Parkinson's Disease Isradipine Safety Study

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00753636
• Collaborator: Northwestern Memorial Hospital (Other)
• Enrollment: 31
• Location: 1
• Arm: 1
• Duration (Months): 22
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The objective of this study is to establish the safety and tolerability of isradipine, sustained release preparation in patients with PD. This study is a logical continuation of the project that is being completed now and is conducted in preparation to NIH submission of the pivotal study on the efficacy of this agent for neuroprotection in PD. This study is conducted in parallel with Dr. Surmeier's work on further development of the preclinical data. The focus of his work now is to establishing the correlation between the dose that demonstrated neuroprotective effect in animal model and the dose used for clinical practice.

Hypothesis 1: Patients with PD will be able to tolerate isradipine across the FDA recommended dose range. We expect 10% attrition due to hypotensive effect of the agent.

Hypothesis 2: Patients with PD and concomitant stable hypertension will be able to tolerate isradipine provided that the dose of the concomitant antihypertensive agent is adjusted based on the blood pressure reading.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Dynacirc CR (Isradipine)	Phase 2

Detailed Description

Isradipine safety profile Isradipine, FDA approved for treatment of hypertension since 1990, has a well established data on its efficacy and safety in the hypertensive population (see package insert, Appendix 3). The side effect profile of isradipine is related to the primary mechanism of action of the agent as a vasodilator of the vascular smooth muscles and myocardium, and includes hypotension, bradycardia, weakness, and syncope. As per package insert, the most common adverse effects are headache (13.7% with active treatment versus 14% placebo), dizziness (7.3 vs 4.4) and peripheral edema as reflection of the vasodilatory effect which is dose dependent with incidence of about 3.5% at 5 mg, 8.7% at 10 mg and 8.5% at 20 mg. Of note the incidence of edema is substantially lower compared to CR preparation (9:13:36% for the respective doses). The other side effects include angina, asthenia, flushing, heart failure, and palpitations. According to the package insert, the adverse effects are usually not serious, dose dependent, and respond well to dose reduction or discontinuation of therapy. Isradipine has no effect on atrioventricular or sinoatrial conduction. The only absolute contraindications for isradipine are hypersensitivity to DHP compounds and hypotension defined as systolic blood pressure below 90 mm Hg. Until our studies, isradipine has not been tested in the PD population.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Safety and Tolerability of Isradipine (A Potential Neuroprotective Agent) in Patients With Parkinson's Disease- Stage II
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dynacirc CR (Isradipine) Dynacirc CR (Isradipine) will start at 5mg dose and increased in increments of 5mg every 2 weeks	Drug: Dynacirc CR (Isradipine); Dynacirc CR is given by the recommended schedule for titration. Subjects start on a 5mg dose and are increased in increments of 5mg every 2 weeks provided that the subjects do not have significant adverse events or symptomatic orthostatic hypotension.; Other Names: Isradipine

Outcome Measures

Primary Outcome Measures

1. Tolerability of Isradipine Based on the Number of Participants That Complete the Study [1 year]

Secondary Outcome Measures

1. Safety of the Standard Titration Schedule in PD Population as Measured by the Number of Patients That Are Able to Increase the Dose to 20 mg Daily [1 year]

2. Number of Participants That Tolerated Each Dose of Isradipine [1 year]

   Tolerability= maximum tolerated dose

3. Number of Participants That Tolerated Each Dose Level of Isradipine Between PD Patients Treated With Antihypertensive Agent and Not on Antihypertensive Agent [1 year]

   At the time of enrollment, some patients were currently being treated with antihypertensive agents including Propanolol, Toprol, Lisinopril, Diovan, Norvasc. HTN+: Participants on an antihypertensive agent HTN-: Participants not on an antihypertensive agent

4. Number of Participants That Completed the Study at Each Dose Level of Isradipine [1 year]

5. Change in Motor UPDRS Scores: Baseline vs. Final Visit [12 weeks]

   Baseline visit = Week 0 Final visit = Week 12 Unified Parkinson's Disease Rating Scale (UPDRS)is made up of the following sections: Part I: evaluation of Mentation, behavior, and mood Part II: self evaluation of the activities of daily life Part III: clinician-scored motor evaluation Part IV: Hoehn and Yahr stating of severity of Parkinson disease. Part V: Schwab and England ADL scale Only part three was used for this assessment. The higher the UPDRS score, the greater the disability from PD. The range for scores for Section III is 0 to 108.

6. Pharmacokinetic Data - Mean Serum Concentration and Dosage Exposure Across the Dose Range of Isradipine [1 year]

   Mean Plasma Concentration (+/- SD ng/mL)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with idiopathic Parkinson's disease age 30-75

2. Hoehn and Yahr stage <2.5

3. PD duration less than 5 years

4. For the subjects treated with PD medications, the regimen has to be stable for >1 month prior to enrollment

Exclusion Criteria:

1. Atypical Parkinsonian syndrome

2. Patients with history of stable hypertension treated with other antihypertensive agents will be allowed provided that the doses of concomitant anti HTN therapy can be reduced/adjusted during the study based on the BP readings. The number of concomitant antihypertensive agents should not exceed two. The dose of concomitant antihypertensive agents has to be stable for > 1 month

3. Presence of orthostatic hypotension at the screening visit defined as > 20 mmHg change in systolic BP and 10mm change in diastolic BP after 2 min of standing, or baseline BP <90/60.

4. Presence of other medical conditions that in the opinion of the investigator will preclude safe use of the drug.

5. Presence of cognitive dysfunction as determined by MMSE score <24

6. Failure to sign the informed consent

7. Inability to cooperate with the study procedures

8. Presence of motor fluctuations

9. History of bradycardia defined as heart rate < 55

10. Women of childbearing potential who are not surgically sterilized have to use a reliable measure of contraception and have a negative urine pregnancy test at screening

11. Participation in other investigational drug trials within 30 days prior to screening

12. History of brain surgery for Parkinson's Disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	710 N. Lake Shore Dr.	Chicago	Illinois	United States	60610

Sponsors and Collaborators

• Northwestern University
• Northwestern Memorial Hospital

Investigators

• Principal Investigator: Tanya Simuni, M.D., Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tanya Simuni, Professor of Neurology, Northwestern University
• ClinicalTrials.gov Identifier: NCT00753636
• Other Study ID Numbers: Isradipine II
• First Posted: Sep 16, 2008
• Last Update Posted: Nov 15, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Tanya Simuni, Professor of Neurology, Northwestern University: Parkinson's disease; Isradipine; Neuroprotection
• Additional relevant MeSH terms: Parkinson Disease; Isradipine

Study Results

Participant Flow

Pre-assignment Detail	35 Screened

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Period Title: Overall Study
STARTED	31
COMPLETED	25
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 77.4%
>=65 years	7 22.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.87 (8.23)
Sex: Female, Male (Count of Participants)
Female	13 41.9%
Male	18 58.1%
Region of Enrollment (participants) [Number]
United States	31 100%

Outcome Measures

1. Primary Outcome

Title	Tolerability of Isradipine Based on the Number of Participants That Complete the Study
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
Number [Participants]	25 80.6%

2. Secondary Outcome

Title	Safety of the Standard Titration Schedule in PD Population as Measured by the Number of Patients That Are Able to Increase the Dose to 20 mg Daily
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
Number [Participants]	16 51.6%

3. Secondary Outcome

Title	Number of Participants That Tolerated Each Dose of Isradipine
Description	Tolerability= maximum tolerated dose
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
20mg	16 51.6%
15mg	5 16.1%
10mg	6 19.4%
5mg	4 12.9%

4. Secondary Outcome

Title	Number of Participants That Tolerated Each Dose Level of Isradipine Between PD Patients Treated With Antihypertensive Agent and Not on Antihypertensive Agent
Description	At the time of enrollment, some patients were currently being treated with antihypertensive agents including Propanolol, Toprol, Lisinopril, Diovan, Norvasc. HTN+: Participants on an antihypertensive agent HTN-: Participants not on an antihypertensive agent
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
HTN+ 20mg	2 6.5%
HTN+ 15mg	3 9.7%
HTN+ 10 mg	1 3.2%
HTN+ 5mg	0 0%
HTN- 20mg	14 45.2%
HTN- 15mg	2 6.5%
HTN- 10mg	5 16.1%
HTN- 5mg	4 12.9%

5. Secondary Outcome

Title	Number of Participants That Completed the Study at Each Dose Level of Isradipine
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
20mg	16 51.6%
15mg	4 12.9%
10mg	4 12.9%
5mg	1 3.2%

6. Secondary Outcome

Title	Change in Motor UPDRS Scores: Baseline vs. Final Visit
Description	Baseline visit = Week 0 Final visit = Week 12 Unified Parkinson's Disease Rating Scale (UPDRS)is made up of the following sections: Part I: evaluation of Mentation, behavior, and mood Part II: self evaluation of the activities of daily life Part III: clinician-scored motor evaluation Part IV: Hoehn and Yahr stating of severity of Parkinson disease. Part V: Schwab and England ADL scale Only part three was used for this assessment. The higher the UPDRS score, the greater the disability from PD. The range for scores for Section III is 0 to 108.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
Baseline	7.61 (3.01)
Final	7.08 (2.68)

7. Secondary Outcome

Title	Pharmacokinetic Data - Mean Serum Concentration and Dosage Exposure Across the Dose Range of Isradipine
Description	Mean Plasma Concentration (+/- SD ng/mL)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description
Measure Participants	31
20 mg	2.48 (1.16)
15 mg	2.53 (1.33)
10 mg	1.53 (0.72)
5 mg	0.68 (0.38)

Adverse Events

Arm/Group Title	Isradipine 20mg, 15mg, 10mg or 5 mg
Arm/Group Description	A group is defined by the highest dose received by the subject. Subjects are started at 5mg dose, and may end at the highest dose of 20mg, depending on how they tolerate the drug. Thus, assignment to a group is not randomized but relies on the last/highest dose received.
All Cause Mortality
	Isradipine 20mg, 15mg, 10mg or 5 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Isradipine 20mg, 15mg, 10mg or 5 mg
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Other (Not Including Serious) Adverse Events
	Isradipine 20mg, 15mg, 10mg or 5 mg
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
General disorders
Fatigue	9/31 (29%)	9
Dizziness	10/31 (32.3%)	10
Headache	5/31 (16.1%)	5
Nausea	5/31 (16.1%)	5
Cough	2/31 (6.5%)	2
Soar Throat	2/31 (6.5%)	2
Sinuses	2/31 (6.5%)	2
Cold	2/31 (6.5%)	2
Musculoskeletal and connective tissue disorders
Leg Edema	17/31 (54.8%)	17
Reproductive system and breast disorders
Erectile/sexual Dysfunction	2/31 (6.5%)	2
Respiratory, thoracic and mediastinal disorders
Shortness of breath	2/31 (6.5%)	2

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.