality of life (PDQ-39, MDS- UPDRS Motor and Non-Motor Experience of Daily Living)

 

Detailed Description

STUDY PURPOSE The purpose of this study is to determine if an investigational drug called isradipine immediate release (Isradipine-IR) is safe and helpful in slowing the rate of PD decline. 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. In this study we are comparing 10mg of isradipine to placebo (a pill that looks like the study drug but doesn’t have any active medication in it, like a sugar pill). If a participant is eligible and choose to be in the study they will be randomized to take either: Isradipine (5mg taken by mouth twice daily) OR Placebo Participants have an equal chance of receiving study drug or placebo. Neither participant nor the researchers will know whether the participant is taking study drug or placebo. 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. OBJECTIVES Primary: To establish efficacy of isradipine to slow progression of Parkinson disease (PD) disability as determined by the change in the total (Part I-III) Unified Parkinson Disease Rating Scale (UPDRS) score in the active treatment arm versus placebo between the baseline and 36 month visit. Secondary: To explore long-term efficacy of isradipine 5 mg twice daily to slow progression of disability between baseline and 36 months of treatment as measured by parameters that reflect long term disability in PD: 1) Motor function (characterized by UPDRS Part III in the medications OFF state, UPDRS ambulatory capacity subscore, time to initiation of symptomatic therapy, time to onset of motor complications, dosage and utilization of symptomatic therapy, MDS-UPDRS Motor score) 2) Cognitive function as measured by the Montreal Cognitive assessment Scale (MoCA) 3) Global measures of disability as measured by modified Rankin score 4) Measures of functional status and quality of life (PDQ-39, MDS- UPDRS Motor and Non-Motor Experience of Daily Living) BACKGROUND AND INTRODUCTION Parkinson disease (PD) is the second most common neurodegenerative disease that af-fects 1% of the population above the age 65 [5]. The prevalence of PD will increase substantially in the next 20 years due to the aging of the population and age-related increase of the incidence of the disease [6, 7]. PD is characterized by progressive motor disability that includes bradykinesia, rigidity, resting tremor and gait dysfunction. PD is associated with a spectrum of non-motor symptoms including autonomic, cognitive, mood, sleep dysfunction and sensory abnormalities which are intrinsically related to the widespread PD neuropathological process and can in part precede the onset of motor manifestations [8]. The economical burden of PD is estimated to be $23 billion annually in US and projected to increase to $50 billion by year 2040 [9]. Most of the cost is due to lost productivity and correlates with more advanced stages of the disease signifying the importance of developing treatment strategies that slow progression of accumulating disability [10]. Treatment options for PD are limited to symptomatic therapy geared towards replacement of dopamine deficiency [11]. Despite a wide armamentarium of effective symptomatic therapy for early PD, management of advanced disease is limited. Availability of an effective disease modifying intervention that will slow the progression of the disease will have a substantial impact on the patients’ quality of life and the economic burden of disease. As of today there is no single proven neuroprotective agent in PD [12]. Tested agents targeted various potential mechanisms of PD pathogenesis including oxidative stress (rasagiline, selegiline, Vitamin E), mitochondrial dysfunction (CoQ10, creatine), apoptotic mechanism of cell death (caspase inhibitors) and others [13-21].

Inclusion Criteria

STUDY INCLUSION CRITERIA

1. 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
2. Age equal or greater than 30 years at the time of diagnosis of PD
3. Hoehn and Yahr stage less than or equal to 2
4. Diagnosis of PD less than 3 years.
5. Currently NOT receiving dopaminergic (levodopa, dopa-mine agonist or MAO-B inhibitors) therapy and NOT projected to require PD symptomatic therapy for at least 3 months from the baseline visit
6. Use of amantadine and/or anticholinergics will be allowed provided that the dose is stable for 8 weeks prior to the baseline visit
7. 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
8. 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

STUDY EXCLUSION CRITERIA

1. Subjects with a diagnosis of an atypical Parkinsonism
2. Subjects unwilling or unable to give informed consent
3. 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
4. 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
5. History of congestive heart failure
6. Clinically significant bradycardia
7. Presence of 2nd or 3rd degree atrioventricular block or other significant ECG abnormalities that in the investigator’s opinion would compromise participation in study
8. Clinically significant abnormalities in the Screening Visit laboratory studies or ECG
9. Presence of other known medical or psychiatric comorbidity that in the investigator’s opinion would compromise participation in the study
10. Prior exposure to isradipine or other dihydropyridine calcium channel blockers (see list in Operations Manual) within 6 months of the baseline visit
11. 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
12. 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)
13. 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
14. Presence of cognitive dysfunction defined by a Montreal Cognitive assessment (MoCA) score of less than 26 at screening
15. Subjects with clinically significant depression as determined by a Beck Depression Inventory II (BDI) score greater than 15 at the screening visit
16. History of exposure to typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to the baseline visit
17. History of use of an investigational drug within 30 days prior to the screening visit
18. History of brain surgery for PD
19. Allergy/sensitivity to isradipine or its matching placebo or their formulations
20. Pregnant or lactating woman