Conditions: Parkinson Disease
Keywords: Parkinson Parkinson Disease Parkinson's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 336
Healthy volunteers: no

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.

Arms:
arm 1: Oral capsule of up to 5 mg of isradipine taken twice daily for 36 months. arm 2: Oral capsule taken twice daily for 36 months.

Interventions: intervention 1: Isradipine intervention 2: Placebo (for Isradipine)
Intervention descriptions: intervention 1: Oral capsules Isradipine IR, up to 10 mg, taken twice daily intervention 2: Sugar Pill manufactured to look like Isradipine but has no active ingredients

Protocol document:
Prot_000.pdf: 
A Phase 3 double-blind placebo-controlled parallel group study of isradipine as a disease 
modifying agent in subjects with early Parkinson disease 
Acronym:
STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of 
Isradipine for PD) 
Study Chair: 
Principal Investigator: 
Tanya Simuni, MD 
Professor of Neurology  
Director, Parkinson's disease and Movement Disorders Center 
Northwestern University Medical School  
Department of Neurology, Abbott Hall, 11th Floor
710 North Lake Shore Drive  
Chicago, Illinois 60611  
Coordination Center 
Kevin M. Biglan, MD MPH 
Co-Principal  
Professor of Neurology 
Investigator: 
Clinical Trials Coordination Center 
University of Rochester Medical Center 
MIND 
265 Crittenden Blvd, Suite 240 
Rochester, NY 14620 
Biostatistician: 
David Oakes, PhD 
Department of Biostatistics & Computational Biology 
Saunders Research Building - CTSI 
University of Rochester Medical Center 
265 Crittenden Blvd. 4th Floor, Room #4104 
Box CU420630 
Rochester, New York   14642
Clinical Trials  
Parkinson Study Group (PSG) 
Coordination Center: 
University of Rochester Medical Center 
CHET/CTCC 
265 Crittenden Blvd 
CU 420694 
Rochester, NY 14642-0694 
Phone: 585-275-7311 
Fax: 585-461-3554 
NCT02168842 (Protocol  number added for ClinicalTrials.gov submission, 11/25/2019)


STEADY-PD III Protocol 
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Confidential 
Page 2 of 99
Confidentiality Statement 
This document is a confidential communication of the Parkinson Study Group (PSG).  The recip-
ient agrees that no information contained herein will be published or disclosed without written 
approval.  This document may be disclosed to appropriate institutional review boards, or duly 
authorized representatives of the U.S. Food & Drug Administration, or other regulatory authori-
ties as appropriate under the condition that confidentiality is requested. 
Supported by: 
The National Institute of Neurological 
Disorders and Stroke (NINDS) 
Grant Numbers:  U01NS080818-01A1 and U01NS080840-01A1 
Sponsor of IND: 
Tanya Simuni, MD- IND application 
IND application number 113,513 
Biomarker and DNA sample collection substudy 
Supported by Michael J. Fox Foundation 


 
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INVESTIGATOR AGREEMENT 
 
 
I have carefully read this protocol, including all appendices and the isradipine Package Insert and 
agree that it contains all the necessary information for conducting the study safely. 
 
I will conduct this study in strict accordance with this protocol and according to the current Good 
Clinical Practice (GCP) regulations and guidelines [21 CFR (Code of Federal Regulations) Parts 
11, 50, 54 and 56 and ICH (International Conference on Harmonization of Technical Require-
ments for Registration of Pharmaceuticals for Human Use) Topic E6 (R1)], and local regulatory 
requirements.  Any changes in procedure will only be made if necessary to eliminate immediate 
hazards and/or to protect the safety, rights or welfare of subjects.   
 
I will provide copies of the protocol and all other information relating to the pre-clinical and pri-
or clinical experience, which were furnished to me, to all physicians and other study personnel 
responsible to me who participate in this study.  I will discuss this information with them to as-
sure that they are adequately informed regarding the study drug and conduct of the study. 
 
I will ensure that the drugs supplied to me for this study will be used only for administration to 
subjects enrolled in this study protocol and for no other purpose. 
 
I agree to keep records on all subject information (case report forms, informed consent state-
ments, drug shipment, drug return forms, and all other information collected during the study) in 
accordance with the current GCP, local and national regulations. 
 
 
 
 
 
Site Number 
 
Printed Site Name 
 
 
 
 
 
 
Printed Site Investigator Name 
 
 
 
 
 
 
Site Investigator  Signature 
 
Date 
 
 
 
 
 
 
 


PROTOCOL APPROVAL
A Phase 3 double-blind placebo-controlled parallel group study of isradipine as a disease
modifying agent in subjects with early Parkinson disease
STUDY ACRONYM: STEADY-PD III
Tanya Sirnuni
‘
Dte
Principal Investigator
/7/
Kevin M. Biglan
Date
Co-Principal Investigator
ViVt
O, 7 c’
Date
David Oakes
Biostatistician
STEADY-PD Ill Protocol
Page 4 of99
Version 6OB dated 3lAugust2Ol6
Contidential


 
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DOCUMENT HISTORY 
Document 
Date of Issue      Summary of Change 
Original Protocol 
Version 1.0 
         
6January2014 
      Not applicable 
Version 2.0 
 11March14 
 
Revised information related to collection of home blood 
pressure monitoring to remote internet uploading and 
home BP readings, oversight and site responsibility with 
review of BP readings 
 
Clarified drug titration requirements 
 
Added requirement to report re-initiating blood pressure 
monitoring after Visit 02 
 
Clarified management of subject’s who become pregnant 
 
Changed biomarker serum sample to plasma sample 
 
Changed reporting of SBP from 140 to 160 mm Hg 
 
Added information on reporting of SAEs to Independent 
Medical Monitor 
 
Added responsibility of Blood Pressure Monitor 
 
Clarified Investigator training requirements for UPDRS, 
MDS-UPDRS and C-SSRS 
 
Clarified assessment roles for Investigator and Coordina-
tors for UPDRS and MDS-UPDRS 
 
Clarified processing of AE Incident Reports 
Version 3.0 
         09May14 
 
Revised Kevin Biglan’s title 
 
Added Michael J. Fox Foundation as sponsor of biomarker 
sub-study 
 
Updated Abbreviation Terms to include ADL, DNA and 
Neuro-QOL 
 
Revised inclusion criteria to allow PD symptomatic therapy 
after 3 months from the baseline visit 
 
Revised exclusion criteria to include ALL calcium channel 
blockers 
 
Clarified definition of medication ON state 
 
Changed blood pressure collection from supine to sitting 
position 
 
Added optional DNA collection at Screening visit 
 
Added Neuro-QOL measures to be assessed at Baseline, 
Month 12, Month 24, Month 36 or PW visit and at Symp-
tomatic Treatment Visit 
 
Added Neuro-QOL to study measures for quality of life 
 
For interim PK analysis, clarified DSMB response to seek 


 
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Document 
Date of Issue      Summary of Change 
independent assessment 
 
Removed statement to terminate study for futility if inter-
im analysis shows conditional power of rejecting null hy-
pothesis 
 
Clarified procedures to be completed at Symptomatic 
Treatment Visit, to include Symptomatic Treatment Visit 
replacing regularly scheduled visit, as applicable, and add-
ed collection of labs and ECG if this visit occurs at V06, V08 
or V10 
 
Revised plan to withdraw subject if treatment assignment 
has been disclosed to retain subject off of study drug 
 
Corrected name for Drug Dispensing/Return Log and 
Blindedness Questionnaire throughout 
 
Clarified BP Monitor communication with Site Investigator 
 
Referenced Section 3 of Operations Manual to add guid-
ance to requirements for eligibility waiver process 
 
Changed follow up of adverse events from 2 weeks after 
stopping study drug to 30 days from last visit or until reso-
lution, whichever occurs first 
 
Clarified Data Sharing in Section 11 
 
 
Version 4.0 
         15Dec14 
 
Change in use of amantadine and/or anticholinergics from 
12 week prior to the baseline visit to 8 weeks prior to 
baseline visit 
 
Changed primary care physician to primary care provider 
throughout 
 
Added use of telithromycin to prohibited drug use in ex-
clusion criteria per isradipine package insert 
 
Added association with heart injury to use of prohibited 
antibiotics in exclusion criteria per isradipine package in-
sert  
 
Added the following to data collection: 
        PD Features at Screening Visit 
        Primary Diagnosis at Screening Visit, V11 and PW 
        Socio-Economics at Screening Visit 
        Family History at Screening Visit 
        Mini Environmental Risk Questionnaire (MERQ) at Base-
line 
        Exercise Questionnaire at Baseline, V11 and PW 


 
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 
Changed temperature range for storage of study drug due 
to current manufacturer recommendations 
 
Added instruction to hold study drug if dose missed for 4 
hours or more from scheduled time and resume at next 
scheduled dosing time 
 
Remove instructions for subject to report blood pressure 
to site personnel 
 
Added instruction to continue birth control for two weeks 
after study drug has been discontinued 
 
Added information on prohibited use of Fentanyl Anesthe-
sia 
 
For MoCA, added information on addition of point for edu-
cation of 12 years or fewer 
 
For Neuro-QOL assessments, added information on availa-
ble translation; French-speaking participants not expected 
to complete 
 
Revised Study File and File Document list  
 
For EDC Electronic Signature requirements, added AE Fol-
low up Log 
 
For Adverse Events, included information on phone call 
management for AEs present at V10 or PW visit 
 
Added the following for reportable events: 
        Re-initiation of BP monitoring at V02 
        Completion of DaT Scan 
 
Other minor formatting and language revisions for con-
sistency and clarification 
 
 
DOCUMENT HISTORY 
Document 
Date of Issue 
     Summary of Change 
 
Version 6.0 
 
         31AUG2016 
 
 
 
 
 
 
 
 
 
 
Removed the remote blood pressure monitoring for study 
visits during a study drug taper and at the end of the study  
 
The Telephone Visit T01, T02, T03, or T04 may be conduct-
ed by either the study coordinator or investigator 
 
Visit windows beginning T01 Month 15 through V10 
Month 36 revised from +/- 14 days to +/- 7 days 
 
Added additional description for the UPDRS “ON” and 
“OFF” that should occur for all types of PD medications 
once a symptomatic therapy visit is conducted  


 
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 
Obtain consent for study principal investigator or repre-
sentatives to contact subject for long term follow up after 
study (36 months) completion 
 
Added at the V10 End of Study Visit to review informed 
consent and verify that the subject granted permission for 
long term DNA and biomarker storage 
 
Added a description of blanket retention methods includ-
ing a subject webinar with study principal investigators 
 
Revised the Schedule of Activities footnotes to indicate 
collection of  MERQ, Exercise Questionnaire,  DNA and Bi-
omarker samples at the next in-person visit if missed at the 
Baseline visit  
 
Added the visit status assessment to be completed at all 
visits 
 
Schedule of Activities - Added a Premature Withdrawal 
Follow-Up Visit  
 
Schedule of Activities - Deleted the “X” for Home BP Moni-
toring  
 
Protocol Section 6.2 deleted reference to remote phone 
visits  
 
Protocol Section 9.2.5 revised data entry requirement re-
vised to 5 days 
 
Protocol Section 10.2 added a timeline to retention of sub-
ject contact information (20 years) 
 
Formatting and language revisions for consistency and 
clarification 
 
 
 


 
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TABLE OF CONTENTS 
Page 
 
SYNOPSIS .................................................................................................................................... 13 
SCHEDULE OF ACTIVITIES ................................................................................................... 18 
1. STUDY OBJECTIVES ............................................................................................................ 21 
1.1  Primary Objective .....................................................................................................................21 
1.2  Secondary Objectives ...............................................................................................................21 
1.3  Study Population ......................................................................................................................21 
 
2. BACKGROUND ....................................................................................................................... 21 
2.1  Rationale and Supporting Data .................................................................................................21 
2.2  Isradipine Clinical Experience .................................................................................................24 
2.3  Isradipine Pharmacokinetic Data  .............................................................................................25 
2.4  Epidemiological Data  ..............................................................................................................27 
2.5  Isradipine Side Effect Profile ...................................................................................................27 
2.6  Isradipine in PD Data ...............................................................................................................28 
 
3. STUDY DESIGN ...................................................................................................................... 32 
3.1  Overview ...................................................................................................................................32 
3.2  Study Design Justification  .......................................................................................................32 
 
4. SELECTION AND ENROLLMENT OF SUBJECTS  ........................................................ 33 
4.1  Inclusion Criteria  ......................................................................................................................33 
4.2  Exclusion Criteria  ....................................................................................................................33 
4.3  Study Enrollment, Recruitment and Retention Procedures   ....................................................35 
4.4  Strategies for Retention ............................................................................................................37 
 
5. STUDY INTERVENTIONS  ................................................................................................... 37 
5.1   Study Drug Administration and Duration  ...............................................................................37 
5.2  Study Drug Management  .........................................................................................................38 
5.3  Study Visit Instructions ............................................................................................................42 
5.4  Study Drug Reduction ..............................................................................................................44 
5.5  Study Drug Re-challenge (Resumption of Titration) ...............................................................44 
5.6 Study Drug Suspension  ............................................................................................................45 
5.7 Concomitant Medications  .........................................................................................................48 
5.8  Adherence Assessment  ............................................................................................................49 
 
 


 
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6. CLINICAL AND LABORATORY EVALUATIONS  ......................................................... 50 
6.1   Schedule of Activities  .............................................................................................................50 
6.2  Timing of Evaluations  .............................................................................................................50 
6.3  Special Instructions and Definitions of Evaluations  ...............................................................66 
 
7. MANAGEMENT OF ADVERSE EVENTS ...........................................................................74 
7.1  Isradipine Side Effect Profile  ..................................................................................................74 
 
 
8. STATISTICAL CONSIDERATIONS .....................................................................................76 
8.1  General Design Issues  ..............................................................................................................76 
8.2  Outcomes  .................................................................................................................................77 
8.3  Sample Size and Accrual  .........................................................................................................80 
8.4  Data Monitoring  ......................................................................................................................81 
8.5  Further Considerations in Data Analyses  ................................................................................81 
 
9. DATA COLLECTION, SITE MONITORING, AND ADVERSE EVENT REPORTING82 
9.1 Records Keeping  .......................................................................................................................82 
9.2 Role of Data Management  ........................................................................................................84 
9.3 Quality Assurance  ....................................................................................................................88 
9.4 Adverse Event Reporting  .........................................................................................................88 
 
10. HUMAN SUBJECTS  ............................................................................................................ 94 
10.1 Compliance Statement  ............................................................................................................94 
10.2 Informed Consent  ...................................................................................................................94 
10.3 Institutional Review Board/Independent Ethics Committee ...................................................95 
10.4  Protocol Amendments  ........................................................................................................... 96 
10.5  Subject Confidentiality  ..........................................................................................................96 
10.6  Study Modification/Discontinuation  ......................................................................................96 
 
11.  DATA SHARING.....................................................................................................................97 
 
12. PUBLICATION OF RESEARCH FINDINGS ....................................................................97 
 
13. REFERENCES ........................................................................................................................98 
 
 


 
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Abbreviations or Specialist Terms 
Abbreviation or  
Specialist term 
Definition 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
BDI-II 
Beck Depression Inventory II 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CCB 
Calcium Channel Blockers 
Cmax 
Maximum Observed Plasma Concentration 
CMSU 
Clinical Materials Services Unit 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCC 
Clinical Trials Coordination Center 
DCCA 
Dihydropyridine Calcium Channel Antagonist 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOSD 
End of Study Drug 
GCP 
Good Clinical Practice 
HTN 
Hypertension 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 


 
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MERQ 
Mini Environmental Risk Questionnaire 
MDS-UPDRS 
Movement Disorder Society- Unified Parkinson Disease Rating 
MoCA 
Montreal Cognitive Assessment 
MODHOYA 
Modified Hoehn and Yahr 
MODSEADL 
Modified Schwab and England Activities of Daily Living 
mRS 
Modified Rankin Score 
Neuro-QOL 
Quality of Life in Neurological Diseases 
NINDS 
National Institute of Neurological Disorders and Stroke 
OFF 
Approximately 12 hours after the last dose of symptomatic  
therapy 
ON 
Approximately 1 hour after dose of symptomatic therapy 
PD 
Parkinson disease 
PDQ39 
Parkinson Disease Quality of Life Questionnaire 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PSG 
Parkinson Study Group 
PTM 
Placebo to Match 
REB 
Research Ethics Board 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
STX 
Symptomatic therapy 
UPDRS 
Unified Parkinson Disease Rating Scale 
URT 
Upper Respiratory Tract 
WBC 
White Blood Cell 
WO 
Without 
 
 


 
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SYNOPSIS 
Protocol Title 
A Phase-3 double-blind placebo-controlled parallel group  
study of isradipine as a disease modifying agent in subjects 
with early Parkinson disease 
Protocol Acronym 
STEADY-PD III 
Organization  
Parkinson Study Group (PSG) 
Study Centers 
Approximately 56 PSG sites in North America  
Primary Study  Objective 
To establish efficacy of isradipine to slow progression of Parkin-
son disease (PD) disability as determined by the change in the to-
tal (Part I-III) Unified Parkinson Disease Rating Scale (UPDRS) 
score in the active treatment arm versus placebo between the base-
line and 36 month visit  
Secondary  Study Objective 
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 disa-
bility in PD:  
1) Motor function (characterized by UPDRS Part III in the 
medications OFF state, UPDRS ambulatory capacity sub-
score, 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)  
Study Design 
A randomized, Phase-3, 2-arm, double-blind, parallel group trial 
with subjects 1:1 randomized to 5mg of Isradipine IR twice daily 
or matching placebo twice daily.   
Duration of Treatment 
36 months on randomized treatment of 5mg of Isradipine IR twice 
daily or matching placebo. 
Route and Dosage 
Oral capsules Isradipine IR or matching placebo 


 
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Study Population 
336 subjects with early idiopathic PD not requiring dopaminergic 
therapy  
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 therapy (levodopa, 
dopamine agonist or MAO-B inhibitors) and NOT project-
ed 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 med-
ications (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 se-
rum pregnancy test at the screening visit 
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 comor-
bidity that in the investigator’s opinion would compromise 


 
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participation in the study 
10. Prior exposure to isradipine or other dihydropyridine cal-
cium 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 provid-
ed 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 vis-
it 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 clarithro-
mycin, telithromycin or erythromycin and  calcium chan-
nel blockers has been reported to be associated with in-
creased 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 deter-
mined 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 
Primary Outcome Measure 
Efficacy: 
Efficacy will be defined as the change in total UPDRS score be-
tween the baseline visit and month 36 visit. In case the subject 
was started on symptomatic therapy, UPDRS will be measured in 
the medications ON state (based on the subject/ investigator de-
fined BEST ON, approximately 1 hour after dose of symptomatic 
therapy). 
 


 
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Secondary Outcome 
Measures 
The change in the following measures of disability from baseline 
to 36 months will be analyzed: 
 
I. Motor disability  
1. The change in Motor subscale of the UPDRS  
2. The change in the ambulatory capacity (sum of 5 UPDRS 
questions: falling, freezing, walking, gait, postural stabil-
ity) 
3. The change in the defined UPDRS Part III OFF state 
(measured approximately 12 hours after the last dose of 
medications) once symptomatic therapy has been initiated  
4. The change in the MDS-UPDRS Motor Evaluation sub-
score  
5. The time to initiation of symptomatic therapy 
6. Proportion of subjects that require symptomatic therapy  
7. Analysis of symptomatic therapy utilization as measured 
by levodopa equivalence dose[1]  
8. Time to onset and severity of motor complications as 
measured by UPDRS IV subscale (complications of thera-
py) 
II. Cognitive disability  
1. The change in the cognitive function as measured by the 
change in the MoCA scale [2, 3]  
III. Measures of global disability   
1. The change in the modified Rankin score  
IV. Measures of functional status and quality of life  
1. The change in Activities of Daily Living (ADL) subscale 
of the UPDRS  
2. The change in the MDS-UPDRS Motor and Non-Motor 
Experiences of Daily Living subscore  
3. The change in the modified Schwab and England scale  
4. The change in Parkinson Disease Quality of Life Ques-
tionnaire 39 (PDQ-39) [4]  
5. The change in the Neuro-QOL  
 
Safety and Tolerability: 
1. The ability to complete the 36 months of the study on 
      the originally assigned treatment dosage. 
2. The proportion of subjects requiring dosage reductions 
      secondary to intolerability. 
3. The frequency of adverse events and serious adverse 
events.  
Statistical Analysis and  
Sample Size Justification 
The primary efficacy analysis will use analysis of covariance to 
compare the changes in total UPDRS score from baseline to 36 
months between the active treatment group and the placebo group, 
adjusting for baseline UPDRS and enrolling investigator. Using a 


 
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two-sided alpha level of 5%, the total sample size of 336 gives 
80% power to detect a 4–point difference between the two groups, 
after allowance for 15% dropouts. This effect size is estimated to 
represent a 25% reduction in the rate of worsening after allowance 
for the benefit of symptomatic treatment.  Secondary outcomes 
including measures of motor, cognitive and global disability and 
measures of functional changes and quality of life will be ana-
lyzed in the same way as the primary outcome. Measures of safety 
and tolerability, including ability to complete the study on the as-
signed dosage and the frequency, seriousness and severity of ad-
verse events will be compared using Fisher’s exact test. 
Interim Analyses 
Interim tolerability analysis  
An interim tolerability analysis will be performed after the first 60 
subjects complete the titration period (Visit 03, Month 3).  
 
Interim analysis of the Pharmacokinetic (PK) data  
An interim PK data analysis will be performed (at steady-state) 
after Cmin and Cmax PK data are available for the first 60 sub-
jects who successfully complete titration to the target daily dose 
of 10 mg (Visit 03, Month 3).  
 
Interim futility and efficacy analysis 
An interim analysis for futility and efficacy will be performed af-
ter primary outcome data are available for the first 168 subjects 
(50%) to enroll in the study. If the recruitment rate falls below 
that projected, the interim analysis may be brought forward and 
performed as soon as the first 30% of the subjects to enroll have 
completed (or terminated). In that case, a second interim analysis 
for futility will be conducted on the first 75% of subjects to enroll.  
 
Study Procedures 
See the Schedule of Activities.  
IND  
The IND application # 113,513 
 


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 18 of 99 
 
 
Titration Phase 
Maintenance Phase 
Drug Taper 
 
 
 
 
Visits  
Scre
en 
(SC) 
Base-
line 
(BL) 
V01 
V02 
V03 
V04 
V05 
V06 
Pho
ne 
Visit 
T01 
V07 
Pho
ne 
Visit 
T02 
V08 
Pho
ne 
Visit 
T03 
V09 
Pho
ne 
Visit 
T04 
V10 
EOS
D 
V11 
Post 
drug/ 
Final 
Visit 
Prema-
ture 
With-
drawal 
(PW) 
PW 
Follow-
Up 
Visit11 
Unsched
sched-
uled 
Visit 
(U01, 
U02)5 
 
Symp-
tomatic 
Tx Visit 
Assessments 
-8- 
-30 
day
s 
Day 
0 
Day 
14 +  
3 
days 
Day 
28 +  
3 
days 
Mon
th 3  
+/-7 
days 
Mon
th 6 
+/- 
7 
days 
Mon
th 9 
+/- 
7 
days 
Mon
th 
12 
+/- 
7 
days 
Mon
th 
15 
+/- 
7 
days 
Mon
th 
18 
+/- 
7 
days 
Mon
th 
21 
+/- 
7 
days 
Mon
th 
24 
+/- 
7 
days 
Mon
th 
27 
+/- 
7 
days 
Mon
th 
30 
+/- 
7 
days 
Mon
th 
33 
+/- 
7 
days 
Mon
th 
36 
+/- 
7 
days 
Vis-
it10 
+ 2 
week
s  
 
  
~2 
weeks 
post 
study 
drug 
taper 
  
As 
soon as 
deemed 
neces-
sary 
Informed Consent 
X 
  
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
Incl./Excl Criteria 
X 
Re-
view 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
Demographics 
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
CTCC Unique ID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain name of 
PCP and/or Cardi-
ologist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD Features 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Socio-Economics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med / Neuro HX 
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
Physical/Neuro  
X 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
X 
 
X 
 
  
 
Concomitant Medi-
cation  Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS - BL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Follow-up 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
BDI-II 
X 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
  
X 
MoCA 
X 
 
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
  
X 
Vital Signs  
(including orthos-
tatic BP )  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Safety Labs 
X 
Re-
view 
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
X2  
X13 
Blood Sample for 
DNA14 16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
Biomarkers 16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Pregnancy Test 6 
X 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
  
X13 
Modified Rankin 
scale 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Isradipine PK 
Sample 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X9 
 
 
 
ECG 
X 
 Re-
view 
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
  
X13 
PDQ-39 
  
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
 
X 
 
X 
 
  
X 
Neuro-QOL 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
UPDRS (I-III)3 
  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X (if not 
done at 
PW 
visit) 
  
X 
UPDRS IV1 
  
  
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X (if not 
  
 
STEADY-PD III Schedule of Activities 


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 19 of 99 
 
 
1If endpoint has been reached 
2 During the study drug titration period from BL to V03, blood pressure recording should be re-initiated when a dosage reduction was due to hypo-
tensive symptoms.  Home blood pressure monitoring is not required after the V03 for re-titration. 
3UPDRS motor portion must be completed by the Investigator. Once subject initiated symptomatic therapy, UPDRS Parts 1 and 2 to be completed 
in the ON state, UPDRS Part III will be assessed in the practically defined medication OFF state (approximately 12 hours since last dose of symp-
tomatic therapy) and ON (approximately 1 hour after first dose of symptomatic therapy). Subjects should be instructed NOT to take their PD med-
done at 
PW 
visit) 
UPDRS III Post 
Dose 
 
 
 
 
X14 
X14 
X14 
X14 
 
X14 
 
X14 
 
X14 
 
X14 
X14 
X14 
 
 
X 
MDS- UPDRS4  
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Assess Need for 
Therapy  
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X7 
X 
X7 
X 
X7 
X 
X 
X 
X (if not 
done at 
PW 
visit) 
  
 
Hoehn and Yahr 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X (if not 
done at 
PW 
visit) 
  
X 
Schwab/ England  
  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X (if not 
done at 
PW 
visit) 
  
X 
MERQ16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exercise  
Questionnaire 16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Visit Status As-
sessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
Dispense/Titrate 
Drug 
  
X 
 
X 
 
X 
 
X  
 
X 
 
X  
 
X 
 
X  
 
 
 
  
  X13 
Dose Management 
Log 
  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X if not 
done at 
PW visit 
X8 
X 
Drug Dispens-
ing/Return Log 
Pill count  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X (if not 
done at 
PW 
visit) 
 
 
Adherence Assess-
ment 
 
 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X  
X 
X 
X 
 
X 
 
X 
X 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X15 
X15 
X 
X 
X 
Train BP Monitor-
ing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Home BP Record-
ing2  
X 
X 
X 
X 
  
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
  
Review of Home BP 
Readings 12  
 
X 
X 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blindedness  
Questionnaire 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X (if not 
done at 
PW 
visit) 
 
 
Conclusion of 
Study Participation 
  
  
  
  
  
  
  
  
 
 
  
  
  
 
 
  
X 
X 
XX 
  
  


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 20 of 99 
 
ications at home on the morning of the study visit. Subjects should be instructed to bring their PD medication to the study visit. Medication should 
be taken after completion of UPDRS OFF exam. 
4Once symptomatic therapy has been initiated, MDS-UPDRS in the medication ON state only 
5 If an Unscheduled visit is scheduled to reduce antihypertensive medications, the visit should include all V01 procedures and evaluations 
6 Complete serum pregnancy test for all women unless they are one year postmenopausal or surgically sterile 
7 If a subject reports functional decline requiring symptomatic treatment an Unscheduled visit should be scheduled 
8 Dose management is completed at Unscheduled visit if study drug adjustment is required at the time of this visit 
9 PK sample collection at Premature Withdrawal visit to occur ONLY if visit corresponds to Visits 3 or 4 
10 Blindedness Questionnaire completed by both subject and Investigator 
11 All subjects who are taking study drug at Premature Withdrawal  visit must have Premature Withdrawal  Follow Up visit scheduled to occur 2- 
weeks after drug has stopped.  Subjects who withdraw consent should be asked to agree to present for this visit. 
12 Site staff will access BP vendor website to obtain confirmation notice to proceed or not proceed with drug titration. This confirmation along 
with review of in-person readings will be used to proceed or not proceed with drug titration per study BP requirements. 
13If the symptomatic treatment visit occurs within the window of a regularly scheduled study visit, the symptomatic treatment visit will be com-
pleted in place of the regularly scheduled study visit.  If this visit is conducted in place of the regularly scheduled V06, V08 and V10, visit assess-
ments will include the following additional assessments:  safety labs, pregnancy test6, ECG, drug dispensing/titration. 
14If indicated for Symptomatic Therapy. 
15Follow up of any unresolved Adverse Events or SAEs must be conducted by phone call, 30 days after the final study visit (Visit 11 or Premature 
Withdrawal Follow Up visit). 
16 Once subject has provided consent, conduct/collect at the next in-person visit. 


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 21 of 99 
 
1 STUDY OBJECTIVES 
1.1 
Primary Objective 
To establish efficacy of isradipine to slow progression of Parkinson disease (PD) disability as 
determined by the change in the total UPDRS score in the active treatment arm versus 
placebo between baseline and 36 months in the medications ON state (based on the sub-
ject/ investigator defined BEST ON, approximately 1 hour after dose of symptomatic 
therapy). We hypothesize that isradipine 5 mg BID will result in a 4 point difference in 
the change in total UPDRS  between the active and placebo groups over 36 months, rep-
resenting an overall 25% reduction in the rate of progression. 
1.2 
Secondary Objectives 
To explore long-term efficacy of isradipine 5 mg twice daily to slow progression of disability 
between the 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 Mo-
tor score) 
2) Cognitive function as measured by MoCA  
3) Global measures of disability as measured by modified Rankin score (mRS) 
4) Measures of functional status and quality of life (PDQ-39, MDS- UPDRS Motor and Non-
Motor Experiences of Daily Living subscore) 
 
1.3 Study Population  
 
The study will recruit 336 subjects with early PD not requiring dopaminergic therapy (levo-
dopa, dopamine agonist or MAO-B inhibitors) and NOT projected to require PD symptomat-
ic therapy for at least 3 months from baseline. Use of amantadine and/or anticholinergics will 
be allowed provided that the dose is stable for 8 weeks prior to baseline visit and throughout 
the duration of the study (see Section 4.1 and 4.2 Inclusion/Exclusion criteria). Subjects will 
be randomized in equal numbers to isradipine 5mg twice daily or matching placebo.  Study 
duration is 36 months. Primary efficacy analysis will be performed after all subjects complete 
36 months on their randomized treatment assignment. All subjects who start symptomatic 
therapy will continue in the study and remain on their randomized treatment assignment (see 
rationale section below).  
2 
BACKGROUND 
2.1 
Rationale and Supporting Data 
Parkinson disease (PD) is the second most common neurodegenerative disease that affects 1% of 
the population above the age 65 [5]. The prevalence of PD will increase substantially in 


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 22 of 99 
 
the next 20 years due to the aging of the population and age-related increase of the inci-
dence of the disease [6, 7].  PD is characterized by progressive motor disability that in-
cludes bradykinesia, rigidity, resting tremor and gait dysfunction. PD is associated with a 
spectrum of non-motor symptoms including autonomic, cognitive, mood, sleep dysfunc-
tion and sensory abnormalities which are intrinsically related to the widespread PD neu-
ropathological process and can in part precede the onset of motor manifestations [8]. The 
economic burden of PD is estimated to be $23 billion annually in US and projected to in-
crease 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 develop-
ing  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 target-
ed 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]. 
 
The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic 
(DA) neurons in the substantia nigra pars compacta (SNc). The selective vulnerability of DA 
SNc neurons may lend important clues to the etiology of PD. Data from the laboratory of  
Surmeier suggest that this selective vulnerability may be due to the reliance of these neurons 
on L-type Cav1.3 Ca2+ channels [22].  This research has shown that adult SNc DA neurons 
have a very distinctive physiology in that they are Ca2+-dependent autonomous pacemakers 
[22]. That is, their basal activity is intrinsically generated and dependent upon a particular 
class of voltage-dependent L-type Ca2+ channels. The reliance upon Cav1.3 channels grows 
with age, paralleling the increasing sensitivity to toxins, like MPTP and rotenone. More im-
portantly for PD, their work shows that pretreatment of SNc DA neurons with isradipine, a 
potent dihydropyridine antagonist of L-type Ca2+ channels (DCCA), protects these neurons in 
in vitro and in vivo models of Parkinsonism.  
 
There are a number of regions of the brain that have cell loss paralleling that of the SNc [8, 
23-26]. Although the available data set is fragmented, neurons in the dorsal motor nucleus of 
the vagus (DMV), locus ceruleus (LC), raphe nuclei (RN), pedunculopontine nucleus (PPN), 
lateral hypothalamus (LH), tuberomammillary nucleus, basal forebrain (BF) and olfactory 
bulb all are slow pacemakers like SNc DA neurons. DMV cholinergic neurons, which are 
thought to be among the earliest neurons with α-synuclein in PD, are spontaneously active 
[27]; this activity is autonomously generated and depends upon L-type calcium channels (J. 
Surmeier, unpublished observations). Serotonergic neurons in the RN have broad spikes and 
are calcium-dependent autonomous pacemakers [28]. This is also true of PPN cholinergic 
neurons [29]. Perhaps the neurons most affected in PD other than SNc DA neurons are LC 
noradrenergic neurons [23]. Like SNc DA neurons, they are autonomous pacemakers (with 


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STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 24 of 99 
 
SN dopaminergic neurons is graded with Cav1.3 antagonism. First, the green line is a 
plot of Cav1.3 antagonism as a function of isradipine concentration predicted from a 
modulated receptor model (Bean 1984), assuming a mean membrane potential of -50 mV. 
Second, the dose-response relationship for serum isradipine concentration and protection 
of SN dopaminergic neurons against an acute intrastriatal 6-OHDA injection derived 
from Ilijic et al.(Ilijic, Guzman et al. 2011) [32], is shown in red. Adjacent is a similar 
plot extrapolated from earlier work (Chan, Guzman et al. 2007) [31] using a chronic 
MPTP model. Note the alignment of the protection and Cav1.3 channel antagonism rela-
tionships. At the top, the dotted lines mark the estimated serum Cmax and Cmin values 
for 5 mg twice daily dose of  Isradipine IR (Holmes and Kutz 1993) [40]. Cmax serum 
concentration was 5.5+2.8 ng/ml (14.3 nM+7.5); Cmin concentration was 0.4+0.2 ng/ml 
(1.1 nM+0.5); grey boxes show the upper and lower limits of the Cmax and Cmin distri-
butions. Note that these are within the range predicted for toxin protection. Also shown is 
the ‘C floor’; this is the value below which there should be little antagonism of Cav1.3 
channels and no protection.  
 
This model was used to predict antagonism of Cav1.3 channels as a function of isradipine 
concentration (Fig. 1B, green line). Plots of the relationship between serum isradipine 
concentration and neuroprotection achieved against the toxins 6-OHDA and MPTP (Fig. 
1B red lines) revealed the graded relationship between channel antagonism and protec-
tion. To relate this work to the clinical trial using 10 mg/day Isradipine IR, the Cmax and 
Cmin values were plotted (Fig. 1B, dashed vertical lines). From these data, we predict 
that at Cmax roughly 90% of the Cav1.3 channels will be antagonized; at Cmin, this val-
ue will fall to just above 30%. Importantly, this range spans the one needed for protection 
against the toxins. Also plotted is the ‘Cfloor’ value (0.25 nM or 0.098 ng/ml); at this 
concentration, Cav1.3 channel antagonism is predicted to be roughly 10%. Although less 
than that needed to achieve protection against MPTP, this level of antagonism should still 
provide some measure of protection against the slowly progressing pathology in PD. 
However, if isradipine concentration falls below this level for part of the day, little or no 
protection should be afforded during this period.  
.  
 
2.2 Isradipine Clinical Experience 
 
The study will utilize Isradipine immediate release preparation. Currently there are no 
Cav1.3 Ca2+ channel selective DCCAs. Isradipine is the most potent DCCA that is FDA 
approved 
for 
treatment 
of 
hypertension 
since 
1990 
(http://www.drugs.com/pro/isradipine.html).  Isradipine is available in immediate release 
(IR) and was previously available in a controlled release (CR) preparation in 5-20 mg 
dose range. Peak serum levels occur in about 1.5 hours for the IR preparation and 8-10 
hours for the CR preparation. The duration of the pharmacological effect of the IR prepa-
ration is 12 hours and 24 hours for the CR preparation after a single dose (for hyperten-
sion).  Isradipine achieves maximal pharmacodynamic effect at a steady state in 2-4 
weeks. Isradipine IR is administered twice daily. The serum concentration remains rela-
tively stable for 24 hours once the steady state has been achieved. Isradipine is metabo-
lized by CYP3A4 hepatic isoenzymes into at least 6 inactive compounds and excreted in 


 
 
 
 
STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 25 of 99 
 
the urine (60-65%) and feces (25-30%). No initial dose adjustment for mild hepatic or re-
nal impairment (creatinine clearance 30-80 ml/min) is required. Isradipine serum concen-
tration can be affected by the compounds that block P-450 CYP 3A4 enzyme (see Section 
5.2.11.1).  
 
2.3       Isradipine Pharmacokinetic Data 
 
There are limited published data on the pharmacokinetics of isradipine in normal volun-
teers [34, 35, 37-39]. There is no comparative PK data on isradipine CR vs. IR presented 
in the isradipine CR NDA application 020336 (Sandoz Pharm, data on file). Christensen 
et al (1993) has conducted a comparative study of pharmacokinetics and   pharmacody-
namics of Isradipine CR vs. regular in 30 subjects with moderate hypertension. The data 
are summarized in Table 1.  
 
Table 1. Mean values and standard deviations (ranges for half-life) in brackets for the 
two dosages of isradipine (IR and CR formulations) after first dose and in steady state. 
 
Cmax 
ng/ml 
T1/ 2 
hr 
AUC 
hr ng/ml 
CI/F 
1/hr 
First dose 
 
 
 
 
2.5 mg x 1 
(plain) 
2.2 
(0.9) 
9.5 
(3.6-24.5) 
10.2* 
(4.4) 
295 
(148.5) 
5.0 mg x 1 
(SRO) 
1.2 
-- 
-- 
-- 
Steady state 
 
 
 
 
2.5 mg x 1 
(plain) 
2.3 
(1.0) 
13.1 
(3.5 – 25.1) 
9.9** 
(4.5) 
314 
(166.1) 
5.0 mg x 1 
(SRO) 
1.8 
(1.4) 
-- 
-- 
23.1xx 
(11.6) 
336.0 
(321.9) 
*: from 0 to infinity 
**: from 0 to 12 hr 
xx: from 0 to 24 hr 
 
Based on the published PK data [40], we expect that in patients Isradipine IR 5 mg twice 
daily will achieve serum Cmax in the range of 5.53 (+2.80) ng/ml and Cmin in the range 
of 0.4 ( + 0.2) ng/ml[40].  
 
We collected data on the trough plasma isradipine concentration across the 5-20mg daily 
dose exposure of Isradipine CR in PD subjects [unpublished data]. Blood samples for 
plasma isradipine concentration measurements were collected in the morning before the 
daily dose of the study drug (Cmin) at baseline and every 2 weeks during study visits. 
Plasma isradipine concentrations were measured by liquid chromatography-tandem mass 
spectrometry. Ten subjects participated in the PK substudy. Details of these findings are 
in Table 2. There was a good linear correlation between mean plasma isradipine concen-
tration and isradipine dose in the 5-15 mg/day dose range. PK values were consistent 
with the data obtained from normal volunteers.  The sample size for 20mg dose was not 
large enough to be reliable (n=4) as the majority of subjects in that sub-study cohort were 


 
 
 
 
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unable to tolerate a 20mg dosage. 
 
Table 2. Mean plasma Cmin in PD subjects treated with escalating dosages of Isradipine 
CR 
 
 
 
 
 
 
 
 
 
 
Our data are consistent with the PK data provided by the manufacturer from the NDA 
application 020336 (Sandoz Pharm, data on file) for Isradipine CR in normal volunteers 
(Dynacirc CR) as seen in Table 3. 
 
Table 3. Pharmacokinetics of Isradipine CR in normal volunteers 
Study 162 Steady-state plasma isradipine modified release pharmacokinetic parameters 
Hours 0 – 24 on Day after once-daily dosing for 7-days each dosing period 
(n=27, except as indicated) 
 
1 x 5mg 
2 x 5mg 
4 x 5 mg 
 
Mean, SD, 
min max 
Mean, SD, 
min, max 
Mean, SD 
min, max 
AUC 0-24 h 
(ng*h/mL) 
18.39,10.58 
7.240, 54.67 
35.00, 17.20 
11.75, 87.41 
65.30, 23.07 
33.35, 117.56 
Cmax 
(ng/mL) 
1.219, 0.689 
0.49, 3.50 
2.259, 1.104 
0.88, 5.08 
3.817, 1.315 
2.16, 6.75 
Cmin 
(ng/mL) 
0.693, 0.455 
0.22, 2.34 
1.326, 0.613 
0.43, 2.71 
2.534, 1.087 
1.06, 5.61 
 
In conclusion, there are sufficient data on the PK profile of Isradipine IR and CR in nor-
mal volunteers and hypertensive population to support comparable pharmacokinetics. Da-
ta generated from our studies of Isradipine CR in a PD population demonstrate compara-
ble Cmin concentrations compared with studies in normal volunteers supporting the no-
tion that there is no expected difference in PK profile of isradipine in a PD population 
versus a hypertensive population.  
 
In addition, the above data support that isradipine 5 mg twice daily should provide serum 
concentration in the range of the level demonstrated to be neuroprotective in animal 
models. 
 
 
2.4       Epidemiological Data 
 
Isradipine CR 
Dose 
5 mg 
10 mg 
15 mg 
20 mg 
N   
10 
9 
9 
4 
Mean Plasma 
Cmin   
( + SD)  
(ng/mL) 
0.68 
±  
0.38  
1.53 
±  
0.72 
2.53 
±  
1.33 
2.48 
±  
1.16 


 
 
 
 
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Recent epidemiological data also supports potential neuroprotective effect of DCCAs in 
PD: two studies demonstrated reduced risk of development of PD in subjects treated with 
calcium channel blockers (CCBs) compared to other antihypertensive agents[41], [42]. 
Ritz et al[42] assessed risk of the new diagnosis of PD in a cohort of 1,931 patients with 
new diagnosis of PD versus 9,651 matched controls [42]. The study demonstrated a 27% 
risk reduction (OR= 0.73) of a new diagnosis of PD in subjects treated with centrally act-
ing DCCA compounds compared to other CCBs or other antihypertensive agents. That 
study provides strong supporting evidence of channel specific selectivity of potential neu-
roprotective effect of CCBs restricted to DCCA compounds.  A more recent study by 
Pasternak et al[43]  assessed risk of incident PD using the Danish Civil Registration sys-
tem that contain information on all prescriptions filled by all of the country’s  pharma-
cies. The study concluded that use of DCCAs was associated with 29% (RR= 0.71) re-
duced risk of incident PD particularly in the elderly population (> age 65) as well as re-
duced mortality but not dementia. 
 
In conclusion, there is solid scientific rationale, preclinical and epidemiological data to 
proceed with a clinical trial of isradipine, as a potential disease modifying agent in PD. 
 
2.5       Isradipine Side Effect Profile  
 
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 hy-
potension, bradycardia, weakness, and syncope.  The most common adverse effect is pe-
ripheral edema as a result of the vasodilatory effect of the agent. The other known side 
effects include angina, asthenia, flushing, heart failure, palpitations, and dizziness. The 
only absolute contraindications for isradipine are hypersensitivity to dihydropyridine 
compounds and hypotension defined as systolic blood pressure below 90 mm Hg. Table 
4. provides detailed safety and tolerability information on Isradipine IR as found in the 
package insert. 
 
 


 
 
 
 
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Table 4. The most common adverse events reported in US clinical trials for Isradipine IR 
 
Isradipine IR 
Placebo 
Active Con-
trols*  
Adverse  
Event 
All  
Doses 
2.5 mg  
twice-
daily  
5 mg  
twice-
daily†  
10 mg  
twice-
daily††  
(N=297) 
%  
(N=414)  
%  
Headache 
13.7 
12.6 
10.7 
22.0 
14.1 
9.4 
Dizziness 
7.3 
8.0 
5.3 
3.4 
4.4 
8.2 
Edema 
7.2 
3.5 
8.7 
8.5 
3.0 
2.9 
Palpitations 
4.0 
1.0 
4.7 
5.1 
1.4 
1.5 
Fatigue 
3.9 
2.5 
2.0 
8.5 
0.3 
6.3 
Flushing 
2.6 
3.0 
2.0 
5.1 
0.0 
1.2 
Chest pain 
2.4 
2.5 
2.7 
1.7 
2.4 
2.9 
Nausea 
1.8 
1.0 
2.7 
5.1 
1.7 
3.1 
Dyspnea 
1.8 
0.5 
2.7 
3.4 
1.0 
2.2 
Abdominal discom-
fort 
1.7 
0.0 
3.3 
1.7 
1.7 
3.9 
Tachycardia 
1.5 
1.0 
1.3 
3.4 
0.3 
0.5 
Rash 
1.5 
1.5 
2.0 
1.7 
0.3 
0.7 
Pollakiuria 
1.5 
2.0 
1.3 
3.4 
0.0 
<1.0 
Weakness 
1.2 
0.0 
0.7 
0.0 
0.0 
1.2 
Vomiting 
1.1 
1.0 
1.3 
0.0 
0.3 
0.2 
Diarrhea 
1.1 
0.0 
2.7 
3.4 
2.0 
1.9 
* Propranolol, prazosin, hydrochlorothiazide, enalapril, and captopril. 
† Initial dose of 2.5 mg twice-daily followed by maintenance dose of 5.0 mg twice-daily. 
†† Initial dose of 2.5 mg twice-daily followed by sequential titration to 5.0 mg twice-
daily, 7.5 mg twice-daily, and maintenance dose of 10.0 mg twice-daily. 
In open-label, long-term studies of up to 2 years in duration with immediate-release is-
radipine, the adverse events reported were generally the same as those reported in the 
short-term controlled trials. The overall frequencies of these adverse events were slightly 
higher in the long-term than in the controlled studies, but in the controlled studies most 
adverse reactions were mild and transient. 
 
The safety profile of isradipine in the PD population has been explored in two studies.  
 
2.6  
Isradipine in PD Data 
  
We have conducted an Open label dose escalation safety and tolerability study of Is-
radipine CR in patients with early PD [44]. The study enrolled 31 subjects and demon-
strated dose dependent tolerability of Isradipine CR:  94% for a 5 mg dosage; 87% for a 
10 mg dosage; 68% for a 15 mg dosage; and 52% for a 20 mg dosage. Isradipine had no 
significant effect on blood pressure or PD motor disability. The two most common 


 
 
 
 
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reasons for dosage reduction were leg edema (7) and  dizziness (3). There was no 
difference in isradipine tolerability between subjects with and without dopaminergic 
treatment. Conclusion:  That study supports good tolerability of Isradipine CR  at daily 
dosages up to 10 mg in subjects with early PD.   
 
A pilot phase II double-blind, placebo-controlled, tolerability and dosage finding 
study of Isradipine CR as a disease modifying agent in patients with early Parkinson 
Disease (STEADY-PD) [36]. The objective of the study was to establish safety and tol-
erability of Isradipine CR across the FDA approved dosing range (5-20mg) in a larger 
cohort of patients with early PD and to evaluate comparative efficacy of three dosages of 
Isradipine CR provided that they are tolerable. The study recruited subjects with early PD 
not requiring dopaminergic therapy (stable dose of amantadine, anticholinergics and 
MAO-B inhibitors are allowed).  The study was a multicenter 52 weeks, randomized, 4-
arm double-blind parallel group trial with 100 subjects randomized to 5 mg, 10 or 20 mg 
of Isradipine CR or matching placebo daily. The dosage that was most tolerable and 
demonstrated preliminary efficacy was to be used in the proposed pivotal efficacy study. 
Tolerability of each active dosage was compared with the tolerability of placebo. Tolera-
bility threshold was defined as more than 30% difference in the tolerability of each active 
treatment group relative to placebo. Provided that the dosage was tolerable, the choice for 
the dosage selection was to be based on efficacy defined as the change in total UPDRS 
score between the baseline visit and month 12 or the time of sufficient disability to re-
quire  dopaminergic therapy (last visit before subject goes on dopaminergic therapy), 
whichever occurred first. Comparison was made between three active treatment arms. 
Power calculations for comparative efficacy analysis were made based on three point dif-
ference in total UPDRS between the active treatment groups. The dosage that demon-
strated the greatest efficacy would be selected for the pivotal study. The study included a 
prespecified interim analysis for tolerability after 50 subjects had completed 12 weeks of 
the study.  
 
Between September 2009 and October 2010, 115 subjects were screened and 99 enrolled 
in the study. There were 69 males, 30 females, predominantly White non-Hispanic, mean 
age at entry 59 (SD 9.77) years, average 0.95 (+ 0.92) years from diagnosis, with no im-
balances among treatment groups. Mean total UPDRS (Part I-III) at entry was 25.02 
(+9.9), with no significance imbalances. Compliance with the treatment was excellent 
(99.94% (SD 0.43) based on the pill count. 
 
Tolerability of Isradipine CR.  All subjects were included in the tolerability analysis 
based on the intention to treat. A pre-specified interim tolerability data analysis conduct-
ed by the DSMB in July 2010 (without breaking the blind of the investigators) showed 
that the Isradipine CR 20 mg dosage was intolerable. Based on the protocol, newly re-
cruited subjects randomized to the 20 mg group after the results of the interim analysis 
became available were titrated to the 15 mg maximum dose (N=4). There were 8/99 early 
terminations, 5/8 occurred in the 20 mg dosage group with the others equally distributed 
between the groups. Dosage reductions and suspensions had a clear dose-response rela-
tion. In terms of the primary definition of tolerability, completing the study, there was no 
difference between the placebo, 5 mg and 10 mg groups. In terms of the secondary defi-


 
 
 
 
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nition, completing without dosage adjustment (reduction or suspension due to intolerabil-
ity) the numbers were 96% (25/26) for placebo, 83% (19/23) for 5 mg, 73% (19/26) for 
10 mg, 50% (2/4) for 15 mg, and 35% (7/20) for 20 mg dose groups. Based on the above 
data, 5 and 10 mg dosages met pre-specified tolerability parameters.  There was clear ev-
idence of intolerability in the 20 mg group. The size of the 15 mg cohort (N=4) was small 
though also failed the tolerability parameters.  
 
Safety: There were 7 (2 in placebo, 2 in 5mg, 1 in 10 mg, 2 in 20 mg arms) serious ad-
verse events (SAE’s), with scant evidence of any relationship to study drug. AEs affect-
ing in aggregate over 5% of the subjects are presented in Table 5.  
 
 
Table 5. Adverse events occurring in more than 5% of the PD participants:  
Adverse Events  
 
Placebo 
N(%) 
5mg 
N(%) 
10mg 
N(%) 
15mg 
N(%) 
20mg 
N(%) 
Subjects 
PERIPHERAL EDEMA a.All  
1(3.85) 4(17.39) 9(34.62)* 4(100.00)* 12(60.00)* 
30 
b.wo/Mild 1(3.85) 0(0.00) 4(15.38) 1(25.00) 
5(25.00) 
  
DIZZINESS 
a.All 
7(26.92) 5(21.74) 6(23.08) 1(25.00) 
5(25.00) 
24 
b.wo/Mild 2(7.69) 2(8.70) 0(0.00) 
0(0.00) 
0(0.00) 
  
NASOPHARYNGITIS 
 
a.All 
2(7.69) 4(17.39) 7(26.92) 
0(0.00) 
4(20.00) 
17 
b.wo/Mild 2(7.69) 1(4.35) 1(3.85) 
0(0.00) 
0(0.00) 
  
HEADACHE 
 
a.All 
3(11.54) 3(13.04) 6(23.08) 
0(0.00) 
4(20.00) 
16 
b.wo/Mild 1(3.85) 1(4.35) 1(3.85) 
0(0.00) 
0(0.00) 
  
CONSTIPATION 
a.All 
3(11.54) 2(8.70) 3(11.54) 
0(0.00) 
4(20.00) 
12 
b.wo/Mild 0(0.00) 0(0.00) 2(7.69) 
0(0.00) 
1(5.00) 
  
FATIGUE 
 
a.All 
2(7.69) 1(4.35) 3(11.54) 
0(0.00) 
3(15.00) 
9 
b.wo/Mild 1(3.85) 0(0.00) 0(0.00) 
0(0.00) 
0(0.00) 
  
NAUSEA 
 
a.All 
3(11.54) 2(8.70) 1(3.85) 
0(0.00) 
2(10.00) 
8 
b.wo/Mild 2(7.69) 1(4.35) 0(0.00) 
0(0.00) 
0(0.00) 
  
URT INFECTION 
 
a.All 
1(3.85) 2(8.70) 5(19.23) 
0(0.00) 
0(0.00) 
8 
b.wo/Mild 0(0.00) 1(4.35) 0(0.00) 
0(0.00) 
0(0.00) 
  
DEPRESSION 
 
a.All 
2(7.69) 3(13.04) 1(3.85) 
1(25.00) 
1(5.00) 
8 
b.wo/Mild 1(3.85) 1(4.35) 0(0.00) 
0(0.00) 
1(5.00) 
  
SOMNOLENCE 
 
a.All 
2(7.69) 3(13.04) 2(7.69) 
0(0.00) 
0(0.00) 
7 
b.wo/Mild 0(0.00) 2(8.70) 0(0.00) 
0(0.00) 
0(0.00) 
  
INSOMNIA 
 
a.All 
2(7.69) 3(13.04) 1(3.85) 
0(0.00) 
0(0.00) 
7 
b.wo/Mild 0(0.00) 2(8.70) 0(0.00) 
0(0.00) 
1(5.00) 
  
DYSPEPSIA 
 
a.All 
3(11.54) 1(4.35) 1(3.85) 
0(0.00) 
1(5.00) 
6 
DIARRHEA 
 
a.All 
2(7.69) 1(4.35) 2(7.69) 
0(0.00) 
1(5.00) 
6 
b.wo/Mild 1(3.85) 0(0.00) 1(3.85) 
0(0.00) 
0(0.00) 
  
SINUSITIS 
 
a.All 
3(11.54) 2(8.70) 1(3.85) 
0(0.00) 
0(0.00) 
6 
b.wo/Mild 2(7.69) 1(4.35) 0(0.00) 
0(0.00) 
0(0.00) 
  
BACK PAIN 
a.All 
1(3.85) 0(0.00) 2(7.69) 
0(0.00) 
3(15.00) 
6 


 
 
 
 
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b.wo/Mild 1(3.85) 0(0.00) 0(0.00) 
0(0.00) 
2(10.00) 
  
HYPOTENSION 
 
a.All 
1(3.85) 1(4.35) 2(7.69) 
1(25.00) 
1(5.00) 
6 
MUSCLE SPASMS 
 
a.All 
0(0.00) 2(8.70) 1(3.85) 
0(0.00) 
2(10.00) 
5 
b.wo/Mild 0(0.00) 0(0.00) 0(0.00) 
0(0.00) 
1(5.00) 
  
*p< 0.05 
Only peripheral edema showed imbalance between the four groups, with numbers 
1,4,9,16  respectively. The trend persisted when events judged to be mild were eliminated 
(1,0,4,6).  AEs that lead to dosage reduction or suspension included leg edema (N=14), 
dizziness (N=4), combination of two (N=2), and reduction of blood pressure (N=3).  
 
There was no significant impact of the drug on blood pressure readings and no direct as-
sociation of dizziness with the change in blood pressure and other vital signs. Six subjects 
(6%) reported hypotension as an adverse event and two had orthostatic hypotension (1 
placebo, 1 in 20 mg dosage). One subject had rebound hypertension after drug withdraw-
al.  
 
Efficacy: There was no statistically significant difference in the change in UPDRS or 
other variables between the active treatment groups. Adjusted differences in UPDRS be-
tween each active dosage group and placebo were 0.04 (SD 2.0) pts 5 mg, -1.10 (1.97) 
pts 10 mg, -2.00 (2.01) pts 20 mg. Positive signs denote worsening, negative signs im-
provement.  These results suggest a possible trend toward efficacy for the 10 and 20 mg 
dosage. There was no evidence of any difference in the endpoint of disability requiring 
therapy among the four groups 15 (placebo), 14 (5 mg), 14 (10 mg), 11 (20/15 mg). All 
the Kaplan-Meier curves approximate a 50% endpoint rate at the one year.  
 
There was no consistent evidence of a symptomatic effect of isradipine based on the 
wash-in or washout effects. Of note, the placebo group actually fared worst during the 
washout.  
 
In conclusion, these studies demonstrate dose-dependent tolerability of Isradipine CR in 
patients with early PD and establishes 10 mg dosage as the tolerability threshold. Surpris-
ingly, but consistent with the previously completed open label dosage escalation study Is-
radipine CR had no significant impact on blood pressure in our cohort. The safety profile 
of isradipine in the PD population was consistent with the isradipine package insert [45]. 
The most common AE was leg edema which is related to the potent vasodilatory effect of 
CCBs rather than fluid retention [46].  
 
Based on the results of these studies, the 10mg dosage will be the target for the proposed 
pivotal Phase III study of isradipine as a potential disease modifying agent in early PD. 
That dose achieves serum concentration in the range that was neuroprotective in preclini-
cal models of Parkinsonism.   
 
3 
STUDY DESIGN 
 


 
 
 
 
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3.1  
Overview 
The study is designed as a randomized Phase-3, 2-arm, double-blind, parallel group trial 
with subjects randomized to Isradipine IR 5 mg or matching placebo twice daily.  
Primary efficacy analysis will be performed after all subjects complete 36 months on 
their randomized treatment assignment. We expect that nearly all subjects will require 
symptomatic therapy (e.g., levodopa or dopamine agonist) prior to the end of the 36 
months study; if so they will still continue on their randomized treatment assignment in 
conjunction with the symptomatic therapy. In that case the primary statistical analysis 
will be based on UPDRS assessed in the medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic therapy). 
Once a subject starts symptomatic therapy, the ON and OFF assessments should be com-
pleted for all PD medications including dopamine agonists, MAO inhibitors, or any other 
dopaminergic therapies.  
 
3.2  
Study Design Justification  
 
 
PD is a slowly progressive neurodegenerative disease. A majority of the currently con-
ducted studies designed to investigate the efficacy of the potential disease modifying 
agents enroll subjects with newly diagnosed PD not yet requiring symptomatic therapy 
and use the time to initiation of symptomatic therapy as either the primary outcome 
measure or the time to end point. While the limitations of such a design are well-
recognized, it is driven by lack of objective biomarkers of PD progression and obvious 
impact of symptomatic therapy on standard clinical outcome measures. These factors jus-
tify at least initial testing of the putative disease modifying therapy in the cohort of de 
novo subjects. However, on average 50% of the subjects require symptomatic therapy in 
the course of 12 month studies [20].  
 
The current study design (Fig. 2) will collect the primary outcome data on the efficacy of 
the intervention at 36 months with the objective to provide long term information on the 
efficacy, tolerability and safety of isradipine in PD. The collected data will inform us on 
the longer term benefit of Isradipine IR 5 mg twice daily mg on motor disability as meas-
ured by the change in the total UPDRS score between baseline and month 36. We expect 
that nearly all subjects will require symptomatic therapy (e.g. levodopa or dopamine ago-
nist) prior to the end of the 36 months study; if so they will still continue on their ran-
domized treatment assignment in conjunction with the symptomatic therapy and the pri-
mary outcome measure will be UPDRS measured in the medications ON state (see Sec-
tion 8). We also will collect a number of secondary efficacy and safety outcomes even af-
ter the initiation of symptomatic therapy.  This will allow us to explore if any short term 
effects of isradipine are maintained even after symptomatic therapy has been initiated. 
Figure 2 


 
 
 
 
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4 SELECTION AND ENROLLMENT OF SUBJECTS 
 
Approximately three hundred thirty-six (336) subjects with early idiopathic PD who do not 
require dopaminergic therapy will be enrolled.  The inclusion and exclusion criteria are de-
scribed below.  The study is planned as a multi-center study with approximately 56 partici-
pating sites in North America.  See Section 8 for justification of the sample size. 
4.1 
Inclusion Criteria 
1.  Subjects with early idiopathic PD (presence of at least two out of three cardinal manifes-
tations 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 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 
6. Use of amantadine and/or anticholinergics will be allowed provided that the dosage is 
stable for 8 weeks prior to the baseline visit  
7. If subjects is taking any central nervous system acting medications (e.g. benzodiazepines, 
antidepressants, hypnotics) regimen must be on a stable for 30 days prior to the baseline 
visit  
8.  Women of childbearing potential may enroll but must use a reliable measure of contra-
ception and have a negative serum pregnancy test at the screening visit 
 
4.2 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 con-
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4. History of clinically significant orthostatic hypotension or presence of orthostatic hypo-
tension 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 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 abnormali-
ties 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 history of hyper-
tension, 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 car-
diologist. Use of any concomitant calcium channel blockers will not be allowed from the 
baseline visit through  the duration of the study 
12. Use of grapefruit juice, ginkgo biloba, St. John’s wort, or ginseng will be prohibited start-
ing 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 have 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 In-
ventory 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 
 
 


 
 
 
 
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4.3 
Study Enrollment, Recruitment and Retention Procedures  
4.3.1  The study will be conducted at approximately 56 PSG clinical sites in North 
America. Each site employs a PSG-credentialed site Investigator and a Study Co-
ordinator. Each site is required to have individual Institutional Review Board 
(IRB)/Research Ethics Board (REB) approval. All PSG site Investigators are well 
trained and qualified in the administration of the UPDRS and will be required to 
provide certification of training on the MDS-UPDRS. Training sessions will be 
performed at the orientation meeting with special emphasis on the primary out-
come measure. New sites, identified after the orientation meeting, will be trained 
individually. Enrollment will be closed as soon as the 336 subjects have been en-
rolled. The clinical trial will be posted on a number of websites to include: NIH’s 
clinical trials website, Clinicaltrials.gov, and the PSG website. Based on our prior 
experience with clinical trials in PD and the sites’ feedback, we anticipate most 
subjects will be recruited for this trial through the site’s center.  
 
4.3.2 Once a study site has obtained IRB/REB approval, a site can start identifying po-
tential participants for the study.  Subjects that are asked to participate in this trial 
will be tracked on a Confidential Participant Log which is kept by the site study 
staff in a secure location.  In addition information regarding how subjects learned 
about the trial, referral sources, reasons for ineligibility and reasons for non- par-
ticipation for eligible subjects will be tracked on the Screening/Demographics 
form in the eClinical system for all subjects who have signed a consent and are 
screened for the study. 
 
 
4.3.2.1   Subject Randomization /Enrollment 
 
All subjects will be assigned a 4-digit Subject ID Number by the site that is pro-
vided by the Clinical Trials Coordinator Center (CTCC).  Study drug will be pre-
coded by the Clinical Materials Services Unit (CMSU) with Enrollment 
ID/randomization kit numbers (based on the randomization plan generated by the 
University of Rochester Biostatistics Department). Pre-assigned drug kits will be 
supplied to the site Investigator.   
 
 The treatment for each subject will be assigned by a randomized code.  A 
blocked randomization scheme will be used to ensure approximately even dis-
tribution of subjects in treatment groups at each site.   
 Once the subject qualifies for the randomized phase of the study, the site In-
vestigator or Study Coordinator will enter data into the eClinical system that 
will assign a unique Enrollment ID Number that will match a study drug kit.  
These numbers are assigned in a randomized order, rather than sequentially. 
 The randomization algorithm and subject enrollment process will be imple-
mented through the Internet accessible Electronic Data Capture (EDC) system 
using authenticated, password-protected accounts for each study site.  The 


 
 
 
 
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EDC system will automatically validate inclusion/exclusion criteria and gen-
erate visit windows.  
 Once the online enrollment process is completed, the site will print an En-
rollment Verification Report that verifies the subject has been randomized.  
The report will note the Enrollment ID Number that was assigned that corre-
sponds to the drug kit number and the upcoming study visit windows.  If a 
site’s EDC system is not operating, the site may alternatively call the CTCC 
for subject enrollment during designated working hours. 
 Once a subject has been allocated an Enrollment ID Number this number can-
not be assigned to another subject. 
4.3.3 During or before a screening visit, the subject will be thoroughly informed about 
all aspects of the study, including all scheduled visits and activities, and will be 
able to ask questions. The subject will be requested to sign and date the informed 
consent form prior to undergoing any study-specific procedures.  The original 
signed and dated informed consent form must be retained by the Investigator in 
the subject’s file and a copy must be provided to the subject. 
4.3.4 Identification Numbers  
 
4.3.4.1 
Subject Identification (ID) Numbers 
Once a potential subject has signed informed consent, a Subject ID 
Number will be assigned in sequential order by the site from a list 
provided to the site by the CTCC.  This 4-digit number will be 
used to identify the subject on all study forms and lab specimens. 
 
4.3.4.2  
Randomization/Enrollment Identification (ID) Number 
An Enrollment ID Number will be assigned by the eClinical sys-
tem at the randomization visit to confirm enrollment and proper re-
ceipt of the randomized study drug assignment.   The Enrollment 
ID Number will be the same as the randomization/drug kit number 
on the study drug container. 
 
4.3.4.3  
CTCC Unique Identification (ID) Number 
Subjects will be instructed how to obtain a 9-digit Unique Identifi-
cation Number at the Screening Visit.  This ID system has the abil-
ity to track individual subjects across multiple CTCC studies with-
out storing any personally identifiable information.  The protected 
system uses an algorithm of nine data element inputs (last name at 
birth, first name at birth, gender at birth, day, month and year of 
birth, city and country of birth, and mother’s maiden name), and 
produces an electronic “fingerprint” output.  The system stores on-
ly the “fingerprint” and clears the individual’s inputted data ele-
ments from memory.  The subject is then assigned a 9-digit CTCC 


 
 
 
 
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Unique ID Number that is associated with their electronic “finger-
print.”   
 
Once a subject signs the informed consent he/she will be directed 
to a secure website where he/she or the site Study Coordinator (if 
the subject requests/prefers) will enter the subject’s nine data ele-
ments.  The CTCC Unique ID Number will be printed and provid-
ed to the subject.  The Study Coordinator will record this number 
on the Demographics Case Report Form (CRF).  
 
If a subject has participated in previous CTCC studies and already 
has an existing CTCC Unique ID Number, this number will be 
used for this study.  A subject can regenerate his/her CTCC Unique 
ID Number. He/She can return to the secure website, enter the 
same nine data elements in the exact same way they were entered 
the first time and will receive their same CTCC Unique ID Num-
ber. 
 
 4.4 
Strategies for Retention 
 
Multiple retention initiatives will be rolled-out to sites intermittently throughout the study 
to enhance subject retention and to provide various avenues for communication with sites 
and subjects. Since study visits occur at 6-month intervals after Month 12 (Visit 06), re-
tention strategies will be key to minimizing subject withdrawals. Visit reminders and in-
centives for visit attendance and protocol adherence may include pocket/wallet reminder 
cards, birthday cards, holiday cards, backpacks, lunch boxes, luggage tags, refrigerator 
reminder magnets and subject newsletters.  
 
In addition, a third-party moderator facilitated webinar between study subjects and study 
investigators, is planned, which will provide study updates and emphasize the importance 
of subject retention.  All meeting materials will be IRB approved prior to implementa-
tion. Study subjects will be able to ask questions of investigators through a moderator in 
order to minimize providing information to study subjects that could compromise the sci-
entific integrity of the study. 
 
5 
STUDY INTERVENTIONS 
5.1  
Study Drug Administration and Duration 
The study will use Isradipine IR 2.5 mg oral capsules and matching placebo. Subjects 
will administer either isradipine or placebo capsules twice daily for 36 months. 
 
 


 
 
 
 
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5.2. 
Study Drug Management 
 
 
5.2.1 Packaging 
 
Study drug [Isradipine IR 2.5mg] will be purchased from the manufacturer. To 
maintain the blind, study drug will be over encapsulated and Placebo to Match 
(PTM) capsules will be manufactured and packaged into its primary container 
closure system. A total of 130 capsules of 2.5 mg active Isradipine IR or PTM 
(0mg Isradipine) will be packaged in each bottle. Each bottle will provide 32 
days (1 month) supply of the study drug that will be administered as 2X 2.5 
mg capsules twice daily.  
 
The Clinical Materials Services Unit (CMSU) in the Center of Human Experi-
mental Therapeutics (CHET) at the University of Rochester will provide second-
ary packaging, labeling and distribution services. CMSU will create identically 
matching 6 month kit boxes containing six (6) 130 capsule count bottles per kit 
box. Each subject is expected to receive six (6), six (6) month kits for this 3 year 
study. 
 
In order to prepare subject study drug kits, CMSU will receive the randomization 
codes and attendant study drug assignment from the Biostatistician at the Univer-
sity of Rochester. 
 
5.2.2 Labeling 
At a minimum the following information will be included on each six (6) month 
kit box and each bottle:  
 Name and address of distribution center 
 Study number/Acronym 
 Name of the product 
 Pharmaceutical dosage form 
 Route of administration 
 Quantity of dosage unit 
 Directions for use 
 Storage conditions 
 Space for information to be completed by Investigator/designee: 
 Name and telephone number of Investigator 
 Dispensing Date 
 Subject Number 
 Statement “Caution: New Drug – Limited by law to investigational (clini-
cal trial) use” 
 Statement: “Keep out of reach of children” 
 
Labeling will be in both English and French-Canadian text. 
 
 
5.2.3 Storage 
All drug supplies should be stored at controlled room temperature, 20-35C (68-
77F). The study drug must also be stored in a secure location with limited access. 


 
 
 
 
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5.2.4 Accountability of Study Drug Supplies 
Study drug will be shipped from CMSU to each participating site. Sites will be 
required to acknowledge receipt of study drug within 48 hours of receiving a 
shipment.  The site Investigator, Study Coordinator, or Pharmacist must maintain 
accurate records (including dates) of all supplies received.  All study drug sup-
plies issued to, used by, and returned by each subject must be recorded on a Drug 
Dispensing/Return Log completed by the Investigator, Study Coordinator, or 
Pharmacist.  Subjects will return all unused study drug, including empty bottles to 
the site Investigator.  After reconciliation, and CTCC written approval, all remain-
ing study supplies (opened and unopened) including empty bottles may be de-
stroyed at the investigational site per site institutional policy.  
 
 
5.2.5  Coding/Emergency Drug Disclosure 
The Investigator or site Pharmacist (if applicable) will be given a sealed envelope 
containing a set of individual sealed envelopes, each containing the drug code for 
each subject. All sealed code envelopes will be returned to the University of 
Rochester Biostatistics Center at the conclusion of the study, where they will be 
inspected to ensure that they have not been opened.  An individual subject’s enve-
lope or label should be opened only in the case of a medical emergency.  If such 
action is required, the CTCC Clinical Monitor must be notified first, if circum-
stances permit, rather than disclosing the randomization.  If a drug disclosure is 
made, a record must be made by the Investigator/Pharmacist detailing the pur-
pose, date and personnel involved. 
 
Neither premature withdrawal from the study nor most clinical emergencies ne-
cessitate disclosure of treatment assignment.  Most emergency situations can be 
handled by withdrawing study drug without disclosure of treatment assignment.  
However, in rare circumstances under which knowledge of the drug assignment is 
necessary for the treatment of an adverse event, site Investigators must make eve-
ry attempt to discuss the situation with the CTCC Clinical Monitor before decid-
ing whether or not to disclose treatment assignment.  If disclosure of individual 
treatment assignment is undertaken it must be made by the Investigator responsi-
ble for the care of the involved subject (or by the Coordinator or other physician 
as designated by the Investigator).  The subject will be withdrawn from further 
exposure to study drug. In accordance with the intent-to-treat principle these sub-
jects will be encouraged to remain in the study and every attempt will be made to 
continue to follow them and obtain the primary outcome data. 
 
The disclosure envelope/label and contents should be sent to the University of 
Rochester Biostatistics Center within 48 hours of the disclosure. Assigned drug 
treatment must not be revealed to other study staff, CTCC staff or to individuals 
who are not involved directly in the clinical care of the subject unless disclosure 
to him/her is critical to the care of the subject. See Section 4 of the Operations 
Manual for additional information and instructions. 
 


 
 
 
 
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5.2.6 Dosage of Study Drug 
Subjects will initiate study drug at a dosage of 2.5 mg twice daily or matching 
placebo (1 capsule twice daily) and titrate to 5 mg twice daily or matching place-
bo (2 capsules twice daily) after the first 2 weeks.  Study drug must be taken 
twice daily approximately 12 hours apart with or without food. Subjects must re-
main on 5 mg daily dosage level a minimum of 14 days prior to upward titration 
to 10 mg daily dosage (2 capsules twice daily).  Titration period may be extended 
if a dosage escalation is delayed due to a need to reduce a concomitant antihyper-
tensive agent as a result of orthostatic hypotension (see Rules for Study Drug Ti-
tration below).  
 
In addition, random dose adjustments may be done in both study groups (active or 
placebo) using an algorithm devised by the Biostatistician at the University of 
Rochester in order to preserve the study blinding. All subjects have to enter the 
maintenance phase no later than at Visit 03 (Month 3). Dosage reductions will be 
allowed for intolerability (see Section 5.4). 
 
 
5.2.7  Study Drug Titration 
 
 
           Blood Pressure Monitoring: 
 
1. All subjects will require home blood pressure monitoring for at least 7 days 
prior to baseline. Blood pressure monitoring continues during dose titration.    
2. Using a home digital blood pressure device, subjects will obtain blood pres-
sure readings at home twice daily in the morning and in the evening, approxi-
mately 12 hours apart. The blood pressure readings will be obtained in a sit-
ting position and after 2 minutes in a standing position. Blood pressure record-
ings will be uploaded via internet access in real time to the BP Vendor. Dur-
ing drug escalation or de-escalation, site investigators and study staff will be 
blinded to home blood pressure recordings unless unblinding is warranted for 
subject safety. Home blood pressure recordings will be monitored remotely by 
an assigned BP Clinical Monitor who will have acess to the BP vendor web-
based database. The BP Clinical Monitor will communicate with the Site In-
vestigator if needed to discuss drug titration management.  
3. During drug titration, the BP Clinical Monitor will have access to the BP 
Vendor database and will assess home blood pressures out of range to include 
Systolic Blood Pressure less than 90 mmHg or greater than 160 mmHg and 
Diastolic Blood Pressure less than 60mmHg or greater than 90 mmHg. 
4. Site Investigators and Coordinators will have limited access to the BP vendor 
web-based blood pressure database, in order to maintain the blind, and will be 
required to access the database prior to the Baseline visit and for each visit 
during drug titration to confirm titration can continue.  The database will pro-
vide site staff with a confirmation notice to state that titration can proceed or 
cannot proceed. The Site Investigator and Coordinator will not be able to view 
BP data on the vendor website.  See Section 13 of the operations manual for 
additional information on the site staff access to the website. Random delays 


 
 
 
 
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in dose titration may be done in both study groups (active or placebo) at the 
direction of the Biostatistician at the University of Rochester in order to pre-
serve the study blinding. 
5. For subjects where the BP vendor confirmation message states drug titration 
may proceed, confirmation of in-person blood pressure readings must also 
meet titration requirements as outlined in “Rules for Study Drug Titration” be-
low. 
6. For subjects where titration cannot proceed, the Site Investigator may contact 
the Clinical Monitor to obtain information on additional BP data, if needed.  
The CTCC Project Manager should be notified within 24 hours of any reduc-
tion or suspension of drug titration. See Section 7 of the Operations Manual 
for guidance on reporting requirements. 
 
Rules for Study Drug Titration: 
 
1. The average home blood pressure readings and in-person blood pressure (BP) 
readings must meet pre-specified criteria (see Section 4 and Section 13 of Op-
erations Manual) and the subjects should not have orthostatic BP changes to 
proceed with randomization. Orthostatic changes are defined as:  greater 
than 20 mmHg drop in systolic BP AND greater than or equal to 10 
mmHg drop in diastolic BP from sitting to after 2 minutes of standing.   
Site staff may repeat blood pressure readings after 20 minutes if the initial in-
person blood pressure does not meet the required criteria. 
2.  Dosage escalation can only take place at or after an in-person visit (either reg-
ularly scheduled or unscheduled depending on the timing of the dosage esca-
lation) provided the Investigator receives a confirmation notice to proceed 
from the BP vendor website and the in-person BP readings meet the pre-
specified criteria. 
3. During the titration period the subject must escalate no sooner than every 14 
days (see titration instructions below).  If the subject is seen prior to 14 days 
(out of the window at V01 or 14 days after last titration) the subject must 
complete a full 14 days of treatment before going to the next dosage level.   
4. Dosage reductions can occur for intolerance to study drug for any reason at 
any time during the study (see Section 5.4). 
5. Resuming dose titration (re-challenges) will be allowed at any time during the 
study at the discretion of the Investigator. In general, the Investigator should 
limit re-challenges to no more than two attempts per subject unless the Inves-
tigator has a specific reason for doing so (change in subjects concomitant an-
tihypertensive, new AE being addressed etc.). 
6.  For the subjects treated with antihypertensive agents whose average BP 
does not meet the pre-specified criteria (see Section 4 of the Operations Man-
ual) the dosage of concomitant antihypertensive agent can be reduced after 
consultation with the primary care provider (PCP) or cardiologist. This con-
sultation must be clearly documented in the source documents.  Further reduc-
tion of the dosage of antihypertensive agent will be allowed if necessary. The 
dosage of the study drug should not be increased for at least a week after ad-


 
 
 
 
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justment of the concomitant antihypertensive dose and only after the Investi-
gator receives a confirmation notice to proceed from the BP vendor website 
and the in-person BP readings meet the pre-specified criteria..  Further study 
drug dosage escalation should follow the standard titration schedule as dis-
cussed below in section 5.2.7, with increases no sooner than every 14 days. 
7. During the maintenance phase, the dosage of concomitant antihypertensive 
agent can be reduced at any point in the study after consultation with the pri-
mary care provider or cardiologist. This consultation must be clearly docu-
mented in the source documents. For hypotensive symptoms, the dosage of 
the concomitant antihypertensive agent should be reduced prior to considering 
a reduction of the dosage of the study drug. 
8. The study drug must ALWAYS be taken twice daily unless a subject re-
quires dosage reduction to 2.5 mg once daily due to intolerability (see Sec-
tion 5.4).    
9. If dosing has not occurred for 4 hours or more from scheduled dosing time, 
the missed dose should be skipped. 
 
5.3.  
Study Visit Instructions 
 
The Visit Status case report form is required for each study visit and telephone contact 
whether or not the visit or call was actually performed. This form documents whether or 
not the visit took place and the reasons why if it didn’t. It also serves as a reminder to up-
date the AE Log, Concomitant Medication Log, Dose Management Log, and the Drug  
Dispense and Return Log, if needed.  
 
Baseline Visit (Day 0) Instructions: 
Drug randomization will occur at the Baseline visit after review of all inclusion/exclusion 
criteria, receipt of confirmation from the BP vendor website to proceed and the in-person 
BP readings meet criteria for dosage escalation and review of vital signs obtained at the 
site visit.  After entering data into the eClinical system, the site will be given a Randomi-
zation/Enrollment ID number that will correspond to a drug kit.  Record this number on 
the drug dispensing/return log.  Dispense only Bottle 1 from the kit that has been as-
signed during the randomization process.  The subject who meets BP criteria at the Base-
line visit should be instructed to take one capsule from Bottle 1, twice daily (with or 
without food) in the morning after recording their morning blood pressure, and in the 
evening (approximately 12 hours after the morning dose) after recording their evening 
blood pressure.  The subject should continue to take the study drug, unless intolerable 
side effects develop, until they are seen for Visit 01.  Advise the subject to report any side 
effects and changes in medication immediately to study staff.   
 
In case of intolerability, the dosage of study drug should be reduced until intolerability 
resolves or the subject is off the study drug (see Section 4 of Ops Manual). Subjects who 
are unable to tolerate even the lowest dosage of study drug should be encouraged to re-
main in the study off the study drug.   
 


 
 
 
 
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For intolerability, dosage reduction should be attempted prior to discontinuing study drug 
(see Section 5.4). Instructions for dosage reduction can be given either over the phone af-
ter review of the adverse events or at the corresponding in-person visit (either regularly 
scheduled or unscheduled visit depending on the timing of the dosage reduction). For in-
dividuals on concomitant anti-hypertensive medication with adverse events referable to 
hypotension, reduction in the anti-hypertensive agent should be undertaken first (see Sec-
tion 5.2.7 #7 above). Resumption of titration should happen at least a week later only at 
or after the in-person visit (either regularly scheduled or unscheduled visit depending on 
the timing of the dosage escalation) and after the Investigator receives the confirmation 
notice to proceed from the BP vendor website and the in-person BP readings meet criteria 
for dosage escalation. Subjects may resume titration to 5 mg twice daily dosage (2 cap-
sules twice daily) at the discretion of the site Investigator provided blood pressure param-
eters are stable and the other intolerability issues have resolved (see Section 5.5 for re-
challenge directions). 
 
Visit 01 (Day 14/ + 3 days) Instructions: 
After the Investigator receives the confirmation notice from the BP vendor website to 
proceed and the in-person BP readings meet criteria for dosage escalation., the subject 
should be instructed to begin taking two capsules twice daily from Bottle 1 no sooner 
than day 15.  Study drug is taken twice daily (with or without food) in the morning after 
recording their morning blood pressure and in the evening (approximately 12 hours after 
the morning dose) after recording their evening blood pressure. The subject should con-
tinue to take the study drug, unless intolerable side effects develop, until they are seen for 
Visit 02. Advise the subject to report any side effects or changes in medication immedi-
ately to study staff.  In case of intolerability, dosage reduction should be attempted prior 
to discontinuing study drug (see Section 5.4 for dose reduction instruction).  For individ-
uals on concomitant anti-hypertensive medication with adverse events referable to hypo-
tension, reduction in the anti-hypertensive agent should be undertaken first (see 5.2.7 #7 
above).  
 
Visit 02 (Day 28 /+ 3 days) Instructions: 
After the Investigator receives the confirmation notice from the BP vendor website to 
proceed and the in-person BP readings meet criteria for dosage escalation., the subject 
should be instructed to continue taking two capsules twice daily (unless a dosage re-
duction has taken place).  Subjects will be provided with 6 months study drug kits con-
taining the remaining 5 one-month supply bottles.  Study drug is taken 2 capsules twice 
daily (with or without food) in the morning and in the evening, approximately 12 hours 
after their morning dose. The subject should continue to take the study drug, unless side 
effects develop, until they are seen for Visit 03. Subjects should be instructed to use all of 
the capsules in one bottle before opening the next bottle of study drug. Advise the subject 
to report any side effects or changes in medication immediately to study staff.  In case of 
intolerability, dosage reductions should be attempted prior to discontinuing study drug. 
For individuals on concomitant anti-hypertensive medication with adverse events refera-
ble to hypotension, reduction in the anti-hypertensive agent should be undertaken first 
(see Section 5.2.7 #7). Instructions for dosage reduction and re-challenges are per the 
Section 5.3.  


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STEADY-PD III Protocol 
 
Version 6.0B dated 31August2016 
 
Confidential 
Page 46 of 99 
 
radipine 
IR 
related 
adverse 
events 
is 
available 
at: 
http://www.drugs.com/pro/isradipine.html. The safety profile of Isradipine IR 
in the PD population has not been systematically studied (see Section 2.5 for 
information on the side effect profile). 
 
 Isradipine serum concentration can be increased by the compounds that block 
P-450 CYP 3A4 enzyme. Examples of inhibitors of CYP 3A4 include 
conivaptan, amiodarone, anti-retroviral protease inhibitors, systemic anti-
fungals, and other agents (see list in Operations Manual). Use of these com-
pounds is allowed but the subjects should be monitored for potential adverse 
events related to increase in the drug serum concentration. Grapefruit juice, 
ginkgo biloba, ginseng are CYP3A4 inhibitors and are prohibited in this 
study.  
 Use of clarithromycin, telithromycin and erythromycin will be prohibited start-
ing from the screening visit and for the duration of the study as concomitant 
use of clarithromycin, telithromycin or erythromycin with calcium channel 
blockers has been reported to be associated with increased risk of kidney and 
heart injury. 
  
 Isradipine serum concentration can be reduced by the compounds that induce 
P-450 CYP 3A4 enzyme (see list in Operations Manual). St. John’s wort is 
CYP 3A4 inducer and will be prohibited in this study.  
 Calcium channel blockers including isradipine should be used cautiously in pa-
tients with gastroesophageal reflux (GERD) or hiatal hernia as these agents re-
lax esophageal sphincter. 
 Female subjects of childbearing potential will be advised to use adequate birth 
control throughout the study as the effects of Isradipine IR on the fetus are un-
known. Adequate birth control methods include surgical sterilization, a partner 
who has had a vasectomy, oral contraceptives, condom plus spermicidal 
cream/jelly, cervical cap plus spermicidal cream/jelly, diaphragm plus spermi-
cidal cream/jelly, or intrauterine device (in place for at least 3 months) plus 
spermicidal cream/jelly.  Abstinence is considered an acceptable contraceptive 
regimen.  Birth control should continue for two weeks after study drug has 
been discontinued. 
If a subject becomes pregnant during the study, it is important that they contact 
the site Investigator immediately.  If a subject reports a pregnancy, study drug 
must be tapered immediately.  Any subject becoming pregnant during the 
study will be tapered from the study drug immediately and can continue to 
participate in the study off of study drug. In addition, all attempts will be 
made to follow the subject until delivery.  The pregnancy must be reported 
immediately to the CTCC.  
 The only absolute contraindications for Isradipine IR are hypersensitivity to 
dihydropyridine compounds and hypotension defined as systolic blood pres-
sure below 90 mm Hg. 


 
 
 
 
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 Isradipine IR should be used with caution in subjects with bradycardia. Sub-
jects with clinically significant bradycardia (as determined by Investigator) will 
be excluded from the study. 
 
 Calcium channel blockers, including isradipine, have been shown to have 
negative inotropic effect on cardiac functions and may therefore exacerbate 
heart failure in patients with reduced left ventricular systolic function, regard-
less of current symptoms. 
 
Per the Physician’s Desk Reference 2012 Warnings/Precautions: “Although 
acute hemo-dynamic studies in patients with congestive heart failure have 
shown that immediate-release DynaCirc® (isradipine) reduced afterload with-
out impairing myocardial contractility, it has negative inotropic effect at high 
doses in vitro and possibly in some patients. Caution should be exercised 
when using Isradipine IR in congestive heart failure patients, particularly 
in combination with a beta-blocker.”  
 
Investigators are encouraged to exercise caution when enrolling subjects with a 
history of myocardial infarction with a subsequent reduced ejection fraction or 
those with a documented reduction (less than 40%) in their ejection fraction or 
concomitant beta-blockers. 
5. 7  
Concomitant Medications 
 
 
5.7.1  
Allowed Concomitant Medications 
 
Subjects with history of hypertension treated with no more than 2 other antihypertensive 
agents except for calcium channel blocking antihypertensive agents (see list in Section 2 
of the Operations Manual) will be allowed provided that the dosages of concomitant anti 
hypertensive therapy can be reduced/adjusted during the study based on the BP readings 
in consultation with the subjects primary care provider or cardiologist. Procedures for the 
adjustment of the concomitant antihypertensive therapy are outlined in section 5.2. 
 
Use of amantadine, or anticholinergics will be allowed. The dosage has to be stable for 8 
weeks prior to baseline visit and for the duration of the study if feasible.  Initiation or an 
increase in dosage of these medications or the initiation of dopaminergic therapy during 
the study will result in the subject reaching time for symptomatic treatment and all as-
sessments as described in the symptomatic treatment visit will need to be completed. Any 
change in the dosage of these medications will require CTCC notification.  
 
A stable regimen of central nervous system acting medications (benzodiazepines, antide-
pressants, hypnotics) is allowed. The dosage has to be stable for 30 days prior to the base-
line visit. The dosage can be adjusted during the study at the discretion of the Investiga-
tor.  Central nervous system acting medications can be initiated during the study, if need-
ed, at the discretion of the Investigator. 
 


 
 
 
 
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5.7.2 Disallowed Medications 
 
The following medications are not allowed during subject participation in the study: 
 
 Use of calcium channel blockers (see list in Section 2 of the Operations Manual).  
 Use of antipsychotics or other dopamine blocking agents within 6 months of the base-
line visit and for the duration of the study. Only the atypical neuroleptics, clozapine 
and quetiapine, will be allowed during the study at the discretion of the Investigator. 
 Use of grapefruit juice, ginkgo biloba, St. John’s wort or ginseng (as they interfere 
with the metabolism of isradipine) starting from the screening visit and for the dura-
tion of the study.  
 Use of clarithromycin, telithromycin and erythromycin will be prohibited starting 
from the screening visit and for the duration of the study as concomitant use of clar-
ithromycin, telithromycin or erythromycin and calcium channel blockers has been re-
ported to be associated with increased risk of kidney and heart injury.  If antibiotic 
treatment is required, use of antibiotics other than clarithromycin, telithromycin or 
erythromycin is recommended.  If clarithromycin, telithromycin or erythromycin 
treatment is required, study drug should be stopped through the duration of treatment 
and restarted after treatment per the re-titration rules above (see Section 5.3). 
Fentanyl anesthesia use has been associated with hypotension with concomitant use 
of calcium channel blockers and should be avoided if possible.  
If any disallowed medications are required and cannot be discontinued, study 
drug should be stopped and the subject should continue to be followed in the 
study off of study drug. Once a disallowed medication is stopped, the subject 
should be restarted on study treatment per the re-titration rules above (see Sec-
tion 5.3). 
5. 8 
 Adherence Assessment 
 
AT EACH STUDY VISIT, THE SITE INVESTIGATOR AND/OR STUDY COORDINATOR 
WILL ASSESS THE SUBJECT’S ADHERENCE WITH THE STUDY REQUIREMENTS.  
THIS WILL INCLUDE CHECKS OF PROTOCOL COMPLIANCE, CONCOMITANT MEDI-
CATION USE, BLOOD PRESSURE RECORDS, AND USE OF STUDY DRUG IN ORDER 
TO ASSESS THE RELIABILITY OF SUBJECT-GENERATED DATA.  USE OF STUDY 
DRUG (PILL COUNTS) WILL BE ASSESSED AT VISIT 01 AND EVERY SCHEDULED 
DRUG RETURN VISIT THEREAFTER. IN EXTREME CIRCUMSTANCES SUBJECTS 
WHO CONSISTENTLY FAIL TO COMPLY WITH THE STUDY REQUIREMENTS MAY 
BE WITHDRAWN FROM THE STUDY. 6 CLINICAL AND LABORATORY EVALUA-
TIONS 
 
6.1  
Schedule of Activities (see page 17) 
 
6.2  
Timing of Evaluations 
 
6.2.1  Screening Visit (Visit SC) 


 
 
 
 
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The Screening Visit will take place within 8 to 30 days of the Baseline Visit.   
 
Prior to performing any study activity, the subject will be thoroughly informed on all as-
pects of the study, including all scheduled visits, activities, and procedures, and will be 
requested to sign and date the IRB/REB approved informed consent form.  Subjects who 
have signed an informed consent form will be assigned a subject ID number. A 9-digit 
CTCC Unique Identification Number will also be assigned if the subject consents for the 
use of 9 pieces of information required to obtain the CTCC Unique Identification Num-
ber for use in future research 
 
The Investigator will assess subjects for study eligibility. All the inclusion criteria must 
be met and none of the exclusion criteria may apply unless the site is given a waiver (ex-
ception) by the study PI or designee for particular criteria. See Section 3 of the Opera-
tions Manual for additional information and instructions on the requirements for waivers. 
All results from the Screening Visit procedures must be available before determining a 
subject’s eligibility for the study.   
 
Procedures & Evaluations 
 Obtain written informed consent 
 Request the name of the subject’s primary care provider and cardiologist, if applica-
ble 
 Subject ID Number assigned 
 Obtain a 9-digit CTCC Unique Identification Number, if subject agreed to in In-
formed Consent form 
 Inclusion/Exclusion criteria 
 Demographics 
 Document PD diagnosis date and PD Features 
 Assess primary diagnosis/probability of PD 
 Assess socio-economic status 
 Assess family history of PD 
 Medical  and Neuro History (General) 
 General Neurological Exam 
 General Physical Exam 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Beck Depression Inventory-II (BDI-II) 
 Montreal Cognitive Assessment Scale (MoCA) 


 
 
 
 
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 Vital Signs (blood pressure, heart rate, temperature, weight, height) 
 Safety Laboratory tests (serum chemistry, hematology, urinalysis) 
 Collect blood sample for DNA and Biomarker, if subject agreed in consent form  
 PK plasma sample  
 Plasma sample for storage for future potential biomarker studies (only for subjects 
who consent for biomarker sampling)  
 Serum pregnancy test – Complete for all women unless they are one year postmeno-
pausal or surgically sterile 
 Electrocardiogram (12-lead ECG) 
 Assess Need for Symptomatic Therapy  
 Modified Hoehn & Yahr Scale 
 Training on Home Blood Pressure Monitoring  
Instruct subjects: Subjects should be instructed how to use the home digital blood pres-
sure monitoring device. Subjects' proficiency on using the device should be tested in the 
office by confirmation they are able to follow the written instructions provided. Subjects 
should be instructed to obtain blood pressures twice daily, in the morning and at bedtime, 
approximately 12 hours apart. A minimum of 7 complete days of blood pressure data 
must be available for the generation of a may proceed confirmation from the BP vendor 
website at the Baseline visit. 
Subjects should be instructed to immediately report any adverse events or changes in 
concomitant medications to the site Investigator or Coordinator. 
Record all above activities in source documentation, including the process of obtaining 
the informed consent. 
6.2.2.   Baseline Visit (Visit BL, Day 0) 
 
The Baseline Visit must be within 8 to 30 days of the Screening Visit. All laboratory re-
sults, including blood work and ECG must be reviewed prior to the Baseline visit. A min-
imum of 7 complete days of blood pressure data must be available for the generation of a 
proceed confirmation from the BP vendor website. 
 
Subjects will be randomized to one of the two treatment groups according to a computer-
generated randomization scheme and will be assigned an Enrollment ID number.  Sub-
jects will be provided with study drug labeled with the same Enrollment ID number.  
 
Procedures & Evaluations 
 Review Inclusion/Exclusion criteria to ensure subject is eligible 
 Review laboratory results from Screening Visit 
 Review ECG 


 
 
 
 
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 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Generate a proceed or not proceed confirmation from BP vendor website 
 Modified Rankin Scale  
 PD Quality of Life Scale (PDQ-39)  
 Quality of Life in Neurological Diseases (Neuro-QOL) 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III the motor portion 
of the UPDRS must be completed by the Investigator at each visit. 
 Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS)  
 Assess Need for Symptomatic Therapy 
 Modified Hoehn & Yahr Scale 
 Modified Schwab & England Activities of Daily Living 
 Mini Environmental Risk Questionnaire (MERQ) 
 Exercise Questionnaire 
 Randomization/Enrollment ID Number assignment once all eligibility criteria are met 
 Study Drug Dispensing – begin titration of study drug (see Section 5.2.7) 
 Drug Dispensing/Return Log 
 Dose Management Log 
 Adverse Event Log – see Section 9.4. 
 Instructions on blood pressure recording  
Administration of study drug: The first dose of study drug is to be taken the next day in 
the morning (see Section 5.2, Study Drug)  
Compliance and study drug storage requirements: subjects to bring study drug bottles at 
each visit (whether or not empty), and store study drug at proper temperature. 
Instruct subjects: Subjects should be instructed to take their blood pressure twice daily, in 
the morning and in the evening, approximately 12 hours apart, BEFORE taking study 
drug.  
Subjects should be instructed to immediately report any adverse events or changes in 
medication to the site Investigator or Coordinator.  
Record all above activities in source documentation. 
 
6.2.3  Visit 01 (Day 14 +3 days) and Visit 02 (Day 28 + 3 days)  


 
 
 
 
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During the titration period, Visits 01-02, visits can occur within a three-day window (+ 
3).  Whenever possible, subjects should not be seen prior to the target date. 
 
For subjects who require reduction of antihypertensive medication, an additional 
Unscheduled visit may be scheduled to complete the titration. This visit should be 
scheduled at least 7 days following the reduction of the concomitant antihyperten-
sive agent (see Section 5.2.7 for instructions on dose titration) and should include all 
procedures performed at Visit 1. Titration schedule has to be completed by Visit 03 
(Month 3) when all subjects enter the Maintenance Phase.   
 
 
 
 
Procedures & Evaluations: 
 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II and III.   Only com-
plete UPDRS Part IV if symptomatic therapy has been initiated. 
 Assess Need for Symptomatic Therapy (completed only if subject has not reached 
need for symptomatic therapy) 
 Modified Hoehn & Yahr Scale  
 Modified Schwab & and England Activities of Daily Living 
 Dispense and Titrate study drug (Visit 02 ONLY; see Section 5.2.7) 
 Dose Management Log  
 Adherence Assessments (see Section 6.3.13) 
 Drug Dispensing/Return Log (pill counts)  
 Adverse Event Log 
 Instructions on blood pressure recording (Visits 01, 02 only)  Generate a proceed or 
not proceed confirmation from BP vendor website** 
 
**Home blood pressure monitoring can be extended longer at the discretion of the 
Investigator or following a may not proceed notification from the BP vendor website.   
Subjects should be instructed to immediately report any adverse events or changes in 
medication to the site Investigator or Coordinator. 
 
Record all above activities in source documentation. 
 
6.2.4 Visit 03 (Month 3 +/- 7 days), Visit 04 (Month 6 +/- 7 days), Visit 05 (Month 9 
+/- 7 days), Visit 07 ( Month 18 +/- 7days) and Visit 09 ( Month 30 +/- 7 days) 
Procedures & Evaluations: 


 
 
 
 
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 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II and III.  Only com-
plete UPDRS Part IV if symptomatic therapy has been initiated. 
Assess Need for symptomatic therapy (completed only if subject has not reached need 
for symptomatic therapy).  
Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py). Subjects should be instructed NOT to take their PD medications at home on the 
morning of the study visit. Subjects should be instructed to bring their PD medication 
to the study visit. Medication should be taken after completion of UPDRS OFF exam.  
UPDRS Parts 1 and 2 are to be completed in the ON state. Once a subject starts 
symptomatic therapy, the ON and OFF assessments should be completed for all PD 
medications including dopamine agonists, MAO inhibitors, or any other dopaminer-
gic therapies. 
 Modified Hoehn & Yahr Scale  
 Modified Schwab & and England Activities of Daily Living  
 
 Adherence Assessments (see Section 6.3.13) 
 Dispense Study Drug (Visits 04, 07 and 09 Only) 
 Dose Management Log  
 Drug Dispensing/Return Log (pill counts)  
 Adverse Event Log 
Plasma PK sample will be collected at Visit 03 (Month 3 +/- 7 days) and Visit 04 (Month 
6 +/- 7 days)   
 Visit should be scheduled in AM as close to 12 hours post evening dose of the study 
drug  
 Subjects should be instructed NOT to take their study drug at home on the morning of 
the study visit. 
 Time of the last dose of the study drug should be documented  
 Plasma PK sample should be collected (samples should be collected as close to 12 
hours post dose as possible) and time of sample collection should be documented 
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 Repeat PK  sample should be collected 2-3 hours post dose  
 Time of the last dose of the study drug should be documented  
 Time of all samples collection should be documented  
 
 Plasma PK sample will be collected at Visit 04 (Month 6 +/- 7 days),  
 Visit should be scheduled to occur within 4-8 hours post morning dose of the 
study drug  
 Subjects should be instructed to take their study drug at home on the morning of the 
study visit 
 Time of the last dose of the study drug should be documented  
 Time of the samples collection should be documented  
Subjects should be instructed to immediately report any adverse events or changes in 
medications to the site Investigator or Coordinator. 
 
Record all above activities in source documentation. 
 
6.2.5    Visit 06 – (Month 12 +/- 7 days) and Visit 08 (Month 24 +/-7 days)  
 
 
Procedures & Evaluations: 
 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Beck Depression Inventory-II (BDI-II) 
 Montreal Cognitive Assessment scale (MoCA)  
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Safety Laboratory tests (serum chemistry, hematology, urinalysis)  
 Serum pregnancy test - Complete all women unless they are one year postmenopausal 
or surgically sterile 
 Modified Rankin 
 Electrocardiogram (12-lead ECG) 
 PD Quality of Life Scale (PDQ-39)  
    Quality of Life in Neurological Diseases (Neuro-QOL)  
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III.  Only complete 
UPDRS Part IV if symptomatic therapy has been initiated. 
 Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
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 Assess Need for symptomatic therapy (completed only if subject has not reached need 
for symptomatic therapy) 
Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py).. Subjects should be instructed NOT to take their PD medications at home on the 
morning of the study visit. Subjects should be instructed to bring their PD medication 
to the study visit. Medication should be taken after completion of UPDRS OFF exam.  
UPDRS Parts 1 and 2 are to be completed in the ON state. Once a subject starts 
symptomatic therapy, the ON and OFF assessments should be completed for all PD 
medications including dopamine agonists, MAO inhibitors, or any other dopaminer-
gic therapies. 
 
 Modified Hoehn & Yahr Scale 
 Modified Schwab & England Activities of Daily Living 
 Dose Management Log   
 Adherence Assessments (see Section 6.3.13) 
 Drug Dispensing/Return Log (pill count)  
 Dispense Study Drug  
 Adverse Event Log  
Subjects should be instructed to immediately report any adverse events or changes in 
medication to the site Investigator or Coordinator. 
           Record all above activities in source documentation. 
             
6.2.6 Telephone Visit T01 (Month 15 +/- 7 days), T02 (Month 21 +/- 7 days), T03 
(Month 27 +/- 7 days) and T04 (Month 33 +/- 7 days)  
 
The Telephone Visit T01, T02, T03, or T04 may be conducted by either the study 
coordinator or investigator.  
 
 
Procedures & Evaluations: 
 
 Concomitant Medication Log 
 Adherence Assessments (see Section 6.3.123 
 Adverse Event Log 
 Assess Need for symptomatic therapy (if a subject is determined to need sympto-
matic therapy over the phone, a Symptomatic Therapy in person office visit 
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conduct the symptomatic therapy treatment assessment at this in person STX 
visit (see Section 6.2.12). 
Subjects should be instructed to immediately report any adverse events or changes in 
medications to the site Investigator or Coordinator. 
Record all above activities in source documentation. 
 
6.2.7 Visit 10/End of Study Drug (EOSD) visit (Month 36 +/- 7 days)  
 
 
Procedures & Evaluations: 
 
 General Neurological Exam 
 General Physical Exam 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Beck Depression Inventory-II (BDI-II) 
 Montreal Cognitive Assessment scale (MoCA)  
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Safety Laboratory tests (serum chemistry, hematology, urinalysis) 
 Serum pregnancy test - Complete all women unless they are one year postmenopausal 
or surgically sterile 
 Plasma sample for storage for future potential biomarker studies ( only for subjects 
who consented for biomarker sampling)  
 Modified Rankin Scale  
 Electrocardiogram (12-lead ECG) 
 PD Quality of Life Scale (PDQ-39)  
 Quality of Life in Neurological Diseases (Neuro-QOL)  
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III.  Only complete 
UPDRS Part IV if symptomatic therapy has been initiated. 
 Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS)  
 Assess Need for symptomatic therapy (completed only if subject has not reached need 
for symptomatic therapy) 
Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 


 
 
 
 
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dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py). Subjects should be instructed NOT to take their PD medications at home on the 
morning of the study visit.  Subjects should be instructed to bring their PD medication 
to the study visit. Medication should be taken after completion of UPDRS OFF exam.  
UPDRS Parts 1 and 2 are to be completed in the ON state. Once a subject starts 
symptomatic therapy, the ON and OFF assessments should be completed for all PD 
medications including dopamine agonists, MAO inhibitors, or any other dopaminer-
gic therapies 
 
 Modified Hoehn & Yahr Scale  
 Modified Schwab & England Activities of Daily Living  
 Dose Management Log  
 Adherence Assessments (see Section 6.3.13) 
 Adverse Event Log  
 Taper study drug  
 Drug Dispensing/Return Log (pill counts) 
 Provide instructions for the drug taper.  Subjects will taper their dosage in a blinded 
fashion to 1 capsule twice a day (equivalent to 5 mg of Isradipine IR or 1 capsule of 
placebo) every 2 days and stop after that (see Section 5.2.11) Review informed con-
sent and verify that the subject continues to grant consent for retention of DNA and 
biomarker samples as well their willingness to be contacted for future research  
Subjects should be instructed to immediately report any adverse events or changes in 
medications to the site Investigator or Coordinator.  
 
Record all above activities in source documentation 
 
6.2.8  Visit 11/Final (On Study/ Off Study Drug Evaluation/ Visit 10 + 2 weeks (+ 7 
days) 
 
 
Procedures & Evaluations: 
 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Review blood pressure records 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III.  Only complete 
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 Assess Need for symptomatic therapy (completed only if subject has not reached need 
for symptomatic therapy) 
Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py). 
 
Subjects should be instructed NOT to take their PD medications at home on the morn-
ing of the study visit.  Subjects should be instructed to bring their PD medication to 
the study visit. Medication should be taken after completion of UPDRS OFF exam.  
Once a subject starts symptomatic therapy, the ON and OFF assessments should be 
completed for all PD medications including dopamine agonists, MAO inhibitors, or 
any other dopaminergic therapies.  
 Modified Schwab & England Activities of Daily Living  
 Modified Hoehn & Yahr Scale  
 Assess primary diagnosis/probability of PD 
 Adverse Event Log  
 Retrieve all study drug 
 Drug Dispensing/Return Log (pill counts) 
 Dose Management Log 
 Conclusion of Study Participation Form 
 Treatment Assignment / Blindedness Questionnaire  
 
If the subject was previously taking an antihypertensive medication that was adjusted 
during the study, consult with the subject’s PCP or cardiologist prior to readjust-
ing/reinitiating antihypertensive medication if BP elevations are noted.  Alternatively, 
at the Investigator's discretion, (s)he may defer adjustments to the PCP or cardiolo-
gist.   
 
Record all above activities in source documentation. 
 
6.2.9   Unscheduled Visits 
 
 
An unscheduled visit may be performed at any time during the study at the subject’s re-
quest or as deemed necessary by the site Investigator.  The date and reason for the un-
scheduled visit will be recorded in the source documentation.   
 
 In most cases, an unscheduled visit will be warranted due to an adverse event, or a signif-
icantly abnormal lab value. 
 


 
 
 
 
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 Procedures & Evaluations: 
 Concomitant Medication Log 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Safety Laboratory tests (serum chemistry, hematology, urinalysis) if clinically indi-
cated 
 Instructions on blood pressure recording (if clinically indicated) 
 Generate a proceed or not proceed confirmation from BP vendor website, if applica-
ble 
 Dose Management Log (if study medicine adjustment required) 
 Adherence Assessments (see Section 6.3.13) 
 Adverse Event Log  
If Unscheduled visit occurs during study drug titration and due to the need to reduce 
antihypertensive medications, this visit should include all V01 procedures and evalua-
tions. 
 
Record all above listed activities in source documents. 
 
 
6.2.10 Symptomatic Treatment Visit 
 
 
If the site Investigator determines that a subject needs PD symptomatic treatment, 
the subject must come in for a PD symptomatic treatment visit.  Subjects who in-
itiate symptomatic therapy will continue in the study on study drug and con-
tinue follow up until the Final visit. The Symptomatic Therapy Visit should 
occur before a subject starts PD symptomatic therapy. Once the subject ini-
tiates symptomatic therapy, UPDRS Part III assessment should be completed 
in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the sub-
ject/investigator defined BEST ON, approximately 1 hour after dose of 
symptomatic therapy). UPDRS Parts 1 and 2 are to be completed in the ON 
state. Once a subject starts symptomatic therapy, the ON and OFF assess-
ments should be completed for all PD medications including dopamine ago-
nists, MAO inhibitors, or any other dopaminergic therapies 
 
If the symptomatic treatment visit occurs within the window of a regularly scheduled 
study visit, the symptomatic treatment visit will be completed in place of the regularly 
scheduled study visit. If this visit is conducted in place of the regularly scheduled 
V06, V08 and V10, visit assessments will include the following assessments:  safety 
labs, pregnancy test6, ECG, drug dispensing/titration. 
 
Procedures & Evaluations: 
 Concomitant Medication Log 


 
 
 
 
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 Montreal Cognitive Assessment scale (MoCA)  
 Beck Depression Inventory II (BDI-II) 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Modified Rankin scale  
 PD Quality of Life Scale (PDQ-39) 
 Quality of Life in Neurological Diseases (Neuro-QOL)  
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, and III.  
 Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS)  
 Modified Hoehn & Yahr Scale  
 Modified Schwab & England Activities of Daily Living  
 Dose Management Log  (if study medicine adjustment required) 
 Adherence Assessments (see Section 6.3.13) 
 Adverse Event Log  
 Record all above listed activities in source documents.  
 
 Initiation of symptomatic therapy is a reportable event and should be reported to 
CTCC. The subjects should remain in the study on their initial study drug assign-
ment.   
 
6.2.11 Premature Withdrawal Visit (PW) 
 
Subjects have the right to withdraw from the study at any time without prejudice.   In the 
event of premature study withdrawal (either subject or Investigator initiated), a Premature 
Withdrawal visit should occur. All efforts should be made to conduct the PW visit 
prior to study drug discontinuation. 
 
Reasons for withdrawal of the subject prior to completion of the study must be stated in 
the CRF and in the site source documentation for all study subjects who were enrolled in 
the study.  The CTCC must be informed by telephone within 24 hours of all study sub-
jects who are withdrawn from the study. 
 
At the time of the premature withdrawal visit, subjects should be instructed to taper their 
study drug if applicable. Subjects will taper their dosage by 5 mg of Isradipine IR or pla-
cebo to one capsule twice daily every 2 days). If a subject has already decreased their 
dosage due to prior intolerability to 5mg or below, then they will discontinue the drug at 
the start of the taper. The subject should be instructed to take the study drug (with or 
without food) in the morning () and in the evening.  


 
 
 
 
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Written directions for drug tapering should be given to the subject.  Visit 11 activities 
should be performed at that time.  
 
Every effort should be made to keep each subject in the study. Subjects coming off study 
drug should be encouraged to continue in the study, off study drug. However, all subjects 
must present for a final (V10 or PW) in-person visit. 
 
Procedures & Evaluations: 
 
 General Neurological Exam 
 General Physical Exam 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Beck Depression Inventory II (BDI-II) 
 Montreal Cognitive Assessment scale (MoCA) 
 Assess primary diagnosis/probability of PD 
 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Safety Laboratory tests (serum chemistry, hematology, urinalysis) 
 Plasma PK sample - To be done only if premature withdrawal corresponds to Visits 3 
or 4 (see instructions Section 6.2.4) 
 Plasma sample for storage for future potential biomarker studies (only for subjects 
who consented for biomarker sampling)  
 Serum pregnancy test - Complete all women unless they are one year postmenopausal 
or surgically sterile 
 Modified Rankin Scale  
 Exercise Questionnaire  
 Electrocardiogram (12-lead ECG) 
 PD Quality of Life Scale (PDQ-39)  
 Quality of Life in Neurological Diseases (Neuro-QOL) 
 Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III.  Only complete 
UPDRS Part IV if symptomatic therapy has been initiated. 
 Assess Need for symptomatic therapy (completed only if subject has not reached need 
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Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py). Subjects should be instructed NOT to take their PD medications at home on the 
morning of the study visit.  Subjects should be instructed to bring their PD medication 
to the study visit. Medication should be taken after completion of UPDRS OFF exam.  
UPDRS Parts 1 and 2 are to be completed in the ON state. Once a subject starts 
symptomatic therapy, the ON and OFF assessments should be completed for all PD 
medications including dopamine agonists, MAO inhibitors, or any other dopaminer-
gic therapies 
 Modified Hoehn & Yahr Scale  
 Modified Schwab & England Activities of Daily Living 
 Dose Management Log   
 Adherence Assessments (see Section 6.3.13) 
 Adverse Event Log 
 Provide written instructions for the drug taper. 
 Retrieve all study drug, if subject is no longer taking drug at the time of PW visit. 
Otherwise retrieve all study drug at time of Premature Withdrawal Follow-up Visit 
 
 Drug Dispensing/Return Log (pill counts) 
 Treatment Assignment / Blindedness Questionnaire - Complete if subject is no longer 
taking drug at time of PW visit. Otherwise, complete questionnaires at time of Prema-
ture Withdrawal Follow-up Visit 
Record all above activities in source documentation. 
 
6.2.12 Premature Withdrawal Follow-up Visit 
 
All subjects who are on study drug at the time of the PW visit should have a visit approx-
imately two weeks after the premature withdrawal visit and after the study drug has been 
tapered off.  As this visit is primarily for the purposes of monitoring subject safety, sub-
jects who withdraw consent should also be asked whether they agree to attend this visit 
for safety checks and follow-up. 
 
Any new AEs reported at this visit must also be reported in the CRF and must be fol-
lowed for 30 days from this visit or until resolution, whichever occurs first. 
 
Procedures & Evaluations: 
 
 Concomitant Medication Log 
 Columbia Suicide Severity Rating Scale (C-SSRS) 


 
 
 
 
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 Vital Signs (blood pressure, heart rate, temperature, weight) 
 Review blood pressure records. If the subject was previously taking an antihyperten-
sive medication that was adjusted during the study, consult with the subject’s PCP or 
cardiologist prior to readjusting/reinitiating antihypertensive medication if BP eleva-
tions are noted.  Alternatively, at the Investigator's discretion, (s)he may defer ad-
justments to the PCP or cardiologist.   
 Adverse Event Log  
 Retrieve all study drug, if drug not retrieved at PW visit 
 Drug Dispensing/Return Log (pill counts), if drug not retrieved at PW 
 Dose Management Log 
 Conclusion of Study Participation Form 
 Treatment Assignment / Blindedness Questionnaire, if not completed at PW 
 
The following assessments should be completed if they were not completed at the PW 
visit: 
 Unified Parkinson’s Disease Rating Scale (UPDRS) – Parts I, II, III.  Only complete 
UPDRS Part IV if symptomatic therapy has been initiated. 
 Assess Need for symptomatic therapy (completed only if subject has not reached need 
for symptomatic therapy) 
Once the subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the last 
dose of symptomatic therapy) and in medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic thera-
py).. Subjects should be instructed NOT to take their PD medications at home on the 
morning of the study visit.  Subjects should be instructed to bring their PD medication 
to the study visit. Medication should be taken after completion of UPDRS OFF exam.  
UPDRS Parts 1 and 2 are to be completed in the ON state. 
 
 Modified Schwab & England Activities of Daily Living  
 Modified Hoehn & Yahr Scale  
 
Record all above activities in source documentation. 
 
6.2.13 Adverse Event Follow-up Visit 
 
All subjects who have unresolved adverse events or SAEs at the time of their final study 
visit (Visit 11 or Premature Withdrawal Follow Up visit) should have a phone call ap-
proximately 30 days after their final study visit.  The purpose of this phone call is to as-
sess the final outcome of the unresolved AEs as either resolved or on-going.  
 


 
 
 
 
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This phone call is not required for subjects whose AEs were resolved prior to at the time 
of the final study visit. 
 
Procedures & Evaluations: 
 
 Adverse Event Log  
 Conclusion of Study Participation Form 
 
6.3  
Special Instructions and Definitions of Evaluations 
 
6.3.1 Informed Consent 
 
This study will be conducted in accordance with the provisions of 21 Code of Federal 
Regulations (CFR) Part 50.  The CTCC must be given an opportunity to review the con-
sent form prior to site IRB/REB submission and before it is used in the study. 
 
In accordance with relevant regulations, an informed consent agreement explaining the 
procedures and requirements of the study, together with any potential hazards/risks must 
be read and/or explained to each subject.  Each subject will sign such an informed con-
sent form.  The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.  A copy of the consent form will be 
given to the subject, parent, or legal guardian, and this fact will be documented in the 
subject’s record. The subject must be assured of the freedom to withdraw from participa-
tion in the study at any time. 
 
It is the Investigator’s responsibility to make sure that the subject understands what she/he 
is agreeing to and that written informed consent is obtained before the subject is involved 
in any protocol-defined procedures including screening procedures.  It is also the Investi-
gator’s responsibility to retain the original signed consent form and provide each subject 
with a copy of the signed consent form. 
 
6.3.2 Documentation of Parkinson Disease 
 
The diagnosis of idiopathic PD should be documented based on the UK brain bank diag-
nostic criteria[47]. The subjects are expected to have 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. 
 
6.3.3 Medical 
History- 
will 
utilize 
NIH 
common 
data 
elements 
form 
http://www.commondataelements.ninds.nih.gov/ 
The form should focus on significant medical history of all problems or conditions other 
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during a subject visit. If the subject reports more than one medical condition per system, 
record each condition on a separate line. 
6.3.4 PD Treatment History 
Treatment history will be reviewed and recorded at the screening visit on the Concomi-
tant Medication Log. All PD treatment taken up to 90 days prior to the Baseline visit 
should be recorded. 
 
6.3.5 Concomitant Treatments 
Concomitant medications will be reviewed and recorded at screening and reviewed for 
accuracy at each study visit and amended as necessary. All medications taken up to 90 
days prior to the Baseline visit should be recorded. 
 
6.3.6 Study Intervention Modification  
Any change in the study drug dose should be captured on the Dose Management Log 
 
6.3.7 Exercise Questionnaire  
Subjects will be asked to complete the Exercise Questionnaire at the Baseline visit, or 
once the subject consents, and at their final visit (Visit 11 or PW).  This scale asks about 
mild to strenuous exercise and includes factors to include minutes per week. See Section 
6 of the Operations Manual for additional details on this assessment. 
 
6.3.8 Mini Environmental Risk Questionnaire (MERQ) 
Exposure to risk factors of interest (pesticides, chemicals, heavy metals, caffeine use, 
smoking history and concomitant medication use) will be assessed using a self-reporting 
questionnaire.  This questionnaire will be completed at the Baseline visit, or once the sub-
ject consents, and at the final visit (Visit 11 or PW). See Section 6 of the Operations 
Manual for additional details on this assessment. 
 
6.3.9 Clinical Assessments 
The study will use NINDS Common Data Elements in developing the CRFs  
http://www.commondataelements.ninds.nih.gov/). 
 
 Efficacy Assessments 
 
1. Unified Parkinson Disease Rating Scale (UPDRS) 
 
Will 
use 
the 
NINDS 
Common 
Data 
Elements 
UPDRS 
CRFs 
(see 
http://www.commondataelements.ninds.nih.gov/). 
 
The Unified Parkinson Disease Rating Scale (UPDRS) is a widely used and well-
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reliability, validity and factor structure of the UPDRS have been extensively stud-
ied [48-50]  
 
The scale has three components, each consisting of questions answered on a 0-4 
point scale.  Part I assesses mentation, behavior and mood; Part II assesses activi-
ties of daily living in the week prior to the designated visit; Part III assesses motor 
abilities at the time of the visit; Part IV assesses complications of therapy   (motor 
fluctuations, dyskinesia, etc) A total of 31 items are included in Parts I, II and III.  
Each item will receive a score ranging from 0 to 4 where 0 represents the absence 
of impairment and 4 represents the highest degree of impairment. 
 
Subjects will be assessed by the Investigator or Coordinator on Parts I and II. The 
Investigator must assess Part III of the UPDRS. The sum of Parts I, II and III at 
each visit will provide a total UPDRS score. Both the primary and secondary end-
points will be based on changes from the Baseline Visit in total UPDRS scores. 
UPDRS Part IV will be completed only on the subjects who have reached the 
endpoint and were started on symptomatic therapy.  
 
The same Investigator or Coordinator should assess the subject on the UPDRS 
(and other site Investigator specific study evaluations) at all study visits. The mo-
tor portion of the UPDRS must be completed by the Investigator. Once the 
subject initiated symptomatic therapy, UPDRS Part III assessment should be 
completed in the defined medications OFF state (approximately 12 hours after the 
last dose of symptomatic therapy) and in medications ON state (based on the sub-
ject/ investigator defined BEST ON, approximately 1 hour after dose of sympto-
matic therapy). UPDRS Parts 1 and 2 are to be completed in the ON state. Once a 
subject starts symptomatic therapy, the ON and OFF assessments should be com-
pleted for all PD medications including dopamine agonists, MAO inhibitors, or 
any other dopaminergic therapies 
 
 Subjects should be instructed NOT to take their PD medications at home on 
the morning of the study visit.  Subjects should be instructed to bring their PD 
medication to the study visit. Medication should be taken after completion of 
UPDRS OFF exam.   
 
2. 
MDS-UPDRS 
 
Use of the MDS-UPDRS is recommended in the NINDS Common Data Elements 
(see http://www.commondataelements.ninds.nih.gov/). 
 
The Movement Disorder Society (MDS)-sponsored new version of the UPDRS is 
founded on the critique that was formulated by the Task Force for Rating Scales 
in Parkinson’s disease (Mov Disord 2003;18:738-750). 
 


 
 
 
 
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MDS version of the UPDRS maintains the overall format of the original UPDRS, 
but addresses issues identified in the critique as weaknesses and ambiguities.  
The MDS-UPDRS has four parts: Part I (non-motor experiences of daily living), 
Part II (motor experiences of daily living, Part III (motor examination) and Part 
IV (motor complications). Part I has two components: IA concerns a number of 
behaviors that are assessed by the Investigator with all pertinent information from 
subjects and caregivers, and IB is completed by the subject with or without the aid 
of the caregiver, but independently of the Investigator. These sections should 
however, be reviewed by the Investigator or Coordinator to ensure that all ques-
tions are answered clearly and the Investigator or Coordinator can help explain 
any perceived ambiguities. Part II is designed to be a self-administered question-
naire like Part IB, but should be reviewed by the Investigator or Coordinator to 
ensure completeness and clarity. Of note, the official versions of Part IA, Part IB 
and Part II of the MDS-UPDRS do not have separate on or off ratings. However, 
for individual programs or protocols the same questions can be used separately for 
on and off. Part III has instructions for the Investigator to give or demonstrate to 
the subject; it is completed by the Investigator. Once the subject initiated symp-
tomatic therapy, the MDS-UPDRS assessments will be completed in the medica-
tion ON state only. Part IV has instructions for the Investigator or Coordinator 
and also instructions to be read to the subject. This part integrates subject-derived 
information with the assessor’s clinical observations. The current study will re-
quest that the MDS-UPDRS be completed in the medication ON state, if applica-
ble. 
 
 The same Investigator or Coordinator should assess the subject on the MDS-
UPDRS (and other site Investigator specific study evaluations) at all study 
visits. The motor portion of the MDS-UPDRS must be completed by the 
Investigator.  
 
 
3.  
 Modified Hoehn & Yahr Scale 
 
The Modified Hoehn & Yahr Scale [51] is an 8-level Parkinson’s disease staging 
instrument. This Investigator assessment will be done at each scheduled visit.  
Subjects with a Modified Hoehn & Yahr score of 3 or greater at the Baseline Visit 
will be excluded from participation in the study.  
 
 
4.   
Modified Schwab & England Independence Scale 
 
The Modified Schwab & England scale [52] is an Investigator and subject as-
sessment of the subject’s level of independence at all scheduled study visits.  The 
subject will be scored on a percentage scale reflective of his/her ability to perform 
acts of daily living in relation to what he/she did before Parkinson’s disease ap-
peared. Scores with associated descriptors range in increments of 10% to 100% 
for normal (subject has full ability and is completely independent; essentially 
normal), to 0% (vegetative functions such as swallowing, bladder and bowel func-


 
 
 
 
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tions are not functioning; bedridden). Scores should be coded in increments of 5, 
(i.e. 095, 090, and 085).  
 
 
5.  
Beck Depression Inventory II (BDI-II) 
 
Will 
use 
the 
NINDS 
Common 
Data 
Elements 
CRFs 
(see 
http://www.commondataelements.ninds.nih.gov/). 
 
The Beck Depression Inventory (BDI-II)  is a validated self-reported 21- item de-
pression scale that was tested and validated as a reliable instrument for screening 
for depression in PD [53]. Subjects will complete the BDI-II at the Screening, the 
symptomatic treatment visit, Visits 06 and 08 and EOSD (V10) or Premature 
Withdrawal Visits. Subjects who score above 15 at screening will be excluded 
from participation in the study and referred for further evaluation and possible 
treatment. If score at any point in study the BDI score is above 15, appropriate as-
sessment and treatment should be conducted. 
 
 
 
6.  
Montreal Cognitive Assessment 
 
Will 
use 
the 
NINDS 
Common 
Data 
Elements 
MoCA 
CRFs 
(see 
http://www.commondataelements.ninds.nih.gov/). 
 
The Montreal Cognitive Assessment (MoCA) is a brief 30-point screening in-
strument that was developed and validated to identify subjects with mild cognitive 
impairment (MCI) [3]. The MoCA has a sensitivity of 90% in detecting MCI 
compared to MMSE sensitivity of 18%. MoCA includes more items aimed at de-
tecting frontal executive dysfunction and visuospatial processing dysfunction 
compared to MMSE. The MoCA is now widely used and shown to be a more sen-
sitive tool for screening for cognitive impairment in PD [2, 54]. MoCA was given 
one of the highest rankings (best) by NINDS CDE among the brief cognitive as-
sessment tools in PD.  
 
If the subject has 12 years of education or fewer, a point is added to his/her total 
score. Note that this number of years does not refer to a particular education level, 
for example, it does not refer to individuals that have or have not completed high 
school. The number of years of education must actually be counted starting after 
kindergarten (kindergarten must not be included in the count). Please note that the 
maximum score is 30, therefore, if a subject scores 30/30, a point is not added if 
he/she has 12 years of education or less. 
 
 
7.  
The Modified Rankin scale  
 
The Modified Rankin Scale (mRS)[van Swieten et. al., 1988] is a widely used 
measure of overall functional disability. It has been used as a as a functional out-
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Wilson et. al., 2002; Wilson et. al., 2005; Shinohara et. al., 2006]. The Modified 
Rankin scale scores range from 0 to 6 with a higher score correlating with higher 
level of disability.   
 
8. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
As required by the FDA, study subjects will be screened for suicidality (suicidal 
behavior or ideation) at screening and at each subject visit. Certified Investigator 
or Coordinator will use the Columbia Suicide Severity Rating Scale (C-SSRS) 
[55] (http://www.cssrs.columbia.edu)  
 
The Columbia Suicide Severity Rating Scale is a structured interview developed 
in the National Institute of Mental Health Treatment of Adolescent Suicide At-
tempters Study to assess severity and monitor suicidal events during a treatment 
period.  The interview can provide an overall assessment of suicidal ideation as 
well as behavior in order to generate a summary measure of suicidality.  This rat-
ing scale has been used in prior interventional studies for both psychotropic and 
non-psychotropic compounds over the past four years. This assessment will be 
administered during the Screening visit to exclude subjects with active suicidality 
and at all scheduled in-person study visits.  Additionally, this assessment will be 
administered as clinically indicated at Unscheduled visits and in the setting of any 
suicide attempt to ensure that the reporting of suicidality and suicide attempts is 
consistent across study centers. Decisions about continued study participation of 
subjects found to be suicidal will be made collaboratively by the site Investigator, 
Principal Investigator, and CTCC Clinical Monitor The site Investigator will 
make a referral to psychiatrist or other Mental Health Care professional, as appro-
priate.  
 
9. 
PD Quality of Life Questionnaire 
 
PD Quality of Life Scale (PDQ-39). PDQ-39 is recommended by the NINDS 
Common 
Data 
Elements 
CRFs 
(see 
http://www.commondataelements.ninds.nih.gov/). 
The questionnaire asks the subject to evaluate how PD has affected their health 
and overall quality of life at that point in time. The total quality of life scale in-
cludes subscales relating to social role, self-image/sexuality, sleep, outlook, phys-
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10. 
Quality of Life in Neurological Diseases (Neuro-QOL 
 
http:www.neuroqol.org 
Neuro-QOL is a set of self-reported measures that assess the health-related quality 
of life of persons with neurological disorders. The quality of life scale includes 
measures for anxiety, depression, upper extremity function (fine motel, ADL), 
lower extremity function (mobility), applied cognition (executive function and 
general concerns), positive affect and well-being and stigma. The questionnaire 
asks the subject to evaluate their quality of life in the past 7 days. The Neuro-
QOL questionnaires are currently available in Spanish but not French translation.  
French-speaking study subjects will not be completing these questionnaires. 
6.3.10 Laboratory Evaluations 
 
Clinical laboratory tests will be performed by a central laboratory specified and the la-
boratory’s reference ranges will be used. The CTCC must be notified by the central la-
boratory during the study of any changes to the reference ranges. All samples for labora-
tory analysis must be collected, prepared, labeled, and shipped according to the laborato-
ry’s requirements.  (Refer to instructions of the laboratory’s manual.) 
 
Blood samples will be collected at the Screening visit, Visits 06 and 08, and V10 (EOSD) 
or Premature Withdrawal Visit and Unscheduled visits (if clinically indicated) for the 
standard clinical safety laboratory analyses noted below. Retests may be performed if 
needed between visits for questionable results. 
 
Clinical laboratory test results will be forwarded to individual Investigators and to the 
CTCC.   
 
 
 
Clinical Laboratory Tests 
 
Clinical Chemistry – albumin, alkaline phosphatase, aspartate transaminase (SGOT; 
AST), alanine transaminase (SGPT; ALT), bicarbonate, blood urea nitrogen (BUN), cal-
cium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), phosphate, potassium, 
sodium, total bilirubin, total creatine kinase (creatine phosphokinase), total protein, uric 
acid   
 
Hematology – Hemoglobin, hematocrit, red blood cell count (RBC), platelet count, white 
blood cell count (WBC) with differential count (bands, monocytes, neutrophils, eosino-
phils, lymphocytes, basophils)  
 
Urinalysis – pH, protein, glucose, ketone, blood microscopic, WBC count, RBC count, 
casts  
 
Pregnancy Tests - Serum pregnancy test at Screening, Visits 06 and 08 and V10 (EOSD) 
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nancy testing should be done for all women unless they are one year postmenopausal or 
surgically sterile.  Any subject becoming pregnant during the study will be tapered from 
the study drug immediately. In addition, all attempts will be made to follow the subject 
until delivery.  Any pregnancy that occurs during the study must be reported to the 
CTCC.  
 
Laboratory reports from the central laboratory will be signed and dated by the site Inves-
tigator following review, and filed with the subject’s source documents. 
 
 
PK samples  
Plasma PK samples will be collected at the Screening visit, Visits 03 (3 months) and 04 
(6 months), or Premature Withdrawal Visit if it corresponds to Visits 03 or 04. The objec-
tive of collecting blood PK samples is to confirm isradipine trough concentrations and to 
establish a sparse PK profile of Isradipine IR based on the samples collected at 2-3 and 4-
8 hours post dose windows. The data will be analyzed to demonstrate an appropriate level 
is achieved for the formulation used in this study and to address high inter-patient varia-
bility in serum concentrations to support the analysis in case variable results were ob-
served. PK samples will be collected as outlined in Section 6.2.4 and shipped according 
to the laboratory’s requirements.  (Refer to instructions in the laboratory’s manual.) 
 
Plasma Biomarker samples 
A blood sample will be collected from each subject at Screening, Month 36 (V10/EOSD) 
visits or at Premature Withdrawal visit and stored.  These samples may be shared with 
other researchers for future unspecified research.  Subjects will be given the option of re-
fusing to have this sample collected, and their decision will not affect their participation 
in the study. 
 
DNA Sample Collection 
A blood sample will be collected from each subject at Screening and stored. These sam-
ples will be used to extract DNA for storage and shared for future unspecified research.  
Subjects will be given the option of refusing to have this sample collected or may request 
that their sample be destroyed at any time, without affecting their participation in the 
study. One of the rationales for the DNA sample collection is to assess if there is correla-
tion of response to isradipine with a particular genetic profile.  
 
 
6.3.11  Electrocardiogram (ECG) 
 
 
A 12-lead resting ECG will be performed utilizing the central ECG laboratory equipment 
at Screening Visit, Visits 06, 08 and at the V10 (EOSD) or Premature Withdrawal visits.  
ECG will also be conducted at the Symptomatic Therapy visit if this visit is conducted in 
place of a regularly scheduled V06, V08 or V10. ECG readings/results will be provided 
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Presence of 2nd or 3rd degree atrioventricular block will exclude the subjects from partici-
pation in the study. Investigator may consider other significant ECG abnormalities as the 
reason for exclusion for participation in study. 
6.3.12 Additional Evaluations 
 
Assess need for Symptomatic Treatment: 
At each visit (except baseline), the Investigator will assess the subject’s need for symp-
tomatic treatment. A questionnaire will be used to facilitate the Investigator’s decision.  
This decision will be based on PD disability posing a threat to the subject’s current occu-
pational status, current abilities (potential capacities) related to occupational matters, to 
handle routine personal finances and domestic responsibilities, and activities of daily liv-
ing.   
 
 
 
6.3.13  Adherence Assessments 
 
 At each study visit, the site Investigator and/or Study Coordinator will assess the sub-
ject’s adherence with the study requirements.  This will include checks of protocol com-
pliance, concomitant medication use, blood pressure recordings, and use of study drug in 
order to assess the reliability of subject-generated data.  In extreme circumstances, sub-
jects who consistently fail to comply with the study requirements may be withdrawn from 
the study. 
  
6.3.14 Treatment Assignment / Blindedness Questionnaire  
 
Subjects and Investigators will be asked to complete the Treatment Assignment/ Blind-
edness Questionnaire during the V11 Final visit or Premature Withdrawal Visit.  The 
Blindedness Questionnaire will be used to assess subject’s and Investigator’s perception 
of the knowledge of their group assignment to placebo versus active treatment.  
 
 
7 
MANAGEMENT OF ADVERSE EVENTS 
 
7.1 
Isradipine Side Effect Profile  
 
Isradipine IR is a dihydropyridine Ca2+ channel antagonist that is FDA approved for 
treatment of hypertension since 1990 (http://www.drugs.com/pro/isradipine.html).  
 
The side effect profile of Isradipine IR 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.  The most common adverse effect is 
peripheral edema as reflection of the vasodilatory effect of the agent. The other side ef-
fects include angina, asthenia, flushing, heart failure, palpitations, and dizziness. Accord-
ing to the package insert, the adverse effects are usually not serious, dose dependent, and 
respond well to dose reduction or discontinuation of therapy.  
 


 
 
 
 
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Isradipine has no effect on atrioventricular or sinoatrial conduction. The only absolute 
contraindications for Isradipine IR are hypersensitivity to dihydropyridine compounds 
and hypotension defined as systolic blood pressure below 90 mm Hg. Isradipine IR 
should be used with caution in subjects with bradycardia. Subjects with clinically signifi-
cant bradycardia will be excluded from the study.  
 
Below is a list of most common potential Isradipine IR related adverse events from the 
drug package insert (http://www.drugs.com/pro/isradipine.html) .(See Table 4 and 5 above 
for list of adverse events.) 
The adverse effects associated with isradipine generally are not serious and respond well 
to either dosage reduction or discontinuation of therapy. Most adverse effects during is-
radipine therapy are related to vasodilatory actions and, in many cases, are dose-related. 
 
The most common cardiovascular adverse effect attributed to isradipine therapy is pe-
ripheral edema, which is a reflection of the potent vasodilatory effect of isradipine, alt-
hough it occurs less frequently than with nifedipine. Peripheral edema may be an indica-
tor of worsening congestive heart failure, but it more commonly is due to peripheral vas-
odilation. 
 
Although calcium-channel blockers are effective in treating angina, worsening of angina 
has occurred in as many as 10% of patients receiving isradipine for angina pectoris. This 
effect may be caused by excessive hypotension, coronary steal, or reflex sinus tachycar-
dia (rare with isradipine). In rare cases, myocardial infarction has occurred but could not 
be attributed solely to the drug and may have been only a reflection of disease progres-
sion. Patients with angina should be observed for worsening symptoms when isradipine 
therapy is begun, particularly if beta-blocker therapy is being withdrawn. 
 
Other common side effects of isradipine, primarily related to vasodilation, include flush-
ing, weakness or asthenia, fatigue, headache, syncope, hypotension, palpitations, dizzi-
ness, and lightheadedness. 
Less common but potentially serious adverse effects of isradipine include angioedema, 
dyspnea, wheezing (especially if underlying respiratory disease or pulmonary edema ex-
ists), vertigo, and visual disturbances. 
 
Gynecomastia has been associated with the use of calcium channel blockers.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
General Design Issues 
The study is designed as a randomized Phase 3, 2-arm, double-blind, parallel group trial 
with subjects randomized to Isradipine IR 5 mg or matching placebo twice daily.  
Primary efficacy analysis will be performed after all subjects complete 36 months on 
their randomized treatment assignment. We expect that nearly all subjects will require 
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months study; if so they will still continue on their randomized treatment assignment in 
conjunction with the symptomatic therapy. In that case the primary statistical analysis 
will be based on UPDRS assessed in the medications ON state (based on the subject/ in-
vestigator defined BEST ON, approximately 1 hour after dose of symptomatic therapy). 
Primary efficacy variable  
The primary efficacy measure is the change in the total UPDRS score in the active treat-
ment arm versus placebo between the baseline and 36 months. In order to provide assur-
ance that any differences between the treatment groups in the primary outcome measure 
are not due to differences in the usages of symptomatic medication, current and cumula-
tive dosages of symptomatic medication at the 36-month visit will also be compared, us-
ing accepted levodopa dose equivalency formulas[1] We will also repeat our UPDRS 
analyses after stratification by medication status (dosage of symptomatic treatment calcu-
lated as the levodopa equivalent dose). We will also perform exploratory analyses along 
the lines suggested by Holford and Nutt[56], based on flexible models of both short term 
symptomatic effects and long-term disease-modifying effects of treatment. 
Secondary efficacy measure  
The study secondary objectives are to explore long-term efficacy of Isradipine IR 5 mg 
twice daily to slow progression of disability between the 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 OFF score, UPDRS ambulatory ca-
pacity subscore, time to initiation of symptomatic therapy, time to onset of motor 
complications, dose and utilization of symptomatic therapy) 
2)  Cognitive function as measured by MoCA  
3) Global measures of disability as measured by modified Rankin score  
4)  Measures of functional status and quality of life (PDQ-39, modified Schwab and Eng-
land, MDS-UPDRS Motor and Non-Motor Experience of Daily Living) 
Interim tolerability analysis  
An interim tolerability analysis will be performed after the first 60 subjects complete the 
titration period of the study (Visit 03 (Month 3). Tolerability will be defined as ability to 
achieve and maintain target daily dosage of study drug (10 mg) by the end of titration pe-
riod. The tolerability threshold will be defined as more than 30% difference in the tolera-
bility of the active treatment group relative to the placebo group. Only dosage reductions, 
discontinuations, and premature terminations due to intolerability will be included in the 
analysis, terminations for other reasons will not be included in this analysis. The study 
may be terminated if tolerability parameters are not met.  These analyses will be conduct-
ed by the unblinded statistician and reported to the DSMB. 
 
Interim analysis of the Pharmacokinetic (PK) data  
An interim PK analysis will be performed (at steady-state) after the first 60 subjects who 
reach target daily dose of 10 mg complete the titration phase of the study to assure that 
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will be analysed. Only data on the subjects who have reached 10mg dose of study drug 
(Isradipine IR or placebo) will be included in the interim analysis. Based on the data dis-
cussed in Section 2.1, we expect the Cmin concentration to be 0.4+0.2 ng/ml (1 SD from 
the Cmin mean). Thus Cmin = 0.2 ng/ml should be established as the threshold of the 
therapeutic effect. In case mean Cmin concentrations fall below 0.2 ng/ml, the following 
paradigm is proposed:  
 
1) May validate the PK data by completing a full PK profile on a small sample of study 
subjects ( N=6 )  
2) In case the AUC 0-12hr falls within the expected range ( 13.9+ 6.1 ng/ml)(Holmes 
and Kutz 1993), the study will proceed as planned  
3) In case AUC 0-12hr is below expected range the DSMB may seek independent as-
sessment of the PK data by a clinical pharmacologist   
4) In case the Cmin values are below Cfloor  (0.25 nM (0.098 ng/ml)) – DSMB may 
consider an alternative dosing regimen 
 
Interim futility and efficacy analysis 
An interim analysis for futility and efficacy will be performed after primary outcome data 
are available for the first 168 subjects (50%) to enroll in the study. The study may be 
terminated for futility if the interim analysis shows that the conditional power of rejecting 
the null hypothesis in favor of a beneficial effect of isradipine is lower than 20% under 
any scenario that is consistent with the data accrued at that time.  A two-sided P-value in 
favor of isradipine of less than 0.001 will be required to stop for efficacy at the interim 
analysis if the recruitment rate falls below that projected, the interim analysis may be 
brought forward and performed as soon as the first 30% of the subjects to enroll have 
completed (or terminated). In that case a second interim analysis for futility will be con-
ducted on the first 75% of subjects to enroll.  
These analyses will be conducted by the unblinded statistician and reported to the DSMB. 
The stringent alpha level for efficacy was chosen so as to have minimal effect on the final 
P-value, should the study run to completion. In addressing futility the DSMB will exam-
ine a range of possible treatment effects consistent with the data obtained in the study at 
the time of analysis.   
8.2 
Outcomes 
8.2.1 Primary Outcome  
 
Efficacy: 
 
Efficacy will be defined as the change in total UPDRS score between the baseline visit 
and month 36. Comparison will be made between active treatment arm and placebo. We 
expect that nearly all subjects will require symptomatic therapy (e.g. levodopa or dopa-
mine agonist) prior to the end of the 36 months study. In that case UPDRS will be as-
sessed in the medications ON state (based on the subject/ investigator defined BEST ON, 
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Medications ON state was chosen based on the following rationale: if disease modifying effect of 
isradipine exists it will be sustained even in the medications ON state; the practical diffi-
culty in withdrawing subjects; the persistent symptomatic benefit of symptomatic therapy 
even in the “defined medications OFF” state. In addition there are no pilot data on the 
longitudinal change of UPDRS in the medications OFF state over 36 months period in de 
novo population to allow power calculations.  
 
Our primary efficacy analysis will use analysis of covariance applied to the change from 
baseline in the total UPDRS score. The baseline value will be entered into the model as a 
continuous variable, the assigned treatment and the enrolling Investigator will be entered 
as a stratification variable.  The primary analysis will be based on the intent-to-treat prin-
ciple and will include all subjects who have 36 month data. A two-sided test with alpha = 
0.05 will be used to declare statistical significance. Sensitivity analyses will be performed 
using data values imputed under various “missingness” mechanisms for the subjects who 
do not complete 36 months of follow-up.  Consistency of results over study sites and with 
respect to major demographic and clinical baseline variables will be assessed descriptive-
ly and by appropriate tests of statistical interaction.  We will also perform an exploratory 
analysis by achieved final dosage (0, 2.5, 5.0, 7.5 and 10.0) for the subjects assigned to 
active treatment.  
 
8.2.2.  Secondary Outcomes  
 
Efficacy analysis (at 36 months): 
The change in the following measures of disability from baseline to 36 months will be 
analyzed: 
 
I. 
Motor disability  
a. The change in UPDRS Part III Motor subscale in the defined medications 
OFF state (approximately 12 hours after the last dose of symptomatic therapy 
for those subjects that have initiated symptomatic therapy) 
b. MDS-UPDRS Motor score in the defined medications ON state (as per the 
primary outcome) 
c. The change in the ambulatory capacity (sum of 5 UPDRS questions: falling, 
freezing, walking, gait, postural stability) 
d. Time to initiation of  symptomatic therapy  
e. Proportion of subjects that start symptomatic therapy  
f. Analysis of symptomatic therapy utilization as measured by levodopa equiva-
lence dose[1]  
g. Time to onset and severity of motor complications as measured by UPDRS IV 
subscale (complications of therapy) for those subjects that have initiated 
symptomatic therapy 
 
For continuous measures, the analysis will proceed in the same way as for the 
primary outcome measure. Logistic regression will be used for the binary out-


 
 
 
 
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come (e) and Cox’s proportional hazards model for the time-to-event outcomes 
(d) and (g).  
 
II. 
Cognitive disability  
a. The change in the cognitive function as measured by the change in the MoCA 
[2, 3]  
III. 
Measure of global disability   
a. The change in the Modified Rankin score  
IV. 
Measures of functional  status and quality of life  
a. The change in Activities of Daily Living (ADL) subscale of the UPDRS  
b. The change in the MDS-UPDRS Part II  
c. The change in the modified Schwab and England scale  
d. The change in Parkinson Disease Quality of Life Questionnaire-39 (PDQ-39) 
[4] 
e. The change in Neuro-QOL  
f. The change in Non-motor and Motor Experiences of Daily Living scores of 
the MDS-UPDRS 
 
While the primary outcome measure at 36 months is the change in the  total UPDRS we 
also will explore the  measures that reflect long term disability in PD including motor and 
cognitive function as well as global measures of disability and quality of life measures (as 
outlined below) between the baseline and 36 months of treatment.  While 36 months is 
not a sufficiently long period of time to assess the impact of an intervention on such long 
term measures of PD disability as gait, balance, and cognitive function; the current analy-
sis  may provide a signal of efficacy that may be followed by a long term confirmatory 
study . We will also examine whether onset of disability requiring symptomatic treatment 
and early changes in total UPDRS and its components are useful predictors of long-term 
disability.  
  
Safety and Tolerability Analysis: 
1. 
The ability to complete the 36 months study on the originally assigned 
treatment dosage 
2. 
The proportion of subjects requiring dosage reductions secondary to intol-
erability 
3. 
The frequency of adverse events and serious adverse   events  
4. 
Laboratory and ECG abnormalities 
5. 
An interim tolerability analysis will be performed after the first 60 sub-
jects complete titration period of the study (Visit 03) as discussed in sec-
tion 9.1  
 
All subjects known to have received study treatment will be included in the safety analy-
sis.   
 
All adverse events and abnormal laboratory values results will be listed by treatment and 
be identified by subject and site.  They will also be tabulated by treatment group, severity 
and perceived relationship to study drug.  Fisher’s exact test will be used to compare each 


 
 
 
 
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active treatment group to the placebo group with regard to the proportion of subjects ex-
periencing a particular adverse event.  Separate analyses will be performed excluding 
mild events and those categorized as unrelated to study drug.  In all comparative anal-
yses, events occurring after Baseline Visit will not be counted if the subject experienced 
the event at the Baseline Visit, unless the severity increases. 
 
A similar approach will be adopted to compare out-of-range laboratory values between 
groups. 
 
The following measures of the effect of the study drug on vital signs, specifically on or-
thostatic blood pressure will be analyzed: 
 
 Changes in vital signs recorded at each visit. 
 The proportions of subjects who develop orthostatic hypotension as defined 
by a drop in systolic blood pressure of greater than or equal 20 mm Hg and a 
drop in diastolic blood pressure of greater than or equal to 10 mm Hg when 
going from a sitting to a standing position. 
 The proportions of subjects who develop symptomatic orthostatic hypoten-
sion, defined as orthostatic blood pressure changes, as defined previously, as-
sociated with presence of positional dizziness or other symptoms. 
 
Comparisons of the active treatment group with the placebo will be made using 
one-sided Fisher’s exact tests supplemented by tests of trend in proportions to ex-
amine exposure-response relations among the four groups.  
 
Exploratory analysis:  
 
An analysis of the correlation between clinical efficacy measures and plasma PK concen-
trations will be performed. The analysis will be based on correlation of the change of the 
efficacy measures and serum concentration of isradipine measured as AUC 0-12 hour 
based on the sparse PK profile collected during the study. 
 
8.3  
Sample Size and Accrual 
 
The key issues in the determination of sample size are the variability of the primary out-
come measure and the magnitude of the treatment effect one wishes to detect. 
As regards the former, there are several sources of data regarding changes in total UP-
DRS in untreated patients to a two, three or four year point, generally following introduc-
tion of symptomatic therapy. Published sources include the CALM-PD study [57] and the 
Swedish selegiline study [58]. Unpublished data are also available from a long-term fol-
low-up of patients originally enrolled in the PRECEPT study [59]. All these studies sup-
port a standard deviation of 12.0 units for the change in total UPDRS from baseline to 36 
months. The same data suggest an average change in total UPDRS of around 4.0 points 
over this same time period.  Of course this change is deceiving, as the change would like-


 
 
 
 
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ly be much greater in the absence of symptomatic treatment. If we assume that treatment 
with levodopa or a dopaminergic agonist provides a “bonus” of 12 points, then the under-
lying true decline in function over  this period would be around 16 points, a value broadly 
consistent with the rate of change in total UPDRS in subjects prior to treatment. We have 
chosen to power our study to detect a four point effect, representing an overall 25% re-
duction in the rate of progression. We believe that a difference of this magnitude would 
be sufficient to influence clinical practice and may suggest the likelihood of longer term 
benefit.    
 
Using the above assumptions, a two-sided test with alpha = 0.05 and beta = 0.8 and mak-
ing allowance for 15% dropouts the required sample size is 168 subjects per group or a 
total 336 subjects.  
8.4  
Data Monitoring 
 
An NINDS-appointed Data and Safety Monitoring Board (DSMB) will be established to 
monitor this clinical trial. The DSMB will be responsible for periodic review of the data 
related to adverse events throughout the trial.  The frequency and format of the DSMB 
meetings, reports, will be established prior to study subject enrollment. The DSMB will 
meet approximately every 6 months.  
  8.5   Further Considerations in Data Analyses 
 
Baseline Comparisons - Baseline values of relevant clinical and demographic variables 
will be tabulated by treatment group and by site.  
 
Missing Data – If a subject is missing five or fewer items on the UPDRS at one visit, the 
values recorded on the previous visit will be carried forward.  If more than five items are 
missing, all the data from the previous visit will be carried forward. 
 
Outliers – This data will be visually checked and with scatter and residual plots.  If cer-
tain outliers appear to be implausible, the sensitivity of the primary analysis to these out-
liers will be assessed by reanalyzing the data with the outliers removed. 
 
Non-Compliance – Compliance, as measured by pill-count, will be summarized descrip-
tively by treatment group and visit. The primary analysis will include all subjects accord-
ing to the intent-to-treat (ITT) principle.  If it is detected that a subject is not taking the 
study drug correctly, the sensitivity of the primary analysis to these subjects will be as-
sessed by reanalyzing the data after removal of these subjects. 
 
Premature Withdrawal or Lost to Follow-Up – Since subjects will continue in the study 
even after initiating symptomatic treatment we expect that premature withdrawals will be 
fairly low, estimated at 15% over the course of the study. To assess the possible influence 
of incomplete follow-up on the primary analysis, supportive analyses will be conducted 
with the 36 month outcome for these subjects imputed according to their UPDRS and 
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case” and “worst case” analyses for these subjects to assess the sensitivity of our analyses 
to the “missing at random” assumption regarding dropouts.   
9 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EVENT REPORTING 
9.1 
Records Keeping 
 
9.1.1  Study File and Site Documents 
 
The Investigator should have the following study documents accessible to the Monitor 
during the study. 
 
1. FDA Form 1572 
2. Curriculum vitae for Investigator and staff with delegated responsibility for direct 
subject evaluation 
3. The signed IRB/REB form/letter stating IRB/REB approval of protocol, consent 
forms, and advertisement notices, documentation of the IRB/REB composition, and 
all IRB/REB correspondence including notification/approval of protocol amend-
ments, notification of serious adverse events to the IRB/REB, and IRB/REB notifica-
tion of study termination 
4. IRB Membership Inquiry Form 
5. IRB/REB approved consent form (sample) and advertisement 
6. Signed protocol (and amendments, where applicable) 
7. Signed Investigator Agreement forms 
8. Signed subject consent forms 
9. Copies of the completed eCRF worksheets (source), supplemental source notes and 
subject completed assessments 
10. Authorization log (Delegation Log - Study Staff and Staff Related Duties) with 
names, signatures, initials and functional role of all persons completing protocol as-
sessments, providing back-up to the site Investigator and Coordinator, if applicable, 
as well as staff entering data to the eClinical system 
11. Copies of laboratory reports/printouts  
12. Any source data/records not kept with the subject’s hospital/medical records 
13. Drug Dispensing/Return Log  
14. Laboratory accreditation and relevant laboratory reference ranges  
15. Signed and dated receipt of supplies 
16. Record of all monitoring visits made by CTCC personnel  
17. Copies of correspondence to and from Northwestern University and CTCC 
18. Package Insert for Isradipine IR. 
19. Certificate for Human Subject Protection Program (HSPP) for each individual named 
on the Delegation log who have direct subject contact 
20. Copy of professional licensure/registration, as applicable, for each individual named 
on the Delegation Log, who has direct subject contact ensuring licensure is in the 
state in which the study will be conducted 
21. Any other documentation as required by the CTCC (e.g., Conflict-of-
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22. Canadian Regulatory Forms (Canadian sites only) 
23. General Correspondence 
 
The Investigator must also retain all printouts/reports of tests/procedures, as specified in 
the protocol, for each subject.  This documentation, together with the subject’s hospi-
tal/medical records, is the subject’s SOURCE DATA for the study. 
 
9.1.2  Maintenance and Retention of Records 
 
It is the responsibility of the site Investigator to maintain a comprehensive and central-
ized filing system of all relevant documentation.  Investigators will be instructed to retain 
all study records required by the CTCC and the federal regulations in a secure and safe 
facility with limited access for one of the following time periods based on notification 
from the CTCC. 
 
Regulations require retention for: 
 
 A period of at least two years after notification from the PI that a U.S. NDA (New 
Drug Application) has been approved for the indication that was investigated.  
 Or if no NDA is filed or approved for such indication, a period of at least two years 
after the investigation is completed or discontinued.  
 
The Investigator will be instructed to consult with the CTCC before disposal of any study 
records and to notify the CTCC of any change in the location, disposition, or custody of 
the study files. 
 
Electronic Records:  
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) appli-
cation will be used for this study.  At the conclusion of the study, a PDF (portable docu-
ment format) file depicting the eCRFs for each site will be provided on electronic media 
for record keeping.  In the event of an audit or regulatory authority inspection, the eCRFs 
can be printed out. 
9.2 
Role of Data Management 
9.2.1 Data Management 
 
An Internet accessible Electronic Data Capture (EDC) system for data management will 
be utilized for this study.  This system is protected by 128-bit server certificates and uti-
lizes authenticated, password-protected accounts for each site.  The EDC system is de-
signed to ensure timeliness and accuracy of data as well as the prompt reporting of data 
from the study on an ongoing basis to the study Principal and Co-Investigators.  The sys-
tem is compliant with relevant FDA regulatory requirements per 21 CFR Part 11. 
 
The University of Rochester’s Biostatistics Center will be responsible for design of the 
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Data management staff at the CTCC will be responsible for all data collection proce-
dures. 
 
Data review, coding and query processing will be done through interaction with the 
CTCC, site personnel and the Study Monitor.  Queries will be generated in real-time as 
the data is entered.  Once the data are submitted to the EDC system, it is immediately 
stored in the central study database located at the CTCC and are accessible for review by 
data management staff.  Any changes to the data will be fully captured in an electronic 
audit trail.  As data recorded by sites in eCRFs are received, narrative text of adverse 
events and concomitant medications will be periodically coded using established coding 
mechanisms.   
 
The cycle of electronic data entry, review, query identification/resolution, and correction 
occurs over the course of the study period until all subjects have completed the study. 
 
Data will be securely transferred to the Biostatistics Center.  Once the Biostatistics Center 
and the CTCC, in conjunction with the Principal Investigator, agree that all queries have 
been adequately resolved and the database has been deemed “clean”, the database will be 
officially signed off and deemed locked.  All permissions to make changes (append, de-
lete, modify or update) the database are removed at this time.   
 
All site personnel, Northwestern University staff and CTCC staff will remain blinded as to 
treatment assignments until the conclusion of the entire study.  The treatment assignments 
are not part of the CTCC electronic database.  A designated unblinded programmer and 
unblinded statistician in the Biostatistics Center will have access to the treatment assign-
ments, and these individuals will not communicate about study-related matters to any oth-
er staff involved in the study.  The study code will be broken by the study-responsible stat-
istician after all outstanding substantive data queries have been resolved. 
 
9.2.2 Investigator Site 
 
 
This study will be conducted under the supervision and direction of the site Investiga-
tor(s) designated by the STEADY-PD III Steering Committee as the site Principal Inves-
tigator at the address provided to the CTCC.  
 
Clinical supplies will be sent to the address specified to the CTCC by the Investigator. 
 
The Investigator must not conduct the study at any sites other than the one(s) designated 
by the STEADY-PD III Steering Committee. 
 
The protocol, informed consent form, and advertisement notices will be approved by the 
site’s specified institutional IRB/REB. 
 
Each site Investigator is responsible for providing copies of the protocol and all other in-
formation relating to the preclinical and prior clinical experience, which were furnished to 
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this study.  The site Investigator will discuss this information with them to assure that they 
are adequately informed regarding the study drug and conduct of the study.  The site In-
vestigator must assure that all study staff members are qualified by education, experience 
and training to perform their specific responsibilities. 
 
9.2.3 Study Monitoring 
 
 
 
CTCC Monitoring Staff   
 
CTCC personnel with primary responsibility for this study are the assigned CTCC Clini-
cal Monitor and Project Managers. If either the CTCC Clinical Monitor or Project Man-
ager changes, the CTCC will inform Northwestern University and the investigative team 
in writing. 
 
All aspects of the study will be monitored by authorized individuals in compliance with 
Good Clinical Practice (GCP) and applicable regulations.  The Monitors will review, on a 
regular basis, the progress of the study with the Investigator and other site personnel. 
 
9.2.4  Study Committees 
 
9.2.4.1 Steering Committee 
 
The Steering Committee (SC) is composed of the Principal and Co-Principal Inves-
tigators, Biostatistician, CTCC Clinical Monitor, NINDS Project Scientist, and in-
dependent investigator members of the Parkinson Study Group with expertise in 
Parkinson disease.  The SC is responsible, along with the Northwestern University, 
for the design of the study protocol and analysis plan, and oversees the clinical trial 
from conception to analysis and publication. 
 
9.2.4.2 Data and Safety Monitoring Board 
 
An independent Data and Safety Monitoring Board (DSMB) will be appointed that 
will be responsible for periodic review of the data related to adverse events 
throughout the trial.  The frequency and format of the DSMB meetings, reports, 
will be established prior to study subject enrollment. 
 
9.2.5 Case Report Forms 
 
Sites will enter subject information and data into an electronic case report form (eCRF) in 
the Electronic Data Capture (EDC) application.  The eCRFs are used to record study data 
and are an integral part of the study and subsequent reports.  Therefore the eCRFs must 
be completed for each subject screened or enrolled according to the subject’s source data 
on a per-visit basis. Authorized study personnel will each be granted access to the elec-
tronic data capture tool via provision of a unique password-protected user-ID that will 
limit access to enter and view data specifically for subjects enrolled at their site.  Data 
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Sites will be supplied with a set of source document worksheets that correspond to the 
electronic case report form (eCRF).  The worksheets will serve as source documents and 
are required to be used to enter data into the eCRFs.  Sites will initially enter all data into 
the subject’s medical chart and/or onto source documentation worksheets prior to enter-
ing data into the eCRFs via computer stations connected remotely to the central server 
through an Internet browser.   
 
9.2.6 Electronic Signatures 
 
An electronic signature from the site Investigator is required on the following eCRFs: 
 
 Investigator Signature Form (for each visit) 
 Adverse Event Form (at the conclusion of the study) 
 Adverse Event Follow up Log (not required if AE log is blank) 
 
It is the site Investigator’s responsibility to ensure that entries are proper and complete.  
During entry of data, error checks will be performed by the EDC that will immediately 
flag problematic data (i.e., missing, out of range, inconsistent) allowing for sites to cor-
rect the data at that time.  Error checks will be implemented in the EDC based upon spec-
ifications defined in the data management plan.   
 
The data entered from the eCRFs will be securely transmitted to a central database stored 
on a secure server located at the CTCC.  Upon completion of a subject’s visit or the 
study, sites have the option to print the completed eCRFs depicting the data that were en-
tered. 
 
At the conclusion of the study, the site will be provided with a PDF (portable document 
format) file on electronic media depicting eCRFs for their site.  The PDF file should be 
printed for each subject participating in the study and filed in the subject’s binder. 
 
9.2.7 Monitoring Visits 
 
To ensure compliance with Good Clinical Practice (GCP) and other applicable regulatory 
requirements, the monitor or representative is responsible for monitoring that sites con-
duct the study according to the protocol, standard operating procedures, and other written 
instructions and regulatory guidelines. 
 
 
Monitoring visits by a Study Monitor will be arranged in advance, at a mutually-
acceptable time, with site personnel.  The site personnel must allow sufficient time for the 
Study Monitor to review CRFs and relevant source documents and queries. The Study Co-
ordinator and/or Investigator(s) should be available to answer questions or resolve data 
clarifications. 
 
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The Investigator must maintain primary source documents supporting significant data for 
each subject in the subject’s medical notes.  These documents, which are considered 
‘source data’, should include documentation of: 
 Demographic information 
 Evidence supporting the diagnosis/condition for which the subject is being studied 
 General information supporting the subject’s consent to participate in the study 
 General history and physical findings 
 Hospitalization or Emergency Room records (if applicable) 
 Each study visit by date, including any relevant findings/notes by the Investigator(s), 
occurrence (or lack) of adverse events, and changes in medication usage including the 
date the study drug commenced and completed 
 Any additional visits during the study 
 Any relevant telephone conversations with the subject regarding the study or possible 
adverse events 
 Original, signed informed consent forms for study participation 
 
The Investigator must also retain all subject specific printouts/reports of tests/procedures 
performed as a requirement of the study (e.g., laboratory and ECG reports).  Laboratory 
reports from the central laboratory will be signed and dated by the Investigator following 
review and filed with the subject’s source documents. This documentation, together with 
the subject’s hospital/site medical records, is the subject’s ‘source data’ for the study.  
During monitoring visits the Study Monitor will need to validate data in the eCRFs 
against these source data. 
 
 
9.2.9 CRF Worksheets 
 
Sites will be supplied with a set of worksheets that correspond to the electronic case report 
form (eCRF) for this study.  The worksheets will serve as source documents for study ob-
servations and assessments and should be used to enter data into the eCRF. Additional 
source documentation for information not specifically included on the source document 
may be recorded on a separate document. 
 
9.2.10 Closeout Visit 
 
Following the completion of the study, Study Monitor(s) or designee may conduct an on-
site closeout visit or a telephone closeout visit to ensure that all data queries have been re-
solved, any protocol deviations are documented appropriately, all relevant study data have 
been retrieved, that study drug and clinical supplies have been/will be properly returned 
and that the Investigator has copies of all study-related data/information on file and ar-
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9.3 
Quality Assurance 
 
9.3.1  QA Audits/Site Visits 
 
During the course of the study and after it has been completed it is likely that one or more 
study site visits will be undertaken by authorized representatives of the CTCC. 
 
The purpose of the audit is to determine whether or not the study is being, or has been, 
conducted and monitored in compliance with the protocol as well as recognized GCP 
guidelines and regulations.  These audits will also increase the likelihood that the study 
data and all other study documentation can withstand a subsequent regulatory authority 
inspection. 
 
If such audits are to occur, they will be arranged for a reasonable and agreed time.  Site 
staff will receive feedback after these visits have taken place.  Action items noted in this 
correspondence should be attended to within 1 week of receipt of the correspondence. 
 
9.3.2  Regulatory Inspections 
 
The study may be inspected by regulatory agencies, such as the Food and Drug Admin-
istration (FDA).  These inspections may take place at any time during or after the study 
and are based on the local regulations as well as ICH guidelines. 
9.4 
Adverse Event Reporting 
 
 
9.4.1  Adverse Event (AE) Definition 
 
An adverse event is any symptom, sign, illness, or experience which develops or worsens 
during the course of the study, whether or not the event is considered related to study 
drug. 
 
Some examples of adverse events are: 
 
 
A change, excluding minor fluctuations, in the nature, severity, frequency, or duration 
of a pre-existing condition. 
 
A deterioration in the subject’s condition due to the subject’s primary disease or a 
pre-existing condition. 
 
Development of an intercurrent illness during the study. 
 
Development of symptoms which may or may not be related to the use of a concomi-
tant medication or study drug. 
 
Appearance of abnormal laboratory results or significant shifts from baseline, but still 
within the reference ranges, following treatment with the study drug, which the Inves-
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9.4.2   Serious Adverse Events (SAE) 
 
A serious adverse drug event is defined as any adverse event that occurs at any dose that 
results in any of the following outcomes: 
 
 death; 
 a life-threatening adverse event; 
 inpatient hospitalization or prolongation of existing hospitalization; 
 a persistent or significant disability/incapacity; or 
 a congenital anomaly/birth defect. 
 
 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon appro-
priate medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include (but are not limited to) allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
This category also includes any event the site Investigator or the CTCC Clinical Monitor 
judges to be serious or which would suggest a significant hazard, contraindication, side 
effect or precaution.  It can also involve the withdrawal of a subject from a study due to 
abnormal lab values, excluding screening labs.   
 
Continued monitoring of marketed products for adverse events is essential and depends 
on voluntary reporting of adverse events.  For purposes of this study the following expe-
riences/events will be considered Serious Adverse Events and reportable to the FDA and 
Health Canada: 
 
1) Death 
2) Life threatening adverse event 
3) An event that is Serious AND Unexpected 
 
Reports of serious adverse events, as defined above, require immediate notification (with-
in 24 hours of the site’s awareness) to the CTCC Project Manager or CTCC Clinical 
Monitor whether or not the Investigator believes that the experience is related to study 
drug or expected.   
 
All other types of serious adverse events will be recorded on the study Adverse Event 
Log and reported to the site’s respective IRB/REB per the institution’s reporting require-
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Note: Hospitalizations that fulfill one of the following conditions do not have to be 
reported as an SAE:  
 Those for elective surgical interventions for which the date had already been deter-
mined/planned before the study participation  
 Those for situations where no untoward medical occurrence has occurred (e.g. hospi-
talization for cosmetic surgery)  
 
9.4.3 Recording of Adverse Events 
 
At each subject visit the site study staff will assess adverse events by recording all volun-
tary complaints of the subject and by assessment of clinical and laboratory features.  At 
each study visit, the subject should be questioned directly regarding the occurrence of any 
adverse event since his/her last visit.   
 
All adverse events, whether observed by the Investigator, elicited from or volunteered by 
the subject, should be recorded on the CRF Adverse Event Log.  This will include a brief 
description of the experience, the date of onset, the date of resolution, the duration and 
type of experience, the severity, contributing factors, and any action taken with respect to 
the study drug. 
 
This recording of adverse events will commence with the signing of the informed consent 
and continue until 2 weeks after stopping study drug at Visit 11 (Visit 10 +2 weeks) or 
Premature Withdrawal Follow-up visit.  All experiences/events occurring up to the Base-
line visit will be recorded as Medical History unless possibly related to a study procedure 
or the severity increases.  
 
New Serious Adverse Events (SAEs) and unresolved AEs ongoing at the time of the last 
subject visit Visit 11 (Visit 10 +2 weeks) on the AE CRF page must be followed for 30 
days from last visit or until resolution, whichever occurs first.  A follow-up phone call 
will be made to all subjects who have unresolved AEs or SAEs 30 days from the date of 
the final study visit (Visit 11 or Premature Withdrawal Follow-up visit). 
 
FOR ADVERSE EVENTS:  The Adverse Event Log CRF must be completed and be 
signed by the Investigator.  This will include information on any action taken as a result 
of the adverse event and the Investigator’s opinion of the possible relationship between 
the experience and the study drug or participation in the study. 
 
All subjects with unresolved adverse events or SAEs at the time of their final study visit 
(Visit 11 or Premature Withdrawal Follow up Visit) should have a phone call approxi-
mately 30 days after their final visit.  The purpose of this phone call is to assess the final 
outcome of the unresolved adverse events as either resolved or ongoing.  The Adverse 
Event Follow-Up Log CRF will be used to document this follow-up and will be signed by 
the Investigator. 
 
FOR PROTOCOL DESIGNATED SERIOUS ADVERSE EVENTS (death, life threaten-
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fill out the MedWatch FDA 3500 form for serious adverse event (SAE).  This will in-
clude: an identification that serious experience criteria have been met; a detailed descrip-
tion of the experience and other relevant information; the current status of the experience; 
if the subject has died, the date of death and autopsy report, if available; and the Investi-
gator’s current opinion of the relationship between the experience and the study 
drug/participation in the study.  The electronic MedWatch form should be sent to the Pro-
ject Manager for review and editing.   
 
9.4.4 Adverse Events Causality Definitions 
 
For each adverse event, the relationship to the study drug must be recorded as one of the 
following on the Adverse Event Log: 
 
 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated 
No possible relationship  The temporal relationship between drug exposure and 
the adverse event onset/course is unreasonable or in-
compatible, or a causal relationship to study drug is 
implausible. 
Unlikely 
Not reasonably related, 
although a causal rela-
tionship cannot be ruled 
out 
While the temporal relationship between drug expo-
sure and the adverse event onset/course does not pre-
clude causality, there is a clear alternate cause that is 
more likely to have caused the adverse event than the 
study drug. 
Possibly 
Causal relationship is 
uncertain 
The temporal relationship between drug exposure and 
the adverse event onset/course is reasonable or un-
known, de-challenge or re-challenge information is 
either unknown or equivocal, and while other potential 
causes may not exist, a causal relationship to the study 
drug does not appear probable. 
Probably 
High degree of certainty 
for causal relationship 
The temporal relationship between drug exposure and 
the adverse event onset/course is reasonable.  There is 
a clinically compatible response to de-challenge (re-
challenge is not required), and other causes have been 
eliminated or are unlikely. 
Definite 
Causal relationship is 
certain 
The temporal relationship between drug exposure and 
the adverse event onset/course is reasonable, there is a 
clinically compatible response to de-challenge, other 
causes have been eliminated, and the event must be 
definitive pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure if neces-
sary. 
 
 
9.4.5 
Adverse Event Severity Definitions 
 


 
 
 
 
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The severity of each adverse event must be recorded as one of the following on the Ad-
verse Event Lo5g: 
 
MILD  
No limitation of usual activities 
MODERATE Some limitation of usual activities 
SEVERE 
Inability to carry out usual activities 
 
9.4.6    Responsibilities of Investigator/CTCC for Reporting Serious Adverse Events 
 
 
 
The Investigator should record all serious adverse events that occur during the study 
period on the Adverse Event Log and in the appropriate source documents. 
 Study Period:  For the purposes of reporting serious adverse events, the study period 
is defined as the time period from when the subject signs the informed consent 
through Visit 11 (Visit 10 +2 weeks) or Premature Withdrawal Follow-up visit. 
 
The Investigator should notify the CTCC Project Manager (PM) by telephone within 
24 hours of his/her becoming aware of the occurrence of the protocol defined serious 
adverse event.  The PM will in turn notify the CTCC Clinical Monitor and Independ-
ent Medical Monitor.  The Study Coordinator will fill out the MedWatch form pro-
vided by the CTCC, and email or fax it to the CTCC Project Manager (preferably pri-
or to calling the CTCC). The MedWatch form must be completed for the protocol 
specified Serious Adverse Events (death, life threatening event, any event that is seri-
ous and unexpected). 
 
Upon completion of the telephone report, the CTCC Project Manager will enter the 
appropriate subject information into the Incident Module.  Upon completion of entry 
of the incident, an immediate notification will be disseminated by email to the Steer-
ing Committee (including PIs and Co-PI), CTCC Clinical Monitor, Independent Med-
ical Monitor, Field Monitoring Staff, CTCC Project Staff, and Biostatistics Center 
Staff. 
 
The following information should be supplied if available at the time of the telephone 
call:  study number, site number, subject number, whether the test treatment has been 
discontinued, date of onset of event, event description, whether event required treat-
ment, death and autopsy report, an identification of which criteria for a serious expe-
rience have been met, the Investigator’s current opinion of the relationship between 
the event and the study drug or study participation. 
 
The Investigator will comply with his/her local Institutional Review Board/Research 
Ethics Board regulations regarding the reporting of adverse events  
 
9.4.7  Reportable Experiences/Events 
 
The following incidents will be considered reportable events and will be reported to the 
CTCC within 24 hours of the event, or the site Investigator’s knowledge of the event. 
 
 Temporary suspension of Study Drug 
 
Study Drug Discontinuation 


 
 
 
 
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 Study Drug reduction/re-challenge 
 Subject withdrawal 
 Pregnancy 
 Protocol specified Serious adverse event (SAE) (death, life threatening event, any 
event that is serious and unexpected) 
 Emergency treatment disclosure 
 Overdosage 
 Initiation of symptomatic therapy  
 Completion of DaT Scan 
 
 


 
 
 
 
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9.4.8    Follow-Up of Unresolved Experiences/Events 
 
 All serious adverse event information will be followed for 30 days from last study 
visit or until resolution, whichever occurs first. 
 The site Investigator and CTCC Clinical Monitor will, as appropriate, provide further 
information on the event especially if the event has not resolved or stabilized at the 
time of completion of the MedWatch form.  This may involve contacting other clini-
cians responsible for the subject’s care to obtain information on diagnoses, investiga-
tions performed and treatment given. 
 
All serious adverse events occurring between the institution of protocol specific proce-
dures (i.e., when the subject signs the informed consent) through Visit 11 (Visit 10 +2 
weeks) or Premature Withdrawal Follow-up visit must be recorded and reported; then 
followed  by the site Investigator for 30 days from the last study visit or until resolu-
tion as noted above.   
 
10       HUMAN SUBJECTS  
 
 
10.1 
Compliance Statement  
 
This study will be conducted in accordance with the Good Clinical Practice (GCP) guide-
lines promulgated by the International Conference on Harmonization (ICH) and the Food 
and Drug Administration (FDA), and any applicable national and local regulations in-
cluding FDA regulations under 21 CFR Parts 11, 50, 54, 56, 312 and 314. 
 
All procedures not described in this protocol will be performed according to the study Op-
erations Manual unless otherwise stated.  Laboratory tests/evaluations described in this 
protocol will be conducted in accordance with quality laboratory standards as described in 
the central laboratory manual unless otherwise stated. 
 
10.2 
Informed Consent 
 
This study will be conducted in accordance with the provisions of 21 Code of Federal 
Regulations (CFR) Part 50.  The CTCC must be given an opportunity to review the con-
sent form prior to site IRB/REB submission and before it is used in the study. 
 
In accordance with relevant regulations, an informed consent agreement explaining the 
procedures and requirements of the study, together with any potential hazards/risks must 
be read and/or explained to each subject.  Each subject will sign such an informed con-
sent form.  The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.   
 
During the consent process, subjects will also be asked for permission to be contacted by 
the study principal investigators or their representatives for future long term follow up af-
ter study completion.    Subjects who consent to be contacted for future research will be 


 
 
 
 
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asked to provide their preferred contact information (phone, mail, email, or other pre-
ferred contact method.). This information will be stored in a secure, password protected 
database at the University of Rochester for 20 years.  This will allow centralized follow 
up for current and former subjects in this study, using methods convenient to the subjects 
(e.g., regular mail, telephone or internet contacts). All potential research projects wishing 
to use subjects who have agreed to future research must be reviewed and approved by the 
STEADY-PD III steering committee.  Any future research involving these subjects will 
require a separate IRB approved protocol and consent process. This will allow us to 1) 
minimize subjects lost-to-follow-up  2) allow for contact and consent of subjects for the 
systematic collection of data following completion of the parent study and 3) simplify 
communications with current and former subjects about future research opportunities 
through direct communication with subjects without having to go through individual 
sites. 
 
 
A copy of the consent form will be given to the subject, or legal guardian, and this fact 
will be documented in the subject’s record. The subject must be assured of the freedom to 
withdraw from participation in the study at any time. 
 
It is the Investigator’s responsibility to make sure that the subject understands what she/he 
is agreeing to and that written informed consent is obtained before the subject is involved 
in any protocol-defined procedures including screening procedures.  It is also the Investi-
gator’s responsibility to retain the original signed consent form and provide each subject 
with a copy of the signed consent form. 
 
10.3 Institutional Review Board/Independent Ethics Committee 
 
Northwestern University and the CTCC will supply all necessary information to the Site 
Investigator for submission of the protocol and consent form to the IRB/REB for review 
and approval.  The Site Investigator agrees to provide the IRB/REB all appropriate mate-
rial.  The trial will not begin until the site Investigator has obtained appropriate IRB/REB 
approval.  A copy of the approval letter and approved consent form must be submitted to 
the CTCC. 
 
The Investigator will request from the IRB/REB a composition of the IRB/REB members 
reviewing the protocol and informed consent.  Appropriate reports on the progress of this 
study by the Investigator will be made to the IRB/REB and the CTCC in accordance with 
institutional and government regulations.  The CTCC will notify the site when the 
IRB/REB may be notified of study completion. It is the Investigator’s responsibility to 
notify the IRB/REB when the study ends.  This includes study discontinuation, whether it 
is permanent or temporary. A copy of the site IRB/REB’s acknowledgement of study 
completion must be submitted to the CTCC. 
 
The Investigator will discuss any proposed protocol changes with the CTCC Project Man-
ager and no modifications will be made without prior written approval by CTCC and 
Northwestern University, except where clinical judgment requires an immediate change 


 
 
 
 
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for reasons of subject welfare.  The IRB/REB will be informed of any amendments to the 
protocol or consent form, and approval, where and when appropriate, will be obtained be-
fore implementation. 
 
10.4 
Protocol Amendments 
 
Changes to the protocol will only be made via an approved protocol amendment.  Protocol 
amendments must be approved by the PI, the study’s Steering Committee and each respec-
tive site’s IRB/REB prior to implementation, except when necessary to eliminate hazards 
and/or to protect the safety, rights or welfare of subjects.  
 
10.5 Subject Confidentiality 
 
Clinical information will not be released without written permission of the subject, except 
as necessary for monitoring by IRB/REB, the FDA, the NINDS, the OHRP, the sponsor, 
or the sponsor’s designee. 
 
The site Investigator must assure that the privacy of subjects, including their personal 
identity and personal medical information, will be maintained at all times.  U.S. sites 
have additional privacy obligations to study subjects under the Health Insurance Portabil-
ity and Accountability Act (HIPAA).  Subjects will be identified by code numbers on 
case report forms and other documents submitted to the CTCC. 
 
After a subject signs an informed consent, it is required that the site Investigator permit 
the study monitor, independent auditor or regulatory agency personnel to review the 
signed informed consent(s) and that portion of the subject’s medical record that is direct-
ly related to the study including electronic medical records.  This shall include all study 
relevant documentation including subject medical history to verify eligibility, laboratory 
test result reports, admission/discharge summaries for hospital admissions occurring 
while the subject is in the study, and autopsy reports for deaths occurring during the study 
(when available).   
 
The subject’s Authorization allows the CTCC to receive and review the subjects’ protected 
health information that may be re-disclosed to any authorized representative of the PI, 
CTCC or central laboratory facility for review of subject medical records in the context of 
the study. 
10.6  Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB/REB, the NINDS, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that re-
search subjects are protected. 
 


 
 
 
 
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11 
DATA SHARING 
Government funded studies require data sharing.  All subjects will be informed that their 
de-identified data collected will be made available for sharing. The study data collected 
will be coded and may be used for future unspecified research purposes, for example to 
develop future studies of PD and related disorders.  
 
The research information collected will be labeled with a unique identification code. By 
using this code, the subject’s identity will not be disclosed to any researchers using this 
data in the future.   
 
12 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures de-
veloped by the Parkinson Study Group.  Any presentation, abstract, or manuscript on the 
primary results will be made available for review by the NINDS and the DSMB prior to 
submission. 


 
 
 
 
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13. 
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Dorsey, E.R., et al., Projected number of people with Parkinson disease in the most 
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Braak, H., et al., Stages in the development of Parkinson's disease-related pathology. Cell 
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Dodel, R.C., et al., The economic impact of Parkinson's disease. An estimation based on 
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Olanow, C.W., R.L. Watts, and W.C. Koller, An algorithm (decision tree) for the 
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Suchowersky, O., et al., Practice Parameter: neuroprotective strategies and alternative 
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Jankovic, J. and C. Hunter, A double-blind, placebo-controlled and longitudinal study of 
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A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. 
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Whone, A.L., et al., Slower progression of Parkinson's disease with ropinirole versus 
levodopa: The REAL-PET study. Ann Neurol, 2003. 54(1): p. 93-101. 
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slowing of the functional decline. Arch Neurol, 2002. 59(10): p. 1541-50. 
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A randomized, double-blind, futility clinical trial of creatine and minocycline in early 
Parkinson disease. Neurology, 2006. 66(5): p. 664-71. 


 
 
 
 
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21. 
A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. 
Neurology, 2007. 68(1): p. 20-8. 
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disease. Nature, 2007. 
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1992. 32(5): p. 667-76. 
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Fronczek, R., et al., Hypocretin (orexin) loss in Parkinson's disease. Brain, 2007. 130(Pt 
6): p. 1577-85. 
25. 
Thannickal, T.C., Y.Y. Lai, and J.M. Siegel, Hypocretin (orexin) cell loss in Parkinson's 
disease. Brain, 2007. 130(Pt 6): p. 1586-95. 
26. 
Jellinger, K.A., A critical evaluation of current staging of alpha-synuclein pathology in 
Lewy body disorders. Biochim Biophys Acta, 2009. 1792(7): p. 730-40. 
27. 
Travagli, R.A. and R.A. Gillis, Hyperpolarization-activated currents, IH and IKIR, in rat 
dorsal motor nucleus of the vagus neurons in vitro. J Neurophysiol, 1994. 71(4): p. 1308-
17. 
28. 
Burlhis, T.M. and G.K. Aghajanian, Pacemaker potentials of serotonergic dorsal raphe 
neurons: contribution of a low-threshold Ca2+ conductance. Synapse, 1987. 1(6): p. 
582-8. 
29. 
Takakusaki, K. and S.T. Kitai, Ionic mechanisms involved in the spontaneous firing of 
tegmental pedunculopontine nucleus neurons of the rat. Neuroscience, 1997. 78(3): p. 
771-94. 
30. 
Williams, J.T. and K.C. Marshall, Membrane properties and adrenergic responses in 
locus coeruleus neurons of young rats. J Neurosci, 1987. 7(11): p. 3687-94. 
31. 
Chan, C.S., et al., 'Rejuvenation' protects neurons in mouse models of Parkinson's 
disease. Nature, 2007. 447(7148): p. 1081-6. 
32. 
Ilijic, E., J.N. Guzman, and D.J. Surmeier, The L-type channel antagonist isradipine is 
neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis, 2011. 43(2): p. 
364-71. 
33. 
Bean, B.P., Nitrendipine block of cardiac calcium channels: high-affinity binding to the 
inactivated state. Proc Natl Acad Sci U S A, 1984. 81(20): p. 6388-92. 
34. 
Johnson, B.A., et al., Kinetic and cardiovascular comparison of immediate-release 
isradipine and sustained-release isradipine among non-treatment-seeking, cocaine-
dependent individuals. Prog Neuropsychopharmacol Biol Psychiatry, 2005. 29(1): p. 15-
20. 
35. 
Christensen, H.R., et al., Bioavailability and pharmacokinetics of isradipine after oral 
and intravenous administration: half-life shorter than expected? Pharmacol Toxicol, 
2000. 86(4): p. 178-82. 
36. 
Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-
modifying intervention in early Parkinson's disease (STEADY-PD). Mov Disord, 2013. 
37. 
Christensen, H.R., H.R. Angelo, and K. Skajaa, Determination of isradipine and its 
pyridine metabolite in serum by capillary column gas chromatography with nitrogen-
selective detection. J Chromatogr, 1992. 574(1): p. 161-5. 
38. 
Christensen, H.R., J.P. Kampmann, and K. Simonsen, A randomized comparison of 
isradipine slow release given once daily with isradipine twice daily on 24 hour blood 
pressure in hypertensive patients. J Hum Hypertens, 1991. 5(2): p. 121-7. 


 
 
 
 
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39. 
Christensen, H.R., K. Simonsen, and J.P. Kampmann, Pharmacokinetics and dynamic 
response of plain and slow release isradipine formulations in moderately hypertensive 
patients. Pharmacol Toxicol, 1993. 73(5): p. 279-84. 
40. 
Holmes, D.G. and K. Kutz, Bioequivalence of a slow-release and a non-retard 
formulation of isradipine. Am J Hypertens, 1993. 6(3 Pt 2): p. 70S-73S. 
41. 
Becker, C., S.S. Jick, and C.R. Meier, Use of antihypertensives and the risk of Parkinson 
disease. Neurology, 2008. 
42. 
Ritz, B., et al., L-type calcium channel blockers and Parkinson disease in Denmark. Ann 
Neurol, 2010. 67(5): p. 600-6. 
43. 
Pasternak, B., et al., Use of calcium channel blockers and Parkinson's disease. Am J 
Epidemiol, 2012. 175(7): p. 627-35. 
44. 
Simuni, T., et al., Tolerability of isradipine in early Parkinson's disease: a pilot dose 
escalation study. Mov Disord, 2010. 25(16): p. 2863-6. 
45. 
physician desk reference PDR.  [cited 2010 February 10]; Available from: 
http://www.pdr.net/druginformation/DocumentSearchn_Local.aspx?DocumentID=32700
580&DrugName=DynaCirc%20CR%20Controlled%20Release%20Tablets. 
46. 
Weir, M.R., C. Rosenberger, and J.C. Fink, Pilot study to evaluate a water displacement 
technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity 
edema due to dihydropyridine calcium antagonists. Am J Hypertens, 2001. 14(9 Pt 1): p. 
963-8. 
47. 
Hughes, A.J., S.E. Daniel, and A.J. Lees, Improved accuracy of clinical diagnosis of 
Lewy body Parkinson's disease. Neurology, 2001. 57(8): p. 1497-9. 
48. 
Goetz, C.G., P.A. LeWitt, and M. Weidenman, Standardized training tools for the 
UPDRS activities of daily living scale: newly available teaching program. Mov Disord, 
2003. 18(12): p. 1455-8. 
49. 
Goetz, C.G., et al., Teaching tape for the motor section of the unified Parkinson's disease 
rating scale. Mov Disord, 1995. 10(3): p. 263-6. 
50. 
Richards, M., et al., Interrater reliability of the Unified Parkinson's Disease Rating Scale 
motor examination. Mov Disord, 1994. 9(1): p. 89-91. 
51. 
Fahn S, E.R., Members of the UPDRS Development Committee, The Unified 
Parkinson’s Disease Rating Scale., in Recent developments in Parkinson’s disease, Vol 
2., M.C. Fahn S, Calne DB, Goldstein M, Editor, Macmillan Health Care Information, 
1987: Florham Park, NJ. p. 153-164. 
52. 
Schwab RS, E.A., Projection technique for evaluating surgery in Parkinson’s disease.  , 
in Third Symposium on Parkinson’s Disease, D.I. Gillingham FJ, Editor 1969, E & S 
Livingstone: Edinburgh, Scotland. p. 152-157. 
53. 
Leentjens, A.F., et al., The validity of the Beck Depression Inventory as a screening and 
diagnostic instrument for depression in patients with Parkinson's disease. Mov Disord, 
2000. 15(6): p. 1221-4. 
54. 
Gill, D.J., et al., The Montreal cognitive assessment as a screening tool for cognitive 
impairment in Parkinson's disease. Mov Disord, 2008. 23(7): p. 1043-6. 
55. 
Posner, K., et al., Columbia Classification Algorithm of Suicide Assessment (C-CASA): 
classification of suicidal events in the FDA's pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry, 2007. 164(7): p. 1035-43. 
56. 
Holford, N.H. and J.G. Nutt, Interpreting the results of Parkinson's disease clinical 
trials: time for a change. Mov Disord, 2011. 26(4): p. 569-77. 


 
 
 
 
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57. 
Holloway, R.G., et al., Pramipexole vs levodopa as initial treatment for Parkinson 
disease: a 4-year randomized controlled trial. Arch Neurol, 2004. 61(7): p. 1044-53. 
58. 
Palhagen, S., et al., Selegiline slows the progression of the symptoms of Parkinson 
disease. Neurology, 2006. 66(8): p. 1200-6. 
59. 
Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson 
disease. Neurology, 2007. 69(15): p. 1480-90. 
 
 

SAP_001.pdf: 
STEADY-PD III  
SAP 01DEC2017 
 
Page 1 of 11 
 
 
 
 
 
 
 
 
 
 
 
STEADY-PD III 
(Efficacy Assessment of Isradipine in early Parkinson Disease) 
 
STATISTICAL ANALYSIS PLAN AND POWER CALCULATIONS 
 
David Oakes, Ph.D. 
Supported by: 
The National Institute of Neurological Disorders and Stroke (NINDS) 
Grant Numbers:   
U01NS080818-01A1 and U01NS080840-01A1 
Sponsor of IND: 
Tanya Simuni, MD- IND application  
IND application number 113,513 
Biomarker and DNA sample collection substudy  
Supported by Michael J. Fox Foundation  
 
 
 
 
ClinicalTrials.gov  NCT02168842


STEADY-PD III  
SAP 01DEC2017 
 
Page 2 of 11 
 
1. Introduction 
 
     A. The statistical analysis of the STEADY-PD III study will be performed by the 
Statistical Center located in the Department of Biostatistics and Computational Biology 
(DBCB) in the University of Rochester Medical Center, under the direction of the 
primary biostatistician, Dr. David Oakes.  
 
     B.  Following our standard procedures, Dr. Oakes will remain blinded throughout the 
study in order that he may participate fully in Steering Committee deliberations. Dr. 
Oakes will attend open sessions of the DSMB but not closed sessions, in which data by 
treatment arm may be discussed.  Tabulations of data by coded treatment group and 
interim analyses as described in Section 8 of this document will be performed by, or 
under the direction of, the unblinded biostatistician, Dr. Michael P. McDermott. Dr. 
McDermott will attend the closed sessions of the DSMB.  
 
     C.  The detailed statistical analysis plan will be finalized during the course of the 
study, implemented in SAS (version 9.2 or higher) and, prior to unblinding, tested on a 
preliminary version of the STEADY-PD III database, using an artificially simulated 
“treatment” classification. The main features of this plan are given below. On completion 
of the final analysis the DBCB will produce full analysis notebooks for distribution to 
Drs. Simuni and Biglan, to the Steering Committee and to the DSMB. Searchable CDs 
containing the same information will also be prepared. The DBCB will assist in 
preparation of abstracts, power point presentations and manuscripts from the study. 
 
 
2. General Considerations 
 
     A.  Intent-to-Treat. Efficacy analyses will use the intent-to-treat principle, whereby all 
subjects are kept in their assigned treatment groups for statistical analysis, even if they 
discontinue study medication or continue on a reduced dosage. Subjects who discontinue 
study medication will be encouraged to remain in the study and their data will be used in 
the primary efficacy analysis.  Subjects who have no post-baseline efficacy data will be 
excluded from the primary analysis as their primary outcome variable will be missing. 
The primary analysis will compare the active treatment group (all subjects randomized to 
receive active isradipine) to the placebo group. All P-values for efficacy outcomes will be 
two-sided.   
 
     B.  Baseline Characteristics.  Demographic and clinical characteristics, including age, 
gender, race and ethnicity, years of education, time since PD diagnosis, UPDRS score at 
entry including its mental, motor and ADL components, MDS-UPDRS, Modified Rankin 
Score, Modified Hoehn and Yahr score, PDQ-39 score, MOCA score (adjusted for 
education level) of the two treatment groups will be presented. Systolic and Diastolic 
blood pressure and other vital signs data will also be shown. 
  
     C.  Subject Disposition. Losses to follow-up, compliance to study medication, protocol 
violations and other notifiable incidents will be tabulated. A CONSORT type diagram 
showing the progress of all enrolled subjects through the study will be prepared. 


STEADY-PD III  
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Page 3 of 11 
(Numbers of subjects screened but ineligible, and those eligible but not enrolled, will be 
provided by the CTCC).   
 
 
3. Primary Efficacy Analysis 
 
A. Outcome Variable. The pre-specified primary outcome variable will be the 
change from baseline to the three-year follow-up visit in the total score from Parts I, II 
and III of the UPDRS score (mental, motor and ADL components). We anticipate that by 
the three year visit a substantial majority of participants will be receiving symptomatic 
medication.  Unlike in previous studies in early PD (e.g. DATATOP, PRECEPT, 
QE3)[1-3] subjects who require symptomatic treatment (typically levodopa or dopamine 
agonists) during the course of the study will continue in the study, receiving their 
assigned study medication. By this strategy we hope to minimize drop-outs.  For subjects 
receiving symptomatic medication the UPDRS will be assessed in the ON state, based on 
the subject/ investigator defined BEST ON, approximately 1 hour after dose of 
symptomatic therapy). Subjects who do not complete the three-year visit will have their 
primary outcome variable set to missing: a variety of sensitivity analyses (see below) will 
be conducted to assess the influence of these subjects on the primary analysis.  
 
B. Statistical Model. The primary analysis will use analysis of covariance applied to 
the change from baseline in the total UPDRS score. The baseline value will also be 
entered into the model as a continuous variable, the assigned treatment and enrolling site 
will be entered as categorical variables. A two-tailed test with alpha = 0.05 will be used 
to declare statistical significance.  
   
C. Adjustments to the Analysis. (i) It may occasionally happen that certain items on 
the UPDRS are missing at a particular visit, for example if a subject is unable to perform 
a test due to injury. To enable the valid data from that visit for that subject to be used in 
the analysis, single missing items on the UPDRS will be carried forward from the 
subject’s previous visit. A maximum of five missing items may be carried forward in this 
way, including from the baseline visit to the one-month visit if necessary. Items missing 
at baseline may be carried forward from the screening visit. (ii) For analyses that include 
the enrolling site as a stratification factor, sites that enroll fewer than four subjects will be 
combined to form a single “super-site”.  
 
 
4. Secondary Efficacy Analyses  
 
A.  36-month data. The changes from baseline to 36 months in the following 
measures of disability will be analyzed in a similar fashion as that for the primary 
outcome variable 
 
I.  
Motor disability 
a.   The change in UPDRS Part III Motor subscale in the defined 
medications OFF state (approximately 12 hours after the last dose of 
symptomatic therapy for those subjects that have initiated symptomatic 
therapy) 


STEADY-PD III  
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Page 4 of 11 
b. MDS-UPDRS Motor score in the defined medications ON state (as per 
the primary outcome) 
c. The change in the ambulatory capacity (sum of 5 UPDRS questions: 
falling, freezing, walking, gait, postural stability)  
d. Proportion of subjects receiving symptomatic therapy  
e. Current usage of symptomatic therapy utilization as measured by 
levodopa equivalence dose[4]  
f. Prevalence of motor complications as measured by UPDRS IV 
subscale (complications of therapy) for those subjects that have 
initiated symptomatic therapy 
II. 
Cognitive disability  
a. The change in the cognitive function as measured by the change in the     
MoCA [5, 6]  
III. 
Measure of global disability   
a. The change in the Modified Rankin score  
IV. 
Measures of functional  status and quality of life  
a. The change in Activities of Daily Living (ADL) subscale of the 
UPDRS  
b. The change in Non-motor and Motor Experiences of Daily Living 
scores of the MDS-UPDRS ( Part I and II)  
c. The change in the modified Schwab and England scale  
d. The change in Parkinson Disease Quality of Life Questionnaire-39 
(PDQ-39) [7]  
 
B. Longitudinal Analyses. Outcome data from all subject visits will be plotted over    
time by treatment group.   
           
I. Time-dependent events  
Kaplan-Meier plots and Cox regression will be used to analyze the following 
events: 
a.   Time to initiation of symptomatic therapy 
b. Time to complications of symptomatic therapy, including wearing-off, 
dyskinesias and sudden “on-offs”.  
     
 II. Early Effects:  
a. Plots of the mean and standard error of the total UPDRS and related 
outcome variables will be constructed.   
b. Changes in total UPDRS from baseline to the one year visit or to the 
initiation of symptomatic therapy between treatment groups will be 
compared using analysis of covariance (as for the three-year analysis). 
c.   Changes in total UPDRS following the introduction of symptomatic 
therapy will be compared between treatment groups in the same way.  
d. Multiple regression analysis and other techniques as appropriate will be 
used to examine whether early outcomes (e.g. short-term changes in 
UPDRS, time to initiation of symptomatic therapy) are useful predictors 
of long-term disability.  
 


STEADY-PD III  
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Page 5 of 11 
C. Sensitivity Analyses.  A variety of sensitivity analyses will be conducted to assess 
the robustness of the comparison between treatment groups. 
 
I. 
Non-parametric methods.  Residual plots will be examined. In the event 
that these show outliers or pronounced non-normality, supplementary 
analyses will be performed after deletion of outliers and/or using 
appropriate non-parametric methods. 
II. 
Missing Data.  Effects of missing data will be assessed (i) by multiple 
imputation and (ii) by “best case” and “worst-case” analysis and (iii) by 
the use of mixed models (which use intermediate study data to project 
final study outcomes when these are missing). 
III. Influence of Symptomatic Medication. Supplementary analyses of the 
final study outcomes will be conducted with current use of symptomatic 
medication (levodopa equivalents) added as an additional predictor 
variable. The purpose of this analysis is to assess whether any differences 
seen in the primary outcome variable could be attributed to differential use 
of symptomatic therapy between the treatment groups.  
  
D.  Subgroup Analyses – Including Gender and Race/ Ethnicity 
       
Recognizing that the study will not have high power to detect treatment effects among 
subgroups, we will conduct exploratory analyses to check the consistency of treatment 
effects on the primary and secondary efficacy measures in relation to selected baseline 
characteristics, including gender and race/ ethnicity. The analysis will use two 
approaches (i) repeating the primary analysis for each subgroup (for example men and 
women; minority and non-minority) separately, (ii) inclusion of additional terms in the 
analysis of covariance model to represent the overall effect of the characteristic (do men 
progress faster than women?)  and for the interaction of the  treatment with the 
characteristic (does the effect of the treatment differ between men and women?).  Results 
for each race/ethnic grouping will be tabulated separately.  
 
 
5. Safety and Tolerability Analysis 
 
A.  Primary Safety and Tolerability Outcomes. 
I. 
The ability to complete the 36 months study on the originally 
assigned treatment dosage 
II. 
The proportion of subjects requiring dosage reductions secondary 
to intolerability 
III. 
The frequency of adverse events and serious adverse   events  
IV. 
Laboratory and EKG abnormalities 
V. 
An interim tolerability analysis will be performed after the first 60 
subjects complete titration period of the study (Visit 03) as 
discussed in section 8.C. 
 
B. Procedure.  
All subjects known to have received study treatment will be included in the safety 
analysis.   


STEADY-PD III  
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Page 6 of 11 
 
All adverse events and abnormal laboratory values results will be listed by treatment and 
be identified by subject and site.  They will also be tabulated by treatment group, severity 
and perceived relationship to study medication.  Fisher’s exact test will be used to 
compare each active treatment group to the placebo group with regard to the proportion 
of subjects experiencing a particular adverse event.  Separate analyses will be performed 
excluding mild events and those categorized as unrelated to study medication.  In all 
comparative analyses, events occurring after Baseline Visit will not be counted if the 
subject experienced the event at the Baseline Visit, unless the severity increases. 
 
A similar approach will be adopted to compare out-of-range laboratory values between 
groups. 
 
The following measures of the effect of the study drug on vital signs, specifically on 
orthostatic blood pressure will be analyzed: 
 
 Changes in vital signs recorded at each visit. 
 The proportions of subjects who develop orthostatic hypotension as 
defined by a drop in systolic blood pressure of greater than or equal 20 
mm Hg and a drop in diastolic blood pressure of greater than or equal 
to 10 mm Hg when going from a supine to a standing position. 
 The proportions of subjects who develop symptomatic orthostatic 
hypotension, defined as orthostatic blood pressure changes, as defined 
previously, associated with presence of positional dizziness or other 
symptoms. 
 
Comparisons of the active treatment group with the placebo will be made using by 
Fisher’s exact tests 
 
C. Analysis by Subgroups, Including Race and Gender.  
Primary safety and tolerability data will be tabulated separately for selected subgroups of 
the population defined by baseline characteristics, including gender and race/ethnicity. 
 
6. Exploratory Analysis 
 
An analysis of the correlation between clinical efficacy measures and serum PK 
concentrations will be performed. The analysis will be based on correlation of the change 
of the efficacy measures and serum concentration of isradipine measured as AUC 0-12 
hour based on the sparse PK profile collected during the study. 
 
7. Power and Sample Size Considerations 
 
The key issues in the determination of sample size are the variability of the primary 
outcome measure and the magnitude of the treatment effect one wishes to detect. 
As regards the former, there are several sources of data regarding changes in total 
UPDRS in untreated patients to a two, three or four year point, generally following 
introduction of symptomatic therapy. Published sources include the CALM-PD study [8] 
and the Swedish selegiline study [9]. Unpublished data are also available from a long-


STEADY-PD III  
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Page 7 of 11 
term follow-up of patients originally enrolled in the PRECEPT study [2]. All these 
studies support a standard deviation of 12.0 units for the change in total UPDRS from 
baseline to 36 months. The same data suggest an average change in total UPDRS of 
around 4.0 points over this same time period.  Of course this change is deceiving, as the 
change would likely be much greater in the absence of symptomatic treatment. If we 
assume that treatment with levodopa or a dopaminergic agonist provides a “bonus” of 12 
points, then the underlying true decline in function over  this period would be around 16 
points, a value broadly consistent with the rate of change in total UPDRS in subjects prior 
to treatment. We have chosen to power our study to detect a four point effect, 
representing an overall 25% reduction in the underlying rate of progression. We believe 
that a difference of this magnitude would be sufficient to influence clinical practice and 
may suggest the likelihood of longer term benefit.    
 
Using the above assumptions, a two-sided test with alpha = 0.05 and beta = 0.8 and 
making allowance for 15% dropouts the required sample size is 168 subjects per group or 
a total 336 subjects.  
 
The Table below shows the effect of higher than expected withdrawal rates (20% and 
25%) expressed in three alternative metrics (A) The power to detect a 4.0 point 
difference, (B) The effect size that would be detectable with 80% power and (C) the 
number of additional subjects that would need to be enrolled to maintain power at 80% to 
detect a 4.0 point difference. 
 
   Overall Withdrawal Rate           Power (A)     Effect Size (B)   Additional Subjects (C) 
             15%                                     80%              4.0 pts.                   0 
             20%                                     78%              4.1 pts                  21 
             25%                                     75%             4.25 pts.                45 
 
Power for key secondary outcomes 
 
We will also examine power for some key secondary outcomes of this study.  
Time to Initiation of Symptomatic  Therapy. After allowing for 15% dropouts, half of 
these prior to need for symptomatic therapy, and 10% of subjects not requiring 
symptomatic treatment three years after enrollment, we estimate that approximately 275 
subjects will have reached this milestone by the conclusion of the study. By the formula 
of George and Desu[10], this translates to a detectable hazard ratio of 0.71, i.e. a 29% 
reduction in the risk of reaching this milestone per unit of time.   
 
Rationale for the selection of this secondary outcome: 
Time to initiation of symptomatic therapy has been a primary outcome in a number of 
previously completed studies that examined the efficacy of putative disease modifying 
interventions[2, 3, 11]. While it has been criticized for the subjective nature of the 
measure and being impacted by the change in the treatment algorithms that overall lead to 
the earlier initiation of symptomatic therapy, nevertheless it can be considered a surrogate 
measure of the disease progression and as such should be considered as a key secondary 
outcome.  
 


STEADY-PD III  
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Page 8 of 11 
 Complications of Therapy.  In the CALM-PD study approximately 40% of subjects 
enrolled experienced complications of therapy within two years of follow-up. Since 
subjects in CALM-PD were enrolled at the time they needed therapy, the experience of 
our subjects after three years of follow-up is expected to be similar. A total of 120 
subjects reaching this milestone gives a detectable hazard ratio of 0.60, i.e., a reduction of 
40% in the risk per unit of time. For the purpose of this analysis complications of therapy 
will be measured by UPDRS IV subscale (complications of therapy) for those subjects 
that have initiated symptomatic therapy 
 
Rationale for the selection of this secondary outcome: 
Time to onset of motor complications is considered an important milestone in the disease 
progression signifying transition from early to more advanced disease and has been used 
as a primary outcome in a  number of previously completed studies[12-14] . A disease 
modifying intervention that shows an impact on this milestone will have a meaningful 
impact on the progression of disability and as such should be considered as a key 
secondary outcome.  
 
Symptomatic Therapy (Levodopa Equivalent Dosage). Data on 168 subjects who had a 
follow-up visit in the “Postcept” extension of the “Precept” study between 2.5 and 3.5 
years after their enrollment in Precept showed a mean dosage of 390 units and s.d. of 
277.  These numbers give a detectable effect size of 92 units, approximately a 25% 
reduction in the dosage of symptomatic therapy. 
 
Rationale for the selection of this secondary outcome:  
The dose and type of symptomatic therapy are influenced by a large number of variables 
but nevertheless generally can be considered a surrogate measure of the disease severity. 
In addition there is consistent data on correlation of the dose of levodopa with the time to 
onset of motor complications[14].  A disease modifying intervention that shows an 
impact on this milestone will have a meaningful impact on the progression of disability 
and as such should be considered as a key secondary outcome. 
 
MDS-UPDRS. Data on the 67 subjects from the PPMI cohort who have been followed for 
three years from enrollment, gives changes (mean, s.d.) in the non-motor EDL of (2.55, 
4.37) and in the motor EDL of (3.07, 5.16). These translate to detectable effect sizes of 
1.5 points on the non-motor EDL scale and 1.7 points on the motor EDL scale.   
 
Rationale for the selection of this secondary outcome: 
Patient reported outcomes are an important measure of efficacy of any intervention. Non-
motor disability is an intrinsic part of overall PD disease burden, is directly linked to the 
spread of PD pathology and has been shown in multiple studies to correlate with the 
disease related quality of life impairment [15]. MDS-UPDRS has been substantially 
expanded compared to UPDRS to capture patient reported scope of non-motor disability.   
A disease modifying intervention that shows an impact on this milestone will have a 
meaningful impact on the progression of disability and as such should be considered as a 
key secondary outcome. 
 
 
 


STEADY-PD III  
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8. Interim Analyses  
 
A. Procedure.  Interim analyses will be planned by the primary biostatistician (Dr. 
Oakes) with input from the PI’s  and Steering Committee, but executed by the unblinded 
statistician (Dr. McDermott) and included in the closed session reports to the DSMB.  
 
B. Interim tolerability analysis. An interim tolerability analysis will be performed 
after the first 60 subjects complete the titration period of the study (Visit 03 (Month 3). 
Tolerability will be defined as ability to achieve and maintain target daily dosage of study 
drug (10 mg) by the end of titration period. The tolerability threshold will be defined as 
more than 30% difference in the tolerability of the active treatment group relative to the 
placebo group. Only dosage reductions, discontinuations, and premature terminations due 
to intolerability will be included in the analysis, terminations for other reasons will not be 
included in this analysis. The study may be terminated if tolerability parameters are not 
met.  
 
C. Interim analysis of the Pharmacokinetic (PK) data. An interim PK analysis will 
be performed after the first 60 subjects who reach target daily dose of 10 mg complete the 
titration phase of the study to assure that serum concentrations fall within predicted 
range. Cmin and Cmax serum concentrations will be analyzed. Only data on the subjects 
who have reached 10mg dose of study drug (Isradipine IR or placebo) will be included in 
the interim analysis. For subjects receiving active isradipine, we expect Cmin 
concentration to be 0.4+0.2 ng/ml (1 SD from the Cmin mean). Thus Cmin = 0.2 ng/ml 
should be established as the threshold of the therapeutic effect. In case mean Cmin 
concentrations fall below 0.2 ng/ml, remediating actions will be implemented as 
described in the protocol.  
 
Interim futility and efficacy analysis. Following a decision by NINDS based on a 
recommendation from the Data and Safety Monitoring Board at their October 11, 2017 
meeting, the proposed interim and futility analysis will NOT be performed. The quoted 
text below, taken from the original SAP, is therefore inoperative. “An interim analysis for 
futility and efficacy will be performed after primary outcome data are available for the 
first 168 subjects (50%) to enroll in the study. The study will be terminated for futility if 
the interim analysis shows that the conditional power of rejecting the null hypothesis in 
favor of a beneficial effect of isradipine is lower than 20% under any scenario that is 
consistent with the data accrued at that time.  A two-sided P-value in favor of isradipine 
of less than 0.001 will be required to stop for efficacy at the interim analysis. If the 
recruitment rate falls below that projected, the interim analysis may be brought forward 
and performed as soon as the first 30% of the subjects to enroll have completed (or 
terminated). In that case a second interim analysis for futility will be conducted on the 
first 75% of subjects to enroll. The stringent alpha level for efficacy was chosen so as to 
have minimal effect on the final P-value, should the study run to completion. In 
addressing futility the DSMB will examine a range of possible treatment effects 
consistent with the data obtained in the study at the time of analysis.”   
 
E. General Reporting to the DSMB. Two weeks prior to each DSMB meeting the 
Biostatistics Center will distribute “open” and ‘closed” session reports. The open session 


STEADY-PD III  
SAP 01DEC2017 
 
Page 10 of 11 
report will include only aggregate data; the closed session report will include the same 
data classified by treatment group, coded Red or Blue.  The actual codes - Active 
Isradipine or Placebo - will be available to the committee should the DSMB Chair 
request this information. In any case the color coding will be consistent within and 
between reports.  The reports will include tables of subject enrollments, baseline 
characteristics, disposition, listings of deaths, withdrawals, unblindings, serious adverse 
events, drug discontinuations and dosage reductions and other study incidents. Adverse 
events, out of range laboratory values, major changes from baseline in vital signs data 
including blood pressure measurements, (see 5B above) will be tabulated with flags 
indicating nominal imbalances between treatment groups (P < 0.05).  Home blood 
pressure measurements will not included in the study data-base, however clinical 
monitor actions in response to blood pressure alerts will be included.   
 
 
9.  Sample Size Review and Re-estimation  
 
The assumptions made in the power calculation will be kept under constant review. 
While primary outcome data will not be available for any subject till three years after 
commencement of enrollment, we will monitor recruitment and retention rates 
throughout and compare the aggregate experience of Steady-PD III subjects, including 
short-term changes in UPDRS, and the usage of symptomatic therapy, with those 
observed in other recent studies in early PD, including PRECEPT and QE3. Where 
applicable, for example in regards to dosage adjustments, we will also compare the 
aggregate experience in STEADY-PD III with the experience in STEADY-PD II.  A 
formal reassessment of the required sample size, including a blinded evaluation of the 
variability of the primary outcome measure, will be made prior to the conclusion of 
enrollment in the study and at the time of each interim analysis. 


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References 
 
 
1. 
Effects of tocopherol and deprenyl on the progression of disability in early 
Parkinson's disease. The Parkinson Study Group. N Engl J Med, 1993. 328(3): p. 
176-83. 
2. 
Parkinson Study Group Mixed lineage kinase inhibitor CEP-1347 fails to delay 
disability in early Parkinson disease. Neurology, 2007. 69(15): p. 1480-90. 
3. 
Parkinson Study Group, Q.E.I., et al., A randomized clinical trial of high-dosage 
coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol, 
2014. 71(5): p. 543-52. 
4. 
Tomlinson, C.L., et al., Systematic review of levodopa dose equivalency reporting 
in Parkinson's disease. Mov Disord, 2010. 25(15): p. 2649-53. 
5. 
Zadikoff, C., et al., A comparison of the mini mental state exam to the Montreal 
cognitive assessment in identifying cognitive deficits in Parkinson's disease. Mov 
Disord, 2008. 23(2): p. 297-9. 
6. 
Nasreddine, Z.S., et al., The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc, 2005. 53(4): p. 
695-9. 
7. 
Peto, V., et al., The development and validation of a short measure of functioning 
and well being for individuals with Parkinson's disease. Qual Life Res, 1995. 
4(3): p. 241-8. 
8. 
Holloway, R.G., et al., Pramipexole vs levodopa as initial treatment for 
Parkinson disease: a 4-year randomized controlled trial. Arch Neurol, 2004. 
61(7): p. 1044-53. 
9. 
Palhagen, S., et al., Selegiline slows the progression of the symptoms of Parkinson 
disease. Neurology, 2006. 66(8): p. 1200-6. 
10. 
George, S.L. and M.M. Desu, Planning the size and duration of a clinical trial 
studying the time to some critical event. J Chronic Dis, 1974. 27(1): p. 15-24. 
11. 
Effect of deprenyl on the progression of disability in early Parkinson's disease. 
The Parkinson Study Group. N Engl J Med, 1989. 321(20): p. 1364-71. 
12. 
Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. 
Arch Neurol, 2009. 66(5): p. 563-70. 
13. 
Rascol, O., et al., A five-year study of the incidence of dyskinesia in patients with 
early Parkinson's disease who were treated with ropinirole or levodopa. 056 
Study Group. N Engl J Med, 2000. 342(20): p. 1484-91. 
14. 
Warren Olanow, C., et al., Factors predictive of the development of Levodopa-
induced dyskinesia and wearing-off in Parkinson's disease. Mov Disord, 2013. 
28(8): p. 1064-71. 
15. 
Barone, P., et al., The PRIAMO study: A multicenter assessment of nonmotor 
symptoms and their impact on quality of life in Parkinson's disease. Mov Disord, 
2009. 24(11): p. 1641-9. 
 


 
                               STEADY-PD III   STATISTICAL ANALYSIS PLAN - CLARIFICATION  
         The purpose of this document is to clarify two aspects of the SAP from December 2017.   
(1) Combining sites with low enrollment.  The SAP, section 3.C. states that for analyses that use sites 
as a stratification factor, sites with enrolling fewer than four subjects will be combined to form a 
single “super-site”.   The sites affected  are 016 (Ottawa) three subjects, 030 (Calgary) two 
subjects, 034 (IND) three subjects, 069 (PMDI), three subjects, 110 (UC Irvine), three subjects, 
132 (LSU) three subjects, 139 (PHREI), two subjects, 305 (Alberta) three subjects, making a grand 
total of 22 subjects. 
 
(2) Influence of Symptomatic Medication on the Primary Outcome. Section 4C. III states that 
“Supplementary analyses of the final study outcome will be conducted with current use of 
symptomatic medication (levodopa equivalents) added as an additional predictor variable’’.  
Since use of symptomatic medication is a post-randomization variable and may be determined 
in part by post-randomization values of the outcome variable, it should not be used as a 
predictor variable. Subjects who show a more rapid early decline may be more likely to receive 
symptomatic medication. This could result in an artefactual positive correlation between use of 
symptomatic medication and rapidity of disease progression which might distort the estimate of 
the randomized treatment.  To avoid this artefact we will estimate the effect on the primary 
outcome of both current and cumulative dosages of symptomatic medication from a mixed 
model analysis using data from all study visits and which explicitly allows subjects to have 
differing underlying rates of disease progression.  In essence this analysis uses each subject as 
his or her own control in estimating the influence of symptomatic medication on disease 
progression.   It will be performed on the aggregate data from the final study data-base, prior to 
breaking the blind as to the randomized treatment. The estimated coefficients of the two LED 
variables (current and cumulative levodopa equivalent doses) will then be used to adjust each 
subject’s final UPDRS value to the projected value that the subject would have had if he or she 
had not received symptomatic medication. Since these projections will not use the randomized 
treatment, the treatment effect on the projected outcome variables can be estimated using the 
same model as the primary analysis, i.e. stratifying by site and including baseline UPDRS as a 
covariate. This analysis will have the correct alpha-level under the overall null hypothesis (no 
effect of isradipine relative to placebo on either disease progression or usage of symptomatic 
medication) irrespective of whether the relationship between these two outcome variables is 
modeled accurately.  A member of the Steering Committee asked about the possible influence 
of body weight on the effect of LED.   To assess this we conducted preliminary analyses on the 
aggregate study data with the raw values of current and cumulative LED divided by the subject’s 
weight giving LED per kilo of body weight.  In addition to confirming the reality of the artefact 
described above the results were very similar to those using the original values of LED, so we 
propose not to adjust for  body weight in this prespecified supplementary analysis.                                                 
                                                                                                     David Oakes (12/28/2018) 


STEADY-PD III 
Statistical Analysis Plan Summary of Changes 
Statistical Analysis 
Plan Version Date 
Summary of Changes
1-Sep-14 Original Version 
6-Mar-15 Addition of Subgroup Analysis - Including Gender and Race/Ethnicity
6-Oct-15 Minor formatting changes, added power for selected secondary analyses and subgroup 
analyses.
16-Dec-15 Section D.  Subgroup Analysis - Including Gender and Race/Ethnicity.  Clarified the will 
NOT have enough power to detect treatment effects among subgroups. 
1-Dec-17 Per DSMB meeting 11OCT2017, the interim and futility analysis will not be performed. 
Clarified in the plan. 
28-Dec-18 Clarification to the SAP - Combining sites with low enrollment and influence of 
symptomatic medication of the primary outcome, section 4C. 
Version 1.0
Page 1
03JUL2019