Efficacy of Isradipine in Early Parkinson Disease

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT02168842
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Michael J. Fox Foundation for Parkinson's Research (Other), The Parkinson Study Group (Other)
• Enrollment: 336
• Locations: 54
• Arms: 2
• Actual Duration (Months): 48
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	Drug: Isradipine; Drug: Placebo (for Isradipine)	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 336 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3 Double-blind Placebo-controlled Parallel Group Study of Isradipine as a Disease Modifying Agent in Subjects With Early Parkinson Disease
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Isradipine Oral capsule of up to 5 mg of isradipine taken twice daily for 36 months.	Drug: Isradipine; Oral capsules Isradipine IR, up to 10 mg, taken twice daily
Placebo Comparator: Placebo (for Isradipine) Oral capsule taken twice daily for 36 months.	Drug: Placebo (for Isradipine); Sugar Pill manufactured to look like Isradipine but has no active ingredients

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change in Total Unified Parkinson Disease Rating Scale (UPDRS) Score [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the total (Part I-III) UPDRS score in the active treatment arm versus placebo between the baseline and 36 month visit. The change of UPDRS ranges from -30 to 80, larger value shows more disability from PD.

2. Adjusted Mean Change in Adjusted UPDRS Score [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the adjusted UPDRS Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change of adjusted UPDRS ranges from -100 to 150, larger value shows more disability from PD.

Secondary Outcome Measures

1. Adjusted Mean Change in LED [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the LED(levodopa equivalent dose) in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED ranges from -100 to 3000, larger value shows more disability from PD.

2. Adjusted Mean Change in LED Cumulative [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the LED(levodopa equivalent dose) cumulative in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED cumulative ranges from 0 to 1200000, larger value shows more disability from PD.

3. Adjusted Mean Change in UPDRS Part IV [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part IV in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part IV ranges from -10 to 10, larger value shows more disability from PD.

4. Adjusted Mean Change in MDS-UPDRS nmEDL [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS nmEDL(Non-Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MDS-UPDRS nmEDL ranges from -6 to 10, larger value shows more disability from PD.

5. Adjusted Mean Change in MDS-UPDRS mEDL [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS mEDL(Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MDS-UPDRS mEDL ranges from -8 to 35, larger value shows more disability from PD.

6. Adjusted Mean Change in UPDRS Score to 1 Year [Baseline to 12 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS nmEDL(Non-Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 12 month visit. The change of UPDRS ranges from -22 to 23, larger value shows more disability from PD.

7. Adjusted Mean Change in UPDRS Part II [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part II (ADL Function) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part II ranges from -12 to 19, larger value shows more disability from PD.

8. Adjusted Mean Change in UPDRS Part III OFF [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part III OFF rating in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part III OFF ranges from -30 to 100, larger value shows more disability from PD.

9. Adjusted Mean Change in SE/ADL [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the SE/ADL in the active treatment arm versus placebo between the baseline and 36 month visit. The change of UPDRS ranges from -70 to 20, larger value shows improvement of PD.

10. Adjusted Mean Change in Modified Rankin Score [Baseline to 36 months of treatment]

    Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Modified Rankin Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Modified Rankin Score ranges from -1 to 3, larger value shows worsening of conditions.

11. Adjusted Mean Change in MoCA Score [Baseline to 36 months of treatment]

    Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MoCA Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MoCA Score ranges from -10 to 6, larger value shows improvement of conditions.

12. Adjusted Mean Change in PDQ39 Total Score [Baseline to 36 months of treatment]

    Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the PDQ39 Total Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in PDQ39 Total Score ranges from -16 to 44, larger value shows worsening of conditions.

13. Adjusted Mean Change in Ambulatory Capacity [Baseline to 36 months of treatment]

    Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Ambulatory Capacity in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Ambulatory Capacity ranges from -4 to 12, larger value shows worsening of conditions.

14. Adjusted Mean Change in BDI Total Score [Baseline to 36 months of treatment]

    Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the BDI Total Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in BDI Total Score ranges from -9 to 22, larger value shows worsening of conditions.

15. Risk of Need for Antiparkinsonian Therapy [Baseline to 36 months of treatment]

    Number of participants with need for Antiparkinsonian Therapy.

16. Risk of Need for Dyskinesia [Baseline to 36 months of treatment]

    Number of participants with need for Dyskinesia Therapy.

17. Risk of Need for Fluctuations [Baseline to 36 months of treatment]

    Number of participants with need for Fluctuations Therapy.

Other Outcome Measures

1. Adjusted Mean Change in UPDRS PIGD Score [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS PIGD Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS PIGD Score ranges from -1 to 3, larger value shows worsening of conditions.

2. Adjusted Mean Change in UPDRS Tremor Score [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Tremor Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Tremor Score ranges from -1 to 2, larger value shows worsening of conditions.

3. Adjusted Mean Change in H/Y Stage [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the H/Y Stage in the active treatment arm versus placebo between the baseline and 36 month visit. The change in H/Y Stage ranges from -1 to 3, larger value shows worsening of conditions.

4. Adjusted Mean Change in Levodopa [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Levodopa in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED ranges from -200 to 2000, larger value shows more disability from PD.

5. Adjusted Mean Change in Levodopa Cumulative [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Levodopa Cumulative in the active treatment arm versus placebo between the baseline and 36 month visit. The change of Levodopa cumulative ranges from 0 to 800000, larger value shows more disability from PD.

6. Adjusted Mean Change in Systolic BP, Seated [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Systolic BP, Seated in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Systolic BP, Seated ranges from -65 to 50. larger value shows worsening of conditions.

7. Adjusted Mean Change in Diastolic BP, Seated [Baseline to 36 months of treatment]

   Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Diastolic BP, Seated in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Diastolic BP, Seated ranges from -35 to 25. larger value shows worsening of conditions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Banner Sun Health Research Institute	Sun City	Arizona	United States	85315
3	The Parkinsons & Movement Disorder Institute	Fountain Valley	California	United States	92708
4	University of California	Irvine	California	United States	92697
5	University of California San Diego	San Diego	California	United States	92093
6	University of California, San Francisco	San Francisco	California	United States	94143
7	Rocky Mountain Movement Disorders Center	Englewood	Colorado	United States	80113
8	Institute of Neurodegenerative Disorders	New Haven	Connecticut	United States	06510
9	University of Miami	Miami	Florida	United States	33136
10	University of South Florida	Tampa	Florida	United States	33613
11	Emory University School of Medicine	Atlanta	Georgia	United States	30329
12	Pacific Health Research & Education Institute	Honolulu	Hawaii	United States	96819
13	Northwestern University	Chicago	Illinois	United States	60611
14	Rush University Medical Center	Chicago	Illinois	United States	60612
15	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
16	LSU Health Science Center	Shreveport	Louisiana	United States	71103
17	University of Maryland	Baltimore	Maryland	United States	21201
18	Johns Hopkins University	Baltimore	Maryland	United States	21287
19	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
20	Boston University Medical Center	Boston	Massachusetts	United States	02118
21	University of Michigan	Ann Arbor	Michigan	United States	48109
22	Michigan State University	East Lansing	Michigan	United States	48824
23	Struthers Parkinson's Center	Golden Valley	Minnesota	United States	55427
24	University of Minnesota	Minneapolis	Minnesota	United States	55414
25	Washington University	Saint Louis	Missouri	United States	63110
26	Nebraska Medical Center	Omaha	Nebraska	United States	68198
27	University of Nevada School of Medicine	Las Vegas	Nevada	United States	89102
28	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
29	Atlantic Neuroscience Institute	Summit	New Jersey	United States	07901
30	Albany Medical College	Albany	New York	United States	12208
31	Health Quest Kingston	Kingston	New York	United States	12401
32	Columbia University Medical Center	New York	New York	United States	10032
33	Weill Medical College of Cornell University	New York	New York	United States	20021
34	University of Rochester	Rochester	New York	United States	14618
35	University of Cincinnati	Cincinnati	Ohio	United States	45267
36	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
37	Ohio State University	Columbus	Ohio	United States	43221
38	Oregon Health & Science University	Portland	Oregon	United States	97239
39	Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033
40	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19107
41	Medical University of South Carolina	Charleston	South Carolina	United States	29401
42	University of Texas Health Science Center	Houston	Texas	United States	77030
43	University of Utah	Salt Lake City	Utah	United States	84108
44	University of Virginia	Charlottesville	Virginia	United States	22903
45	Sentara Neurology Specialists	Virginia Beach	Virginia	United States	23456
46	Booth Gardner Parkinson's Care Center	Kirkland	Washington	United States	98034
47	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
48	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
49	University of Alberta Hospital	Edmonton	Alberta	Canada	t6g 2g3
50	Ottawa Hospital Civic Site	Ottawa	Ontario	Canada	K1Y 4E9
51	The Centre for Addiction and Mental Health	Toronto	Ontario	Canada	m3b 2s7
52	Toronto Western Hospital, University Health Network	Toronto	Ontario	Canada	M5T 2S8
53	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
54	Centre Hospitalier Affilie	Quebec City	Quebec	Canada	G1J 1Z4

Sponsors and Collaborators

• University of Rochester
• National Institute of Neurological Disorders and Stroke (NINDS)
• Michael J. Fox Foundation for Parkinson's Research
• The Parkinson Study Group

Investigators

• Principal Investigator: Tanya Simuni, MD, Northwestern University
• Principal Investigator: Robert Holloway, MD MPH, University of Rochester

Study Documents (Full-Text)

• Study Protocol - Aug 31, 2016
• Statistical Analysis Plan - Dec 1, 2017

More Information

Publications

None provided.

• Responsible Party: Robert Holloway, Principal Investigator, University of Rochester
• ClinicalTrials.gov Identifier: NCT02168842
• Other Study ID Numbers: STEADY-PD III; U01NS080818-01A1; U01NS080840-01A1
• First Posted: Jun 20, 2014
• Last Update Posted: Jan 14, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Robert Holloway, Principal Investigator, University of Rochester: Parkinson; Parkinson Disease; Parkinson's Disease
• Additional relevant MeSH terms: Parkinson Disease; Isradipine

Study Results

Participant Flow

Recruitment Details	Patients were recruited from 57 Parkinson Study Group sites in North America from November 2014 through November 2015.
Pre-assignment Detail	413 patients were assessed for eligibility. 12 patients declined to participate and 65 patients were excluded (9 exclusionary medications, 2 other medical psychiatric or surgical, 5 disease too advanced, 6 diagnosis uncertain, 23 didn't meet other inclusion criteria, 20 other). 336 patients were enrolled and underwent randomization

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Period Title: Overall Study
STARTED	170	166
COMPLETED	162	158
NOT COMPLETED	8	8

Baseline Characteristics

Arm/Group Title	Isradipine	Placebo (for Isradipine)	Total
Arm/Group Description	Oral capsule of up to 5 mg of isradipine taken twice daily for 36 months. Isradipine: Oral capsules Isradipine IR, up to 10 mg, taken twice daily	Oral capsule taken twice daily for 36 months. Placebo (for Isradipine): Sugar Pill manufactured to look like Isradipine but has no active ingredients	Total of all reporting groups
Overall Participants	170	166	336
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.11 (8.73)	61.61 (9.34)	61.86 (9.03)
Sex: Female, Male (Count of Participants)
Female	48 28.2%	58 34.9%	106 31.5%
Male	122 71.8%	108 65.1%	230 68.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 2.4%	6 3.6%	10 3%
Not Hispanic or Latino	166 97.6%	160 96.4%	326 97%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	1 0.6%	2 0.6%
Asian	6 3.5%	5 3%	11 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.6%	1 0.3%
Black or African American	3 1.8%	7 4.2%	10 3%
White	159 93.5%	149 89.8%	308 91.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.6%	3 1.8%	4 1.2%
Region of Enrollment (participants) [Number]
United States	154 90.6%	149 89.8%	303 90.2%
Canada	16 9.4%	17 10.2%	33 9.8%
Disease Duration (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	9.89 (8.13)	10.56 (9.35)	10.22 (8.75)
Family History of PD (Count of Participants)
Count of Participants [Participants]	30 17.6%	35 21.1%	65 19.3%
Handedness (Count of Participants)
Right	147 86.5%	142 85.5%	289 86%
Left	20 11.8%	19 11.4%	39 11.6%
Mixed	3 1.8%	5 3%	8 2.4%
On Symptomatic Therapy (Amantadine) (Count of Participants)
Count of Participants [Participants]	15 8.8%	11 6.6%	26 7.7%
On Symptomatic Therapy (Anticholinergics) (Count of Participants)
Count of Participants [Participants]	3 1.8%	2 1.2%	5 1.5%
UPDRS Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	23.66 (8.64)	22.58 (8.53)	23.13 (8.59)
Mental Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.61 (0.87)	0.81 (1.21)	0.71 (1.05)
ADL Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.96 (2.88)	5.45 (3.26)	5.2 (3.08)
Motor Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	18.08 (7.3)	16.32 (6.53)	17.21 (6.97)
UPSDRS PIGD Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.17 (0.19)	0.17 (0.17)	0.17 (0.18)
UPDRS Tremor Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.51 (0.32)	0.50 (0.29)	0.51 (0.3)
H/Y Stage (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.72 (0.46)	1.6 (0.5)	1.66 (0.48)
SE/ADL (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	94.44 (5.23)	94.04 (6.8)	94.24 (6.05)
Modified Rankin Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.09 (0.31)	1.09 (0.33)	1.09 (0.32)
MoCA Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	28.14 (1.41)	28.04 (1.29)	28.09 (1.35)
BDI Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.09 (3.71)	4.8 (4.29)	4.44 (4.02)
PDQ39 Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.13 (6.15)	9.08 (8.52)	8.10 (7.47)
Systolic BP, Seated (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	128.12 (17.17)	127.69 (14.6)	127.91 (15.93)
Diastolic BP, Seated (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	76.55 (9.72)	77.83 (8.52)	77.18 (9.16)

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change in Total Unified Parkinson Disease Rating Scale (UPDRS) Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the total (Part I-III) UPDRS score in the active treatment arm versus placebo between the baseline and 36 month visit. The change of UPDRS ranges from -30 to 80, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Oral capsule of up to 5 mg of isradipine taken twice daily for 36 months. Isradipine: Oral capsules Isradipine IR, up to 10 mg, taken twice daily	Oral capsule taken twice daily for 36 months. Placebo (for Isradipine): Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	2.99	3.26

2. Primary Outcome

Title	Adjusted Mean Change in Adjusted UPDRS Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the adjusted UPDRS Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change of adjusted UPDRS ranges from -100 to 150, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	13.49	13.85

3. Secondary Outcome

Title	Adjusted Mean Change in LED
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the LED(levodopa equivalent dose) in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED ranges from -100 to 3000, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline LED measurement. So LED had 1 more observation than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mg]	389	375

4. Secondary Outcome

Title	Adjusted Mean Change in LED Cumulative
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the LED(levodopa equivalent dose) cumulative in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED cumulative ranges from 0 to 1200000, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline LED Cumulative measurement. So LED Cumulative had 1 more observation than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mg]	676	697

5. Secondary Outcome

Title	Adjusted Mean Change in UPDRS Part IV
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part IV in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part IV ranges from -10 to 10, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. 46 patients had missing measures at the visit of 36 months.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	134	140
Least Squares Mean (95% Confidence Interval) [score on a scale]	1.18	1.07

6. Secondary Outcome

Title	Adjusted Mean Change in MDS-UPDRS nmEDL
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS nmEDL(Non-Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MDS-UPDRS nmEDL ranges from -6 to 10, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	1.93	1.76

7. Secondary Outcome

Title	Adjusted Mean Change in MDS-UPDRS mEDL
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS mEDL(Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MDS-UPDRS mEDL ranges from -8 to 35, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	2.32	2.57

8. Secondary Outcome

Title	Adjusted Mean Change in UPDRS Score to 1 Year
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MDS-UPDRS nmEDL(Non-Motor Experiences of Daily Living) in the active treatment arm versus placebo between the baseline and 12 month visit. The change of UPDRS ranges from -22 to 23, larger value shows more disability from PD.
Time Frame	Baseline to 12 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. There were 169 patients in Isradipine group and 165 in placebo group who reached 1-year visit.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	169	165
Least Squares Mean (95% Confidence Interval) [score on a scale]	4.65	5.3

9. Secondary Outcome

Title	Adjusted Mean Change in UPDRS Part II
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part II (ADL Function) in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part II ranges from -12 to 19, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	2.3	2.5

10. Secondary Outcome

Title	Adjusted Mean Change in UPDRS Part III OFF
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Part III OFF rating in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Part III OFF ranges from -30 to 100, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. 58 patients had missing measures at the visit of 36 months.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	129	133
Least Squares Mean (95% Confidence Interval) [score on a scale]	4.60	4.50

11. Secondary Outcome

Title	Adjusted Mean Change in SE/ADL
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the SE/ADL in the active treatment arm versus placebo between the baseline and 36 month visit. The change of UPDRS ranges from -70 to 20, larger value shows improvement of PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline SE/ADL measurement. So SE/ADL had 1 more observation than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [units on a scale]	-4.14	-4.41

12. Secondary Outcome

Title	Adjusted Mean Change in Modified Rankin Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Modified Rankin Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Modified Rankin Score ranges from -1 to 3, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline measurement for primary efficacy while had finished baseline Modified Rankin Score. So Modified Rankin Score had 1 more observation than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.18	0.29

13. Secondary Outcome

Title	Adjusted Mean Change in MoCA Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the MoCA Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in MoCA Score ranges from -10 to 6, larger value shows improvement of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline MoCA Score. So MoCA Score had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.04	-0.07

14. Secondary Outcome

Title	Adjusted Mean Change in PDQ39 Total Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the PDQ39 Total Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in PDQ39 Total Score ranges from -16 to 44, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. 7 patients had missing PDQ39 scores at the visit of 36 months.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	158	155
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.80	3.42

15. Secondary Outcome

Title	Adjusted Mean Change in Ambulatory Capacity
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Ambulatory Capacity in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Ambulatory Capacity ranges from -4 to 12, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [score on a scale]	0.59	0.50

16. Secondary Outcome

Title	Adjusted Mean Change in BDI Total Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the BDI Total Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in BDI Total Score ranges from -9 to 22, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant in Placebo group had missing baseline UPDRS sections while had finished baseline BDI Score. And one participant in Isradipine group had missing BDI score at the visit of 36 months.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	161	159
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.77	1.34

17. Secondary Outcome

Title	Risk of Need for Antiparkinsonian Therapy
Description	Number of participants with need for Antiparkinsonian Therapy.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Include all 336 patients that were randomized, no matter whether or not completed the study.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	170	166
Number (95% Confidence Interval) [participants]	145 85.3%	147 88.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Isradipine, Placebo (for Isradipine)
	Comments
	Type of Statistical Test	Equivalence
	Comments	Comparison of the risk of need for antiparkinsonian therapy in Isradipine group to the risk in placebo group.
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Risk of Need for Dyskinesia
Description	Number of participants with need for Dyskinesia Therapy.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Include all 336 patients that were randomized, no matter whether or not completed the study.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	170	166
Number (95% Confidence Interval) [participants]	24 14.1%	19 11.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Isradipine, Placebo (for Isradipine)
	Comments
	Type of Statistical Test	Equivalence
	Comments	Comparison the risk of need for dyskinesia in Isradipine group to the risk in a placebo group.
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 0.78 to 3.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Risk of Need for Fluctuations
Description	Number of participants with need for Fluctuations Therapy.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Include all 336 patients that were randomized, no matter whether or not completed the study.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	170	166
Number (95% Confidence Interval) [participants]	57 33.5%	64 38.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Isradipine, Placebo (for Isradipine)
	Comments
	Type of Statistical Test	Equivalence
	Comments	Comparison of the risk of need for antiparkinsonian therapy in Isradipine group to the risk in placebo group.
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Other Pre-specified Outcome

Title	Adjusted Mean Change in UPDRS PIGD Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS PIGD Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS PIGD Score ranges from -1 to 3, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.12	0.10

21. Other Pre-specified Outcome

Title	Adjusted Mean Change in UPDRS Tremor Score
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the UPDRS Tremor Score in the active treatment arm versus placebo between the baseline and 36 month visit. The change in UPDRS Tremor Score ranges from -1 to 2, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	158
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.00	0.01

22. Other Pre-specified Outcome

Title	Adjusted Mean Change in H/Y Stage
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the H/Y Stage in the active treatment arm versus placebo between the baseline and 36 month visit. The change in H/Y Stage ranges from -1 to 3, larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline H/Y Stage. So H/Y Stage had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.15	0.21

23. Other Pre-specified Outcome

Title	Adjusted Mean Change in Levodopa
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Levodopa in the active treatment arm versus placebo between the baseline and 36 month visit. The change of LED ranges from -200 to 2000, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline Levodopa. So Levodopa had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mg]	307	307

24. Other Pre-specified Outcome

Title	Adjusted Mean Change in Levodopa Cumulative
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Levodopa Cumulative in the active treatment arm versus placebo between the baseline and 36 month visit. The change of Levodopa cumulative ranges from 0 to 800000, larger value shows more disability from PD.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline Levodopa Cumulative. So Levodopa Cumulative had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mg]	471	508

25. Other Pre-specified Outcome

Title	Adjusted Mean Change in Systolic BP, Seated
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Systolic BP, Seated in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Systolic BP, Seated ranges from -65 to 50. larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline Systolic BP, Seated. So Systolic BP had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mmHg]	-6.11	1.03

26. Other Pre-specified Outcome

Title	Adjusted Mean Change in Diastolic BP, Seated
Description	Efficacy of isradipine to slow progression of Parkinson disease disability to be determined by the change in the Diastolic BP, Seated in the active treatment arm versus placebo between the baseline and 36 month visit. The change in Diastolic BP, Seated ranges from -35 to 25. larger value shows worsening of conditions.
Time Frame	Baseline to 36 months of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population. One participant had missing baseline UPDRS sections while had finished baseline Diastolic BP, Seated. So Diastolic BP had 1 observation more than primary outcomes.

Arm/Group Title	Isradipine	Placebo (for Isradipine)
Arm/Group Description	Receive Isradipine 5 mg twice daily for 36 months. Isradipine: oral immediate-release capsule of Isradipine 10 mg per day.	Receive placebo twice daily for 36 months. Placebo: Sugar Pill manufactured to look like Isradipine but has no active ingredients
Measure Participants	162	159
Least Squares Mean (95% Confidence Interval) [mmHg]	-4.64	-0.71

Adverse Events

Time Frame	Baseline to 36 months of treatment
Arm/Group Title	Isradipine		Placebo (for Isradipine)
Arm/Group Description	Oral capsule of up to 5 mg of isradipine taken twice daily for 36 months. Isradipine: Oral capsules Isradipine IR, up to 10 mg, taken twice daily		Oral capsule taken twice daily for 36 months. Placebo (for Isradipine): Sugar Pill manufactured to look like Isradipine but has no active ingredients
All Cause Mortality
	Isradipine		Placebo (for Isradipine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/170 (1.2%)		1/166 (0.6%)
Serious Adverse Events
	Isradipine		Placebo (for Isradipine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/170 (15.3%)		27/166 (16.3%)
Cardiac disorders
BRADYCARDIA	1/170 (0.6%)	1	0/166 (0%)	0
MYOCARDIAL INFARCTION	0/170 (0%)	0	1/166 (0.6%)	1
STRESS CARDIOMYOPATHY	0/170 (0%)	0	1/166 (0.6%)	1
Congenital, familial and genetic disorders
SPINA BIFIDA	1/170 (0.6%)	1	0/166 (0%)	0
Gastrointestinal disorders
GASTROINTESTINAL HAEMORRHAGE	1/170 (0.6%)	1	1/166 (0.6%)	1
APPENDICEAL MUCOCOELE	1/170 (0.6%)	1	0/166 (0%)	0
DYSPHAGIA	0/170 (0%)	0	1/166 (0.6%)	1
SMALL INTESTINAL OBSTRUCTION	1/170 (0.6%)	1	0/166 (0%)	0
General disorders
CHEST DISCOMFORT	1/170 (0.6%)	1	0/166 (0%)	0
Infections and infestations
SEPSIS	2/170 (1.2%)	2	0/166 (0%)	0
APPENDICITIS	0/170 (0%)	0	1/166 (0.6%)	1
APPENDICITIS PERFORATED	0/170 (0%)	0	1/166 (0.6%)	1
BRONCHIOLITIS	0/170 (0%)	0	1/166 (0.6%)	1
GASTROENTERITIS VIRAL	1/170 (0.6%)	1	0/166 (0%)	0
MENINGITIS	0/170 (0%)	0	1/166 (0.6%)	1
PNEUMONIA	0/170 (0%)	0	1/166 (0.6%)	1
PYELONEPHRITIS ACUTE	0/170 (0%)	0	1/166 (0.6%)	1
URINARY TRACT INFECTION	1/170 (0.6%)	1	0/166 (0%)	0
Injury, poisoning and procedural complications
STRESS FRACTURE	2/170 (1.2%)	2	0/166 (0%)	0
UPPER LIMB FRACTURE	1/170 (0.6%)	1	1/166 (0.6%)	1
HUMERUS FRACTURE	0/170 (0%)	0	1/166 (0.6%)	1
SPINAL FRACTURE	1/170 (0.6%)	1	0/166 (0%)	0
WRIST FRACTURE	0/170 (0%)	0	1/166 (0.6%)	1
Metabolism and nutrition disorders
DEHYDRATION	0/170 (0%)	0	1/166 (0.6%)	1
Musculoskeletal and connective tissue disorders
OSTEOARTHRITIS	3/170 (1.8%)	4	1/166 (0.6%)	1
ARTHRITIS	1/170 (0.6%)	1	1/166 (0.6%)	1
BACK PAIN	1/170 (0.6%)	1	1/166 (0.6%)	1
ARTHRALGIA	0/170 (0%)	0	1/166 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLON CANCER	2/170 (1.2%)	2	0/166 (0%)	0
PROSTATE CANCER	2/170 (1.2%)	2	0/166 (0%)	0
B-CELL LYMPHOMA	0/170 (0%)	0	1/166 (0.6%)	1
BREAST CANCER	0/170 (0%)	0	1/166 (0.6%)	1
CHOROID MELANOMA	1/170 (0.6%)	1	0/166 (0%)	0
METASTATIC SQUAMOUS CELL CARCINOMA	0/170 (0%)	0	1/166 (0.6%)	1
PANCREATIC NEOPLASM	1/170 (0.6%)	1	0/166 (0%)	0
PITUITARY TUMOUR	0/170 (0%)	0	1/166 (0.6%)	1
RECTAL CANCER	0/170 (0%)	0	1/166 (0.6%)	1
SQUAMOUS CELL CARCINOMA	0/170 (0%)	0	1/166 (0.6%)	1
THROAT CANCER	1/170 (0.6%)	1	0/166 (0%)	0
Nervous system disorders
SYNCOPE	1/170 (0.6%)	1	1/166 (0.6%)	1
TRANSIENT ISCHAEMIC ATTACK	2/170 (1.2%)	2	0/166 (0%)	0
APHASIA	0/170 (0%)	0	1/166 (0.6%)	1
BASAL GANGLIA HAEMORRHAGE	0/170 (0%)	0	1/166 (0.6%)	1
CEREBROVASCULAR ACCIDENT	0/170 (0%)	0	1/166 (0.6%)	1
HYPERTENSIVE ENCEPHALOPATHY	0/170 (0%)	0	1/166 (0.6%)	1
INTRAVENTRICULAR HAEMORRHAGE	1/170 (0.6%)	1	0/166 (0%)	0
ISCHAEMIC STROKE	1/170 (0.6%)	1	0/166 (0%)	0
Psychiatric disorders
HALLUCINATION, VISUAL	0/170 (0%)	0	1/166 (0.6%)	1
SUICIDAL IDEATION	0/170 (0%)	0	1/166 (0.6%)	1
Renal and urinary disorders
NEPHROLITHIASIS	1/170 (0.6%)	1	0/166 (0%)	0
URINARY RETENTION	1/170 (0.6%)	1	0/166 (0%)	0
Reproductive system and breast disorders
MENORRHAGIA	0/170 (0%)	0	1/166 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/170 (0.6%)	1	0/166 (0%)	0
PNEUMONIA ASPIRATION	1/170 (0.6%)	1	0/166 (0%)	0
Other (Not Including Serious) Adverse Events
	Isradipine		Placebo (for Isradipine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	163/170 (95.9%)		154/166 (92.8%)
Blood and lymphatic system disorders
LYMPHOPENIA	0/170 (0%)	0	4/166 (2.4%)	5
ANAEMIA	2/170 (1.2%)	2	2/166 (1.2%)	2
Cardiac disorders
PALPITATIONS	6/170 (3.5%)	6	2/166 (1.2%)	2
TACHYCARDIA	4/170 (2.4%)	5	2/166 (1.2%)	2
ATRIOVENTRICULAR BLOCK FIRST DEGREE	3/170 (1.8%)	3	2/166 (1.2%)	2
ATRIAL FIBRILLATION	2/170 (1.2%)	2	2/166 (1.2%)	2
Ear and labyrinth disorders
VERTIGO	2/170 (1.2%)	3	5/166 (3%)	6
EAR DISCOMFORT	3/170 (1.8%)	3	1/166 (0.6%)	1
Eye disorders
CATARACT	4/170 (2.4%)	6	7/166 (4.2%)	9
VISION BLURRED	7/170 (4.1%)	8	2/166 (1.2%)	2
DRY EYE	3/170 (1.8%)	3	4/166 (2.4%)	4
Gastrointestinal disorders
NAUSEA	26/170 (15.3%)	29	32/166 (19.3%)	38
CONSTIPATION	23/170 (13.5%)	24	21/166 (12.7%)	22
GASTROOESOPHAGEAL REFLUX DISEASE	5/170 (2.9%)	6	9/166 (5.4%)	11
DIARRHOEA	7/170 (4.1%)	11	5/166 (3%)	5
DYSPHAGIA	7/170 (4.1%)	9	4/166 (2.4%)	6
ABDOMINAL PAIN UPPER	6/170 (3.5%)	7	4/166 (2.4%)	4
DYSPEPSIA	4/170 (2.4%)	4	4/166 (2.4%)	4
INGUINAL HERNIA	4/170 (2.4%)	4	4/166 (2.4%)	4
VOMITING	3/170 (1.8%)	3	4/166 (2.4%)	4
ABDOMINAL PAIN	3/170 (1.8%)	4	3/166 (1.8%)	3
ABDOMINAL DISTENSION	3/170 (1.8%)	3	3/166 (1.8%)	3
DRY MOUTH	3/170 (1.8%)	3	1/166 (0.6%)	1
SALIVARY HYPERSECRETION	3/170 (1.8%)	3	1/166 (0.6%)	1
General disorders
OEDEMA	31/170 (18.2%)	41	9/166 (5.4%)	11
FATIGUE	23/170 (13.5%)	28	20/166 (12%)	21
CHEST PAIN	6/170 (3.5%)	7	5/166 (3%)	5
PAIN	5/170 (2.9%)	5	2/166 (1.2%)	2
IRRITABILITY	2/170 (1.2%)	3	3/166 (1.8%)	3
ASTHENIA	2/170 (1.2%)	2	2/166 (1.2%)	2
Infections and infestations
NASOPHARYNGITIS	23/170 (13.5%)	26	22/166 (13.3%)	23
UPPER RESPIRATORY TRACT INFECTION	12/170 (7.1%)	13	11/166 (6.6%)	20
SINUSITIS	7/170 (4.1%)	8	13/166 (7.8%)	17
BRONCHITIS	5/170 (2.9%)	5	11/166 (6.6%)	12
URINARY TRACT INFECTION	5/170 (2.9%)	5	8/166 (4.8%)	9
INFLUENZA	3/170 (1.8%)	3	8/166 (4.8%)	8
DIVERTICULITIS	5/170 (2.9%)	6	1/166 (0.6%)	5
TOOTH ABSCESS	4/170 (2.4%)	4	2/166 (1.2%)	2
RESPIRATORY TRACT INFECTION	3/170 (1.8%)	3	2/166 (1.2%)	3
EYE INFECTION	3/170 (1.8%)	3	2/166 (1.2%)	2
HERPES ZOSTER	2/170 (1.2%)	2	3/166 (1.8%)	3
LOWER RESPIRATORY TRACT INFECTION	3/170 (1.8%)	3	2/166 (1.2%)	2
PNEUMONIA	1/170 (0.6%)	1	3/166 (1.8%)	4
TOOTH INFECTION	0/170 (0%)	0	4/166 (2.4%)	4
Injury, poisoning and procedural complications
FALL	7/170 (4.1%)	10	15/166 (9%)	20
LACERATION	5/170 (2.9%)	5	5/166 (3%)	5
MUSCLE STRAIN	6/170 (3.5%)	6	3/166 (1.8%)	3
LIGAMENT SPRAIN	2/170 (1.2%)	3	4/166 (2.4%)	4
CONTUSION	2/170 (1.2%)	3	3/166 (1.8%)	3
WRIST FRACTURE	1/170 (0.6%)	1	3/166 (1.8%)	3
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED	6/170 (3.5%)	6	3/166 (1.8%)	3
BLOOD CREATININE INCREASED	7/170 (4.1%)	7	2/166 (1.2%)	2
Metabolism and nutrition disorders
ABNORMAL LOSS OF WEIGHT	4/170 (2.4%)	4	5/166 (3%)	5
DECREASED APPETITE	3/170 (1.8%)	3	3/166 (1.8%)	3
VITAMIN D DEFICIENCY	4/170 (2.4%)	4	2/166 (1.2%)	2
HYPERGLYCAEMIA	2/170 (1.2%)	2	2/166 (1.2%)	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA	17/170 (10%)	19	20/166 (12%)	26
BACK PAIN	17/170 (10%)	20	15/166 (9%)	16
MUSCULOSKELETAL PAIN	12/170 (7.1%)	14	15/166 (9%)	15
MUSCLE SPASMS	11/170 (6.5%)	12	13/166 (7.8%)	15
PAIN IN EXTREMITY	11/170 (6.5%)	14	9/166 (5.4%)	11
JOINT SWELLING	12/170 (7.1%)	13	7/166 (4.2%)	8
MUSCULOSKELETAL STIFFNESS	8/170 (4.7%)	9	6/166 (3.6%)	9
OSTEOARTHRITIS	7/170 (4.1%)	8	6/166 (3.6%)	6
TENDONITIS	7/170 (4.1%)	8	5/166 (3%)	5
MYALGIA	6/170 (3.5%)	6	6/166 (3.6%)	6
PLANTAR FASCIITIS	2/170 (1.2%)	2	5/166 (3%)	5
BURSITIS	0/170 (0%)	0	6/166 (3.6%)	6
NECK PAIN	0/170 (0%)	0	6/166 (3.6%)	6
ROTATOR CUFF SYNDROME	5/170 (2.9%)	6	0/166 (0%)	0
OSTEOPOROSIS	3/170 (1.8%)	3	2/166 (1.2%)	2
MUSCULAR WEAKNESS	3/170 (1.8%)	3	1/166 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	6/170 (3.5%)	7	5/166 (3%)	8
SQUAMOUS CELL CARCINOMA	3/170 (1.8%)	3	3/166 (1.8%)	3
Nervous system disorders
DIZZINESS	42/170 (24.7%)	55	26/166 (15.7%)	30
HEADACHE	28/170 (16.5%)	40	17/166 (10.2%)	19
SOMNOLENCE	10/170 (5.9%)	11	8/166 (4.8%)	9
HYPOAESTHESIA	8/170 (4.7%)	11	6/166 (3.6%)	8
TREMOR	5/170 (2.9%)	5	9/166 (5.4%)	9
DYSTONIA	8/170 (4.7%)	8	4/166 (2.4%)	5
PARAESTHESIA	5/170 (2.9%)	5	4/166 (2.4%)	5
SCIATICA	4/170 (2.4%)	6	3/166 (1.8%)	3
RESTLESS LEGS SYNDROME	3/170 (1.8%)	3	5/166 (3%)	5
BRADYKINESIA	3/170 (1.8%)	3	4/166 (2.4%)	4
AMNESIA	3/170 (1.8%)	3	3/166 (1.8%)	3
SYNCOPE	4/170 (2.4%)	4	2/166 (1.2%)	2
COGNITIVE DISORDER	2/170 (1.2%)	2	3/166 (1.8%)	3
MEMORY IMPAIRMENT	1/170 (0.6%)	1	3/166 (1.8%)	3
Psychiatric disorders
INSOMNIA	19/170 (11.2%)	22	19/166 (11.4%)	20
ANXIETY	20/170 (11.8%)	22	13/166 (7.8%)	16
DEPRESSION	20/170 (11.8%)	22	13/166 (7.8%)	14
SLEEP DISORDER	9/170 (5.3%)	9	8/166 (4.8%)	8
RAPID EYE MOVEMENTS SLEEP ABNORMAL	7/170 (4.1%)	8	6/166 (3.6%)	6
HALLUCINATION	1/170 (0.6%)	1	6/166 (3.6%)	6
SUICIDAL IDEATION	3/170 (1.8%)	4	1/166 (0.6%)	2
ABNORMAL DREAMS	3/170 (1.8%)	3	2/166 (1.2%)	2
CONFUSIONAL STATE	5/170 (2.9%)	5	0/166 (0%)	0
Renal and urinary disorders
POLLAKIURIA	7/170 (4.1%)	7	7/166 (4.2%)	7
NEPHROLITHIASIS	5/170 (2.9%)	9	4/166 (2.4%)	4
MICTURITION URGENCY	7/170 (4.1%)	8	3/166 (1.8%)	3
PROTEINURIA	2/170 (1.2%)	2	5/166 (3%)	5
URINARY INCONTINENCE	3/170 (1.8%)	3	2/166 (1.2%)	2
HAEMATURIA	0/170 (0%)	0	4/166 (2.4%)	4
Reproductive system and breast disorders
ERECTILE DYSFUNCTION	7/170 (4.1%)	7	2/166 (1.2%)	2
BENIGN PROSTATIC HYPERPLASIA	5/170 (2.9%)	5	3/166 (1.8%)	3
Respiratory, thoracic and mediastinal disorders
COUGH	9/170 (5.3%)	11	9/166 (5.4%)	11
DYSPNOEA	9/170 (5.3%)	9	4/166 (2.4%)	4
PULMONARY MASS	2/170 (1.2%)	2	3/166 (1.8%)	4
RHINORRHOEA	3/170 (1.8%)	3	2/166 (1.2%)	2
EPISTAXIS	1/170 (0.6%)	1	3/166 (1.8%)	4
NASAL CONGESTION	3/170 (1.8%)	3	1/166 (0.6%)	1
Skin and subcutaneous tissue disorders
RASH	6/170 (3.5%)	6	7/166 (4.2%)	7
ALOPECIA	3/170 (1.8%)	3	3/166 (1.8%)	3
ERYTHEMA	1/170 (0.6%)	1	3/166 (1.8%)	3
Vascular disorders
HYPERTENSION	8/170 (4.7%)	8	8/166 (4.8%)	8
ORTHOSTATIC HYPOTENSION	5/170 (2.9%)	6	6/166 (3.6%)	6
HYPOTENSION	4/170 (2.4%)	4	5/166 (3%)	6
FLUSHING	7/170 (4.1%)	8	0/166 (0%)	0
HOT FLUSH	5/170 (2.9%)	6	1/166 (0.6%)	1
DEEP VEIN THROMBOSIS	2/170 (1.2%)	2	2/166 (1.2%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.