A Phase 3, Twelve-week Study to Determine the Efficacy, Safety and Tolerability of P2B001 Once Daily Compared to Its Individual Components in Subjects With Early Parkinson's Disease and to a Calibration Arm of Pramipexole ER.
Phase: PHASE3
Conditions: Parkinson Disease, Early Parkinson's Disease
Sponsor: Pharma Two B Ltd.

Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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NCT Number: NCT03329508 
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1 TITLE 
 
A Phase 3, Twelve-week, Multi-Center, Multinational, 
Randomized, Double-Blind, Double-Dummy, Parallel Group 
Study to Determine the Efficacy, Safety and Tolerability of 
P2B001 Once Daily Compared to its Individual Components 
in Subjects With Early Parkinson’s Disease and to a 
Calibration Arm of Pramipexole ER. 
 
 
 
 
Protocol Number 
P2B001/003 
Version 
3.0 
Version Date  
 18 November 2020 
Clinical Phase 
Phase 3 
Sponsor 
Pharma Two B, 3 Pekeris st. Weizmann 
Science Park Rehovot 7670203 Israel.  
Tel: +972-8-9472672 
Sponsor representative  
David S. Tierney M.D, CEO, 3 Pekeris st. 
Weizmann Science Park Rehovot 7670203 
Israel 
CRO 
PRA Health Science, 4130 ParkLake 
Avenue - Suite 400, Raleigh, North Carolina 
27612, USA 
 
 
 
CONFIDENTIAL 

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NCT Number: NCT03329508 
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The information in this document is considered privileged and confidential, and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review 
Board/Ethics Committee approval, informed consent and the approval of local regulatory 
authorities as required by local law. 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
 
 
 
 
 
 
 

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Study sites and Investigators 
 
Site # 
PI 
Site name  
Site location 
101 
David Kreitzman 
Parkinson's Disease and Movement 
Disorders Center of Long Island 
Commack NY 
USA 
102 
Ramon Gil 
Parkinson's Disease Treatment Center 
of South West Florida 
Port Charlotte FL 
103 
J. Antonelle de Marcaida 
David and Rhoda Chase Family 
Movement Disorders Center 
Vernon CT  
106 
Marie Saint-Hilaire 
Boston University Medical Center 
Boston MA 
107 
Stuart Isaacson 
Parkinson's Disease and Movement 
Disorders Center of Boca Raton 
Boca Raton FL 
111 
Rajesh Pahwa 
University of Kansas Medical Center-
Landon Center on Aging 
Kansas City KS 
113 
Robert Hauser  
University of South Florida 
Tampa FL 
115 
John Morgan 
Augusta University 
Augusta GA 
120 
Lawrence Elmer 
University of Toledo, Gardner-
McMaster Parkinson Center 
Toledo OH 
123 
Aikaterini Kompoliti 
Rush University Medical Center 
Chicago IL 
124 
Andrew Duker 
University of Cincinnati 
Cincinnati OH 
125 
Sotirios Parashos 
Struthers Parkinson's Center 
Golden Valley MN 
127 
Mark Lew 
Keck School of Medicine 
Los Angeles CA 
128 
Andrew McGarry 
Cooper University Health Care 
Camden NJ 
129 
John Goudreau 
Michigan State University 
East Lansing 
130 
Rebecca Thompson 
Dartmouth-Hitchcock Medical Center 
Lebanon NH 
131 
George Ross 
VA Pacific Islands Health Care System 
Honololu HI 
132 
Padraig O'Suilleabhain  
University of Texas Southwestern 
Medical Center - Neurology Clinic 
Dallas TX 
133 
Susan Criswell 
Washington University School of 
Medicine 
St. Louis MO              
134 
Shyamal Mehta 
Mayo Clinic, Scottsdale Arizona 
Scottsdale AZ 
135 
Virgilio Evidente  
Movement Disorders Center of Arizona 
Scottsdale AZ 
136 
Martha McGraw 
Central DuPage Hospital 
Winfield IL 
137 
Henry Moore 
University of Miami Health System at 
Boca Raton 
Boca Raton FL 
138 
Carlos Singer 
University Of Miami 
Miami FL 
140 
Zain Guduru 
University of Kentucky Health Care 
Lexington KY 
141 
Philip Hanna 
JFK Medical Center - The Neuroscience 
Institute 
Edison NJ 
142 
Rohit Dhall 
University of Arkansas for Mediclal 
Sciences 
Little Rock AR 
143 
Sulada Kanchana / 
Dragos Mihaila 
State University of New York Upstate 
Medical University 
Syracuse NY 
144 
Thyagarajan 
Subramanian 
Penn State Health Milton S. Hershey 
Medical Center 
Hershey PA 
145 
Madhavi Thomas 
North Texas Movement Disorders 
Institute 
Bedford TX 

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Site # 
PI 
Site name  
Site location 
146 
David Charles 
Vanderbilt Neuroscience Institute 
Nashville TN 
148 
Thomas Guttuso, Jr. 
University at Buffalo Neurology 
Williamsville NY 
149 
Gerald Calegan 
The NeuroMedical Center 
Baton Rouge LA 
150 
Rajeev Kumar 
Rocky Mountain Movement Disorders 
Center 
Englewood CO 
152 
James Patton 
Asheville Neurology Specialists 
Asheville NC 
153 
Mark Baron 
Hunter Holmes McGuire Veterans 
Affairs Medical Center 
Richmond VA 
154 
Andrew Keegan 
Roskamp Institute 
Sarasota FL 
155 
Fredy Revilla 
Greenville Health System 
Greenville SC 
156 
Winona Tse 
Icahn School of Medicine at Mount 
Sinai 
New York NY 
157 
Daniel Burdick 
Booth Gardner Parkinson's Care Center 
Kirkland WA 
158 
Ramsey Falconer 
Inova Neuroscience Research 
Falls Church VA 
160 
Ivan Bodis-Wollner / 
Daphne Robakis 
SUNY Downstate Medical Center 
Brooklyn NY 
161 
Odinachi Oguh / Natalya 
Schneyder 
UF Health Neurology – Jacksonville 
Jacksonville FL 
162 
Peter LeWitt 
Henry Ford West Bloomfield Hospital 
West Bloomfield MI 
163 
Sarah Pirio Richardson 
Raymond G. Murphy VA Medical Center 
Albuquerque NM 
164 
Mark LeDoux 
Wesley Neurology Clinic / Veracity 
Neuroscience 
Memphis TN 
202 
Susan Fox  
Movement Disorders Centre Toronto 
Western Hospital 
Toronto, Ontario 
Canada 
203 
Barbara Connolly 
Hamilton General Hospital 
Hamilton, Ontario 
401 
Heinz Reichmann  
Universitätsklinikum Dresden 
Dresden, Sachsen 
Germany 
402 
Jost-Julian Rumpf  
Universitätsklinikum Leipzig 
Leipzig, Sachsen 
403 
Reinhard Ehret  
Praxis für Neurologie und Psychiatrie 
Berlin, Berlin 
404 
Siegfried Muhlack 
Sankt Josef-Hospital 
Bochum, Nordrhein-
Westfalen 
405 
Johannes Schwarz 
Klinik Haag 
Haag, Bayern 
406 
Tobias Warnecke  
Universitätsklinikum Münster 
Münster, Nordrhein-
westfalen 
407 
Bernhard Haslinger  
Technischen Universität München 
München, Bayern 
408 
Michel Rijntjes  
Universitätsklinikum Freiburg 
Freiburg, Baden-
Wuerttemberg 
409 
Sven Thonke  
Klinik für Neurologie 
Hanau, Hesse 
410 
Jan Kassubek  
Universitätsklinikum Ulm 
Ulm,  Baden-
Wuerttemberg 
412 
Christian Oehlwein  
Praxis für Bewegungsstörungen und 
Parkinson 
Gera, Thueringen 
455 
Bettina Wieder 
Curiositas ad sanum 
München, Bayern 
 
501 
Alvaro Sanchez Ferro  
HM Centro Integral de Neurociencias 
(CINAC) 
Mostoles, MD 
Spain 

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Site # 
PI 
Site name  
Site location 
503 
Jaime Kulisevsky Bojarski  Private Foundation Hospital de la Santa 
Cruz and San Pablo 
Barcelona, CT 
504 
Maria Cruz Rodríguez 
Oroz 
  
Clinica Universidad de Navarra 
Pamplona, Navarra 
544 
Clinica Universidad de Navarra Madrid 
Madrid, MD 
505 
Ernest  Balaguer  
Hospital Universitari General de 
Catalunya 
Sant Cugat del 
Vallés, Barcelona  
506 
Pedro García-Ruíz  
Hospital Universitario Fundación 
Jiménez Díaz 
Madrid, MD 
507 
Joan 
Carlos 
Martínez 
Castrillo  
Hospital Universitario Ramon y Cajal 
Farmacia 
Madrid, MD 
509 
Gurutz Linazasoro 
Cristobal  
Policlinica Gipuzkoa 
Donostia, Guipuzcoa 
510 
Jorge Hernandez-Vara 
Hospital Universitari Vall d'Hebrón 
Barcelona, CT 
511 
Exuperio Diez-Tejedor  
Hospital Universitario La Paz 
Madrid, MD 
512 
Pilar Sánchez Alonso  
Hospital Universitario Puerta de Hierro 
- Majadahonda 
Majadahonda, MD 
 
 
 
 
 

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TABLE OF CONTENTS 
1 
TITLE ............................................................................................................................................................... 1 
2 
SYNOPSIS ...................................................................................................................................................... 14 
3 
INTRODUCTION ......................................................................................................................................... 27 
3.1 
BACKGROUND ............................................................................................................................................ 27 
3.2 
PRECLINICAL PHARMACOLOGY STUDIES .................................................................................................... 29 
3.3 
TOXICOLOGY STUDIES ................................................................................................................................ 29 
3.4 
CLINICAL STUDIES ...................................................................................................................................... 29 
3.5 
SUMMARY OF NON-CLINICAL AND CLINICAL STUDIES ............................................................................... 31 
4 
STUDY OBJECTIVES ................................................................................................................................. 32 
4.1 
PRIMARY OBJECTIVE .................................................................................................................................. 32 
4.2 
SECONDARY OBJECTIVES ........................................................................................................................... 33 
4.3 
EXPLORATORY OBJECTIVES: ...................................................................................................................... 33 
4.4 
SAFETY & TOLERABILITY OBJECTIVES ....................................................................................................... 34 
5 
INVESTIGATIONAL PRODUCT............................................................................................................... 34 
5.1 
DOSAGE ...................................................................................................................................................... 35 
5.2 
DOSE MODIFICATION .................................................................................................................................. 35 
5.3 
METHOD OF ADMINISTRATION & MEALS ................................................................................................... 36 
6 
STUDY DESIGN ........................................................................................................................................... 36 
6.1 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION .................................................................................... 36 
6.2 
RATIONALE FOR STUDY DESIGN, STUDY POPULATION AND DOSES ............................................................. 39 
7 
STUDY POPULATION ................................................................................................................................ 40 
7.1 
NUMBER OF SUBJECTS ................................................................................................................................ 40 
7.2 
SUBJECTS ENROLMENT ............................................................................................................................... 40 
7.3 
INCLUSION CRITERIA .................................................................................................................................. 40 
7.4 
EXCLUSION CRITERIA ................................................................................................................................. 41 
7.5 
EARLY DISCONTINUATION SUBJECTS ......................................................................................................... 43 
7.6 
SUBJECT REPLACEMENT ............................................................................................................................. 45 
8 
ASSESSMENTS ............................................................................................................................................. 45 
8.1 
SCHEDULE OF ACTIVITIES ........................................................................................................................... 45 
8.2 
EVALUATION OF PRAMIPEXOLE ER (OR PLACEBO) DOSE ........................................................................... 45 
8.3 
SAFETY AND TOLERABILITY ....................................................................................................................... 45 
8.3.1 
Physical and Neurological Exams ......................................................................................................... 45 
8.3.2 
Safety Laboratory Tests – see Appendix II ............................................................................................ 45 
8.3.3 
ECG ....................................................................................................................................................... 46 
8.3.4 
Vital Signs .............................................................................................................................................. 46 
8.3.5 
Concomitant Medications ...................................................................................................................... 46 
8.3.6 
Adverse Events ....................................................................................................................................... 46 
8.3.7 
Sleepiness .............................................................................................................................................. 46 
8.3.8 
Impulsive-Compulsive Disorders ........................................................................................................... 46 

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8.3.9 
Suicidality .............................................................................................................................................. 47 
8.4 
EFFICACY ................................................................................................................................................... 47 
8.4.1 
UPDRS – see Appendix IX ..................................................................................................................... 47 
8.4.2 
Clinical Global Impression - severity (CGI-S) - Appendix IV ............................................................... 47 
8.4.3 
Clinical Global Impression of Improvement (CGI-I) – Appendix XIV .................................................. 48 
8.4.4 
Quality of Life PDQ39 – Appendix X .................................................................................................... 48 
8.4.5 
Health-Related Quality of Life (HRQOL) SF-12v2 questionnaire – Appendix VII ............................... 48 
8.5 
COMPLIANCE .............................................................................................................................................. 49 
8.5.1 
Study Compliance .................................................................................................................................. 49 
8.6 
SCREENING EVALUATIONS ......................................................................................................................... 49 
9 
STUDY CONDUCT....................................................................................................................................... 50 
9.1 
STUDY PERIOD ............................................................................................................................................ 50 
9.2 
STUDY PROCEDURES .................................................................................................................................. 50 
9.2.1 
Detailed Study Plan ............................................................................................................................... 50 
9.2.2 
Visit 1 - Screening Visit ......................................................................................................................... 50 
9.2.3 
Visit 2 - Baseline .................................................................................................................................... 51 
9.2.4 
Visit 3 ..................................................................................................................................................... 52 
9.2.5 
Week 4 Phone Call ................................................................................................................................ 52 
9.2.6 
Visit 4 ..................................................................................................................................................... 52 
9.2.7 
Visit 5 ..................................................................................................................................................... 53 
9.2.8 
Visit 6 – Treatment Termination ............................................................................................................ 53 
9.2.9 
Visit 7 – Safety Follow Up ..................................................................................................................... 54 
9.2.10 
Unscheduled Visits ............................................................................................................................ 54 
9.2.11 
Early Treatment/Study Termination Visit .......................................................................................... 55 
10 
CONCOMITANT MEDICATIONS ............................................................................................................ 55 
10.1 
PROHIBITED MEDICATION .......................................................................................................................... 56 
10.2 
DIETARY RESTRICTIONS ............................................................................................................................. 57 
10.3 
RESCUE THERAPY ....................................................................................................................................... 57 
11 
LABORATORIES ......................................................................................................................................... 57 
11.1 
SAFETY LABORATORY TESTS ..................................................................................................................... 57 
11.2 
VITAL SIGNS, HEIGHT AND WEIGHT ........................................................................................................... 58 
11.3 
ELECTROCARDIOGRAMS (ECG) .................................................................................................................. 59 
12 
STUDY DRUGS SUPPLY ............................................................................................................................ 59 
12.1 
DRUG MANUFACTURING ............................................................................................................................ 59 
12.2 
TREATMENT ASSIGNMENT AND RANDOMIZATION ...................................................................................... 59 
12.3 
PACKAGING AND LABELING ....................................................................................................................... 60 
12.4 
DISTRIBUTION AND SHIPMENT .................................................................................................................... 64 
12.5 
STORAGE, DISPENSING AND RETURN .......................................................................................................... 64 
12.6 
VERIFICATION OF COMPLIANCE WITH TREATMENT REGIMEN .................................................................... 65 
12.7 
ACCOUNTABILITY ....................................................................................................................................... 65 
12.8 
STUDY END ................................................................................................................................................ 66 
12.9 
BLINDING ................................................................................................................................................... 66 
12.9.1 
Emergency Code Breaking ................................................................................................................ 66 

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13 
SAFETY/ADVERSE EVENTS .................................................................................................................... 66 
13.1 
ADVERSE EVENTS DEFINITION .................................................................................................................... 66 
13.2 
AE CAUSALITY DEFINITIONS ...................................................................................................................... 67 
13.3 
REPORTING ORTHOSTATIC HYPOTENSION AS AE ....................................................................................... 68 
13.4 
SERIOUS ADVERSE EVENT (SAE) ............................................................................................................... 69 
13.5 
SAE REPORTING ......................................................................................................................................... 69 
13.6 
PREGNANCY ............................................................................................................................................... 71 
13.7 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) ........................................................... 71 
14 
DATA MANAGEMENT AND QUALITY ASSURANCE ........................................................................ 71 
14.1 
HANDLING OF DATA ................................................................................................................................... 71 
14.2 
CODING OF ADVERSE EVENTS, DRUGS AND DISEASES ............................................................................... 72 
14.3 
DATA QUALITY ASSURANCE ...................................................................................................................... 72 
15 
STATISTICAL METHODOLOGY............................................................................................................. 72 
15.1 
SAMPLE SIZE RATIONALE ........................................................................................................................... 72 
15.2 
SAMPLE SIZE RE-ASSESSMENT ................................................................................................................... 73 
15.3 
RANDOMIZATION ........................................................................................................................................ 74 
15.4 
DATA ANALYSES SETS ............................................................................................................................... 74 
15.5 
OVERALL SIGNIFICANCE LEVEL AND MULTIPLICITY ADJUSTMENT: ........................................................... 75 
15.6 
STUDY POPULATION SUMMARY ................................................................................................................. 76 
15.6.1 
Subject Disposition ............................................................................................................................ 76 
15.6.2 
Study Inclusion and Exclusion Criteria ............................................................................................. 76 
15.6.3 
Demographics and Baseline Characteristics .................................................................................... 76 
15.6.4 
Medical History ................................................................................................................................. 76 
15.6.5 
Prior and Concomitant Medications ................................................................................................. 77 
15.6.6 
Protocol Violations/Deviations ......................................................................................................... 78 
15.6.7 
Efficacy Endpoints and Analyses ...................................................................................................... 78 
15.6.8 
Primary Efficacy Endpoint and Principal Statistical Analysis .......................................................... 78 
15.6.9 
Sensitivity Analyses for the Primary Endpoint .................................................................................. 79 
15.6.10 
Key Secondary Efficacy Endpoints and Analyses.............................................................................. 81 
15.6.11 
The exploratory endpoints to be analyzed are: ................................................................................. 83 
15.7 
SAFETY ASSESSMENTS ............................................................................................................................... 84 
15.7.1 
Adverse Events .................................................................................................................................. 84 
15.7.2 
Laboratory Tests ............................................................................................................................... 85 
15.7.3 
Vital Signs ......................................................................................................................................... 86 
15.8 
ECG ........................................................................................................................................................... 86 
15.9 
COLUMBIA SUICIDE SEVERITY RATING SCALE (CSSRS) ............................................................................ 86 
15.10 
TOLERABILITY ASSESSMENTS ................................................................................................................ 87 
15.11 
EXPLORATORY SAFETY ENDPOINT ......................................................................................................... 87 
15.12 
SAFETY ASSESSMENT SCALES ................................................................................................................. 87 
15.13 
STATISTICAL ANALYSIS PLAN (SAP) ..................................................................................................... 87 
16 
STUDY PERSONNEL .................................................................................................................................. 88 
16.1 
STUDY SITE ................................................................................................................................................ 88 
16.1.1 
The Principal Investigator ................................................................................................................ 88 

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16.1.2 
The Clinical Coordinator or designee ............................................................................................... 88 
16.2 
THE SPONSOR ............................................................................................................................................. 89 
16.3 
CRO ........................................................................................................................................................... 89 
16.3.1 
CRO Clinical Trials Manager ........................................................................................................... 90 
16.3.2 
Statistics and Data Management Centers (S&DM) .......................................................................... 90 
16.3.3 
Medical Monitor ................................................................................................................................ 90 
16.3.4 
Local Clinical Trial Manager (LCTM) ............................................................................................. 90 
16.3.5 
Clinical Research Associate .............................................................................................................. 90 
16.4 
STUDY COMMITTEES .................................................................................................................................. 91 
16.4.1 
Data & Safety Monitoring Board (DSMB) ........................................................................................ 91 
16.4.2 
Subject Central Eligibility Monitoring Committee (EMC) ................................................................ 91 
17 
REGULATORY AND ETHICAL ISSUES ................................................................................................. 91 
17.1 
COMPLIANCE WITH REGULATIONS APPLICABLE TO CLINICAL TRIALS ....................................................... 91 
17.2 
INFORMED CONSENT .................................................................................................................................. 91 
17.3 
ETHICS COMMITTEE (EC) / INSTITUTIONAL REVIEW BOARD (IRB) ............................................................ 92 
17.4 
PROTOCOL AMENDMENTS .......................................................................................................................... 92 
17.5 
SUBJECT CONFIDENTIALITY........................................................................................................................ 92 
17.6 
LIABILITY AND INSURANCE ........................................................................................................................ 93 
18 
DOCUMENTATION .................................................................................................................................... 93 
18.1 
STUDY FILE AND SITE DOCUMENTS ............................................................................................................ 93 
18.2 
SITE DOCUMENTS/EQUIPMENT SUPPLIED BY THE SPONSOR ....................................................................... 93 
18.3 
MAINTENANCE AND RETENTION OF RECORDS ............................................................................................ 94 
18.4 
DATA HANDLING ........................................................................................................................................ 95 
18.4.1 
Source Documents ............................................................................................................................. 95 
19 
STUDY MONITORING ............................................................................................................................... 96 
19.1 
MONITORS AND MONITORING VISITS ......................................................................................................... 96 
19.2 
PRIMARY SOURCE DOCUMENTS ................................................................................................................. 96 
20 
USE  OF INFORMATION AND PUBLICATION ..................................................................................... 97 
20.1 
CONFIDENTIAL INFORMATION .................................................................................................................... 97 
21 
INVESTIGATOR AGREEMENT ............................................................................................................... 98 
22 
APPENDICES ................................................................................................................................................ 99 
22.1 
APPENDIX I: SCHEDULE OF ACTIVITIES: ..................................................................................................... 99 
22.2 
APPENDIX II: LABORATORY TESTS ........................................................................................................... 102 
22.3 
APPENDIX III: THE EPWORTH SLEEPINESS SCALE (ESS) .......................................................................... 103 
22.4 
APPENDIX IV: CLINICAL GLOBAL IMPRESSION - SEVERITY ...................................................................... 104 
22.5 
APPENDIX V: OHAS QUESTION 1 (KAUFMANN H, 2012) ......................................................................... 105 
22.6 
APPENDIX VI: QUESTIONNAIRE FOR IMPULSIVE-COMPULSIVE DISORDERS IN PARKINSON’S DISEASE 
RATING SCALE (QUIP-RS) .................................................................................................................................... 106 
22.7 
APPENDIX VII: HEALTH-RELATED QUALITY OF LIFE (HRQOL) SF-12V2 ............................................... 108 
22.8 
APPENDIX VIII: COLUMBIA SUICIDE SEVERITY RATING SCALE (CSSRS) ................................................ 111 
22.9 
APPENDIX IX: UPDRS  (FAHN S, 1987) ................................................................................................... 115 

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22.10 
APPENDIX X: QUALITY OF LIFE - PDQ39 ............................................................................................. 124 
22.11 
APPENDIX XI : UK PARKINSON'S DISEASE SOCIETY BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA 
(HUGHES AJ, 1992) ............................................................................................................................................... 126 
22.12 
APPENDIX XII: MODIFIED HOEHN & YAHR SCALE ............................................................................... 126 
22.13 
APPENDIX XIII: MINI-MENTAL STATE EXAMINATION (MMSE) .......................................................... 128 
22.14 
APPENDIX XIV: CLINICAL GLOBAL IMPRESSION - IMPROVEMENT ....................................................... 129 
23 
REFERENCES ............................................................................................................................................ 130 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
6-OHDA 
6-hydroxydopamine 
UPDRS ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AR 
Autoregressive 
AUC 
Area under the plasma concentration versus time curve 
Bid 
Twice per day 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CGI-S 
Clinical Global Impression - Severity 
CGI-S 
Clinical Global Impression - Improvement 
CGR 
Country or Geographical Region 
Cmax 
Maximum plasma concentration 
CNS 
Central Nervous System 
CO 
Complete Analysis Set 
CR 
Controlled Release 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CS 
Compound Symmetry 
CSH 
Heterogeneous Compound Symmetry 
CSSRS 
Columbia Suicide Severity Rating Scale 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMC 
Eligibility Monitoring Committee 
ER 
Extended Release 
ESS 
Epworth Sleepiness Scale 
EST 
Early Study Termination 
ETT 
Early Treatment Termination 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
GDNF 
Glial cell-line derived neurotrophic factor 

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Abbreviation 
Description 
DSMC 
Data & safety Monitoring Committee  
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
H&Y 
Hoehn and Yahr 
HR 
Heart Rate 
hr(s) 
Hour(s) 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product  
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
kel 
Elimination rate constant 
Kg 
Kilogram 
LCTM 
Local Clinical Trial Manager 
L-DOPA 
Levodopa  
LSM 
Least Square Means 
M 
Meter 
MAO 
Mono Amine Oxidase 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minute or Minimum 
mITT 
Modified Intent to Treat 
Ml 
Milliliter 
ML 
Maximum-Likelihood 
MMSE 
Mini Mental State Exam 
MPTP 
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
Ms 
Millisecond 
N/A 
Not Applicable 
ºC 
Degrees centigrade 
PD 
Parkinson’s Disease 
PDQ39 
Parkinson’s Disease Questionnaire 39 
PI 
Principle Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
 PT 
Preferred Term  

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Abbreviation 
Description 
PPX 
Pramipexole 
QA 
Quality Assurance 
Qid 
Four times per day 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson's Disease – Rating Scale 
RAF 
Randomization Authorization Form  
RAS 
Rasagiline 
REML 
Restricted ML 
RR 
Respiratory Rate 
RTSM 
Randomization Trial Supply Management 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T½ 
Elimination half-life 
TEAEs 
Treatment Emergent Adverse Events  
Tid 
Three times daily 
Tmax 
Time at which Cmax occurs 
TMF 
Trial Master File 
U 
Unit 
UK 
United Kingdom 
UPDRS 
Unified Parkinson's Disease Rating Scale 
WHO 
World Health Organization 
 
 
 

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2 SYNOPSIS 
 
Name of Sponsor/Company: Pharma Two B 
Name of Product: P2B001, Pramipexole 0.6 mg /Rasagiline 0.75 mg Once Daily (P2B001 
0.6/0.75 mg) 
Name of Active Ingredient: Pramipexole, Rasagiline 
Title of study: A Phase 3, Twelve-week, Multi-Center, Multinational, Randomized, Double-
Blind, Double-Dummy, Parallel Group Study to Determine the Efficacy, Safety and Tolerability 
of P2B001 Once Daily Compared to its Individual Components in Subjects with Early 
Parkinson’s Disease and to a Calibration Arm of Pramipexole ER. 
Study Sites:  
Approximately 70 sites in the United States, Canada, and Europe will be participating in the 
study. 
Planned Study Duration 
16 – 22 months from first patient in until database lock. 
Planned first patient in: December 2017 
Development Phase: 
Phase 3 
Objectives: 
Primary objective: 
To determine the superiority of P2B001 0.6/0.75 mg as compared to its individual components in 
the change of total UPDRS score (defined as sum of parts II and III, scores (0-160).  
Secondary objectives: 
• To determine the superiority of P2B001 0.6/0.75 mg as compared to pramipexole ER in the 
change of Epworth Sleepiness Scale (ESS) score.  
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components in 
the change of Total PDQ39 score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components in 
the change of ADL UPDRS (part II) score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components in 
the change of motor UPDRS (part III) score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components in 
the CGI-S responder’s analysis (change from baseline ≥1 CGI-S points).  
Exploratory objective: 

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• To evaluate the superiority of P2B001 0.6/0.75 mg compared to its individual components in 
the following endpoints: 
- 
Change in each of the 8 PDQ39 subscales scores. 
- 
Change in the score of Health-Related Quality of Life (HRQOL) SF-12v2 questionnaire. 
- 
Clinical Global Impression of Improvement (CGI-I). 
 
• To evaluate the superiority of P2B001 0.6/0.75 mg over pramipexole ER with respect to the 
following outcome measures: 
- 
Proportion (%) of patients with ESS score >10.  
- 
Proportion (%) of patients with ESS Score <10 at baseline and ESS score >10. 
- 
3-Months rate of total number of adverse events. 
- 
Change in the differences in systolic and diastolic blood pressure measured during supine 
and standing positions.   
- 
Proportion (%) of patients with both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
3-Months rate of total number of both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
Proportion (%) of patients with symptomatic Orthostatic Hypotension. 
- 
3-Months rate of total number of symptomatic Orthostatic Hypotension. 
- 
Proportion (%) of patients with daytime sleepiness/drowsiness related AE’s.  
- 
Proportion (%) of patients with gastrointestinal (GI) adverse events  
- 
Proportion (%) of patients presenting neurological adverse events  
- 
Change in the score of Orthostatic Hypotension Symptoms Assessment (OHSA) question 
1. 
 
• To descriptively evaluate the comparability of P2B001 0.6/0.75 mg with reference to the 
calibration arm (pramipexole ER) in total UPDRS score (defined as sum of parts II and III, 
scores (0-160). 
 
Safety & Tolerability Objectives: 
The safety profile of the test product and comparators will be evaluated by changes in the safety 
parameters, including adverse events, concomitant medications, vital signs, laboratory parameters, 
physical and neurological examinations, ECGs, Questionnaire for Impulsive-Compulsive 
Disorders in Parkinson's Disease- Rating Scale (QUIP-RS), Columbia Suicide Severity Rating 
Scale (CSSRS), Orthostatic Hypotension Symptoms Assessment (OHSA) question 1 and Epworth 
Sleepiness Scale (ESS). 

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Tolerability will be assessed by percentage of subjects that complete the trial on treatment 
assigned. 
Adverse events, vital signs and other safety data will be followed up by an independent Data and 
Safety Monitoring Board (DSMB).  
 
Study Design:  
This study is a phase 3, twelve-week, multi-center, multinational, randomized, double-blind, 
double-dummy, parallel group study.  
Up to 525 eligible subjects with early untreated Parkinson’s disease (PD) who are not early 
terminated from the study during screening or baseline visits and are randomized to treatment 
with P2B001 once daily (pramipexole 0.6 mg / rasagiline 0.75 mg), or pramipexole 0.6 mg  once 
daily (PPX 0.6), or rasagiline 0.75 mg once daily (RAS 0.75), or pramipexole ER  titrated to 
optimal dose (1.5, 3.0 or 4.5mg)  using a randomization scheme of 2:2:2:1, respectively.  
Each subject will be asked to take one capsule and 1-3 tablets once daily. The capsules will 
contain either P2B001 0.6/0.75mg or pramipexole 0.6 mg or rasagiline 0.75 mg or matching 
placebo. The tablets will contain either pramipexole ER 0.375 mg or pramipexole ER 1.5 mg or 
matching placebo.  
 
Dosing Regimen: 
• P2B001 pramipexole dihydrochloride 0.6 mg/Rasagiline 0.75 mg Once Daily + Placebo of 
Pramipexole ER. 
• Pramipexole dihydrochloride 0.6 mg Once Daily (PPX 0.6) + Placebo of Pramipexole ER. 
• Rasagiline 0.75 mg Once Daily (RAS 0.75) + Placebo of Pramipexole ER. 
• Pramipexole ER individually titrated to optimal dose + Placebo of P2B001. 
  
Study Structure:  
• Up-titration phase  
• Maintenance phase  
• Down-titration phase 
• Safety follow-up phase.     
 
Up-Titration phase: A 3-6 week double blind, double dummy titration phase with pramipexole ER 
or matching placebo. During this phase subjects will also take 1 capsule of P2B001/RAS 
0.75/PPX0.6/Placebo which does not need titration. For the first 3 weeks the titration of the 
pramipexole ER will be increased by weekly increments up to a daily dose of 1.5 mg as follows: 
0.375, 0.75 and 1.5 mg. If needed, between weeks 3 and 6, the titration can continue to a daily dose 

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of 3.0 mg or 4.5 mg of pramipexole ER or matching placebo or reduced to a minimum of 1.5mg 
with the final level determined based on achieving satisfactory efficacy and tolerability. On 
completion of the dose-titration phase (end of week 6), the minimum therapeutic dose of 
pramipexole ER 1.5 mg per day (or placebo) must be achieved by all the patients. The treatment 
with study medications of patients who cannot achieve this dosage will be discontinued, but the 
subject will be requested to continue with all the study visits. 
 
Study visits for the titration phase: 
Subjects will be required to visit the clinic at the end of week 3 for a titration evaluation to assess 
the subject’s satisfaction with and tolerance to the 1.5 mg dose of pramipexole ER (or placebo). 
At this visit, the PI or sub-Investigator may choose to keep the subject at 1.5 mg or increase the 
dose to 3.0 mg. Other study activities at this visit include assessment of CSSRS and QUIP-RS and 
review of adverse events and concomitant medications.  
At the end of week 4 a phone call to the subject will be conducted by the PI or sub-Investigator to 
assess the subject’s satisfaction with and tolerance to pramipexole ER (or matching placebo) and 
the possible need for increase of the dose. If the PI or sub-Investigator deem necessary, an 
unscheduled visit for a titration evaluation may be conducted at this time. At the end of week 5 
the subject will be required to visit the clinic for a full study visit. In addition to scheduled study 
activities, the dose of pramipexole ER (or matching placebo) will be evaluated again to assess the 
subject’s satisfaction and tolerability. As per the PI’s or sub-Investigator’s instructions, the dose 
may remain at 4.5 mg or decreased back to 3.0 mg or even to 1.5 mg if necessary. Following the 
end of week 6 no changes in dose are allowed. This will be deemed the maintenance dose of 
pramipexole ER or matching placebo tablets for the rest of the study. During all of this time the 
subjects will also take 1 capsule of P2B001/RAS 0.75/PPX0.6/Placebo which do not need 
titration. 
 
Maintenance phase: Once the final dose level has been reached for the pramipexole ER, the 
subject will continue at that dose, together with the once daily P2B001/RAS 0.75/PPX0.6/Placebo 
capsule, until the end of Week 12.  
 
Down-titration phase: a 7-day gradual down titration of pramipexole ER or matching placebo. The 
down titration should be done by reducing the dose every two days by half (except for subjects 
taking 4.5 mg, these should reduce the dose to 3.0 mg and then continue to reduce by half every 
two days). No treatment with a once daily P2B001/RAS 0.75/PPX0.6/Placebo capsule during this 
time.  
 

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Safety follow-up phase: a 7 days period of no treatment of pramipexole ER and 14 day period of 
no treatment for the P2B001/RAS 0.75/PPX0.6/Placebo capsule.  
 
 
 
Study design scheme: 
 
*Titration phase: Subjects can stop titration of pramipexole ER or placebo at 1.5 mg or can continue 
titration and increase the dose to 3.0 or 4.5 mg as optimal dose or decrease back to 3.0 or 1.5 mg. The 
dosage level achieved at the end of the titration phase (end of week 6) is then held constant during the 
maintenance phase ending at the end of week 12. 
Study activities:  

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Subjects will undergo visit specific study activities at screening, baseline, end of weeks 3, 4, 5, 8, 
12/Treatment Termination and a safety follow up at end of week 14 (see Appendix 1, schedule of 
activities).     
UPDRS II +III and ESS assessments will be conducted at the baseline visit, as well as end of 
weeks 5, 8, and 12/Treatment Termination. UPDRS III will also be conducted at screening.  
QUIP-RS will be conducted at the baseline visit, as well as end of weeks 3, 5, 8, 12/Treatment 
Termination and week 14. CSSRS will be conducted at every study visit.  
PDQ39, CGI-S and HRQOL SF-12 v 2 scales will be conducted at baseline and end of week 
12/Treatment Termination.  
CGI-I will be performed at end of weeks 5, 8 and 12/Treatment Termination visits. OSHA 
question 1 will be completed at baseline and end of weeks 5, 8 and 12/Treatment Termination, 
only for subjects experiencing orthostatic hypotension.  
 
Subjects will take study medications (capsule and tablets) by mouth with a glass of water (8oz or 
240ml). Study medications can be taken with or without food and efforts should be made to take 
the study medications at the same time every day.  
To preserve the blind the capsules of once daily P2B001/RAS 0.75/PPX0.6/Placebo will be 
visually identical. The tablets of the pramipexole ER and their placebos will be visually identical.  
 
Number of subjects: 
Up to 525 eligible subjects with early untreated Parkinson’s disease (PD) who are not early 
terminated from the study during screening or baseline visits and are randomized to treatment 
with P2B001 0.6/0.75 or pramipexole 0.6 mg once daily, or rasagiline 0.75 mg once daily, or 
pramipexole ER titrated to optimal dose (1.5, 3.0 or 4.5mg) using a randomization scheme of 
2:2:2:1, respectively. 
Diagnosis and Criteria for Eligibility: 
Inclusion Criteria 
1. Subject is informed and given ample time and opportunity to think about his/her 
participation in this study and has given his/her written informed consent on an EC/IRB 
approved consent form. 
2. Subject is willing and able to comply with all study requirements (protocol, clinic visits, 
procedures and medication administration). 
3. Subject is male or female ≥35.0 years of age to ≤80.0 years of age at the time of 
enrollment. 
4. Subject has Parkinson's disease consistent with the UK Brain Bank Criteria and must have 
bradykinesia with sequence effect.  If rest tremor does not exist must have prominent 
asymmetry of motor function. 

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5. Subject with disease duration less than 3 years since diagnosis. 
6. Subject has a H&Y stage score of < 3. 
7. Subject has a MMSE score ≥ 26. 
8. Women of child-bearing potential (WOCBP)* must use a reliable method of contraception 
(e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive, 
double-barrier methods [such as condom plus diaphragm, condom plus spermicide foam, 
condom plus sponge], or intra-uterine devices) for the entire study duration, and must have 
a negative serum pregnancy test at Screening and negative urine pregnancy at baseline 
visit. 
9. Subject was approved by a central Eligibility Monitoring Committee (EMC) based on 
suitability for the study, and his/her eligibility was confirmed by EMC signature on the 
Randomization Authorization Form (RAF).  
*WOCBP are defined as any female who has experienced menarche and who is NOT permanently 
sterile or postmenopaused. Postmenopausal is defined as 12 consecutive months with no menses 
without an alternative medical cause. 
 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any 1 of the following criteria is met. 
1. Subject has previously participated in this study. 
2. Subject has participated in another study of an investigational medicinal product (IMP) or 
a medical device within the last 30 days or is currently participating in another study of an 
IMP or medical device. 
3. Subject has an atypical parkinsonian syndrome or secondary parkinsonism (e.g., due to 
drugs, toxins, metabolic disorders, encephalitis, cerebrovascular disease or degenerative 
disease). 
4. Subject has a history of psychosis or hallucinations within the previous 12 months. 
5. Subject has cognitive impairment in the judgment of the Investigator that excludes him/her 
from understanding consent or participating in the study. 
6. Subject has previous exposure to levodopa or a dopamine agonist for longer than 4 
weeks; if previous exposure was less than 4 weeks then it must not be within 2 months 
prior to the baseline visit. 
7. Subject has previous exposure to a MAO-B inhibitor for longer than 4 weeks; if 
previous exposure was less than 4 weeks then it must not be within 3 months prior to 
the baseline visit. 
8. Subject who has taken anticholinergic drugs for PD or amantadine for longer than 4 
weeks; if previous exposure was less than 4 weeks then it must not be within 1 month 
prior to the baseline visit. 
9. Subject who is taking non-selective MAO inhibitors. 

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10. Subject who is taking potent CYP1A2 inhibitors, e,g, Ciprofloxacin  
11. Subject who is taking antitussive agent dextromethorphan. 
12. Subject who is taking analgesic agents such as tramadol, meperidine, methadone and 
propoxyphene. 
13. Subject who is taking strong 3A4 inducers, e.g., St. John's Wort or cyclobenzaprine 
(tricyclic muscle relaxant).  
14. Subject who is taking dopamine antagonists, such as the neuroleptics (phenothiazines, 
butyrophenones, thioxanthenes) or metoclopramide. 
15. Marijuana or previous exposure to Marijuana during the last 30 days prior to the baseline 
visit or subject has a history of alcohol or drug abuse or dependence within the prior 12 
months, according to Investigator judgment, (alcohol intake is limited to 1 glass or shot 
per day during the whole study taken not less than 3 hours before or after dosing (see 
section 10.2). 
16. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant 
medication which, in the opinion of the Investigator, makes the subject unsuitable for 
study entry or potentially unable to complete all aspects of the study. 
17. Subject has moderate or severe renal impairment (creatinine clearance <50 mL/min) or on 
dialysis. 
18. Subject has moderate (Child-Pugh categorization B, score 7-9) or severe (Child-Pugh 
categorization C, score 10-15) hepatic impairment. 
19. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response ('Yes') to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (CSSRS) at Screening. 
20. Subject has known hypersensitivity or intolerance to pramipexole or rasagiline or to any 
components or excipients of the test drug or placebo. 
21. Subject who has a history of neuroleptic malignant syndrome. 
22. Subject who is pregnant or breastfeeding. 
23. Subject, who, for any reason, is judged by the Investigator or the eligibility monitoring 
committee (EMC) to be inappropriate for this study, including a subject who is unable to 
communicate or cooperate with the Investigator or who has/had a clinically significant 
illness or abnormal physical examination that may compromise safety of the subject 
during the trial or affect ability of the subject to adhere to study procedures. 
 
A site will not be allowed to randomize subjects unless their diagnosis and suitability for the study 
has been confirmed and documented by both the Investigator and the EMC and they are deemed 
to be a satisfactory candidate by the EMC. 
Test product: 

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a. P2B001 pramipexole dihydrochloride 0.6 mg/rasagiline 0.75 mg Once Daily. 
Reference therapy: 
b. Pramipexole dihydrochloride 0.6 mg Once Daily. 
c. Rasagiline 0.75 mg Once Daily. 
Calibration arm: 
d. Pramipexole ER titrated to optimal dose (1.5, 3.0 or 4.5mg) Once Daily 
 
Duration of treatment: 
Subjects will receive study drug or matching placebo treatment for a total of 12 weeks followed 
by a 7-day gradual discontinuation of treatment of pramipexole ER arm or matching placebo).    
 
Statistical Methodology:  
This study is a phase 3, twelve-week, multi-center, multinational, randomized, double-blind, 
double-dummy, parallel group study. Up  to 525 eligible subjects with early untreated Parkinson’s 
disease (PD) who are not early terminated from the study during screening or baseline visits and 
are randomized to treatment with P2B001 0.6/0.75 (150 subjects), or pramipexole 0.6 mg once daily 
(150 subjects), or rasagiline 0.75 mg once daily (150 subjects), or pramipexole ER titrated to 
therapeutic optimal dose (75 subjects) using a randomization scheme of 2:2:2:1, respectively.  
Randomization will take place following the completion of all screening procedures including 
subject approval by both site PI and the central EMC.  
This study is powered to demonstrate the superiority of (i) P2B001 0.6/0.75mg as compared to its 
individual components in the change from baseline to Week 12/Treatment Termination in Total 
UPDRS score and, (ii) to demonstrate the superiority of P2B001 0.6/0.75mg over pramipexole ER 
in the change from baseline to Week 12/Treatment Termination in the ESS.  
Treatment with pramipexole ER will serve as a calibration arm to better characterize P2B001 
against currently used therapy. Therefore, with the exception of change from baseline to Week 
12/Treatment Termination in the ESS, only descriptive statistics and no formal significance testing 
will be made between the pramipexole ER arm and the other three study arms. 
Week 12/Treatment Termination is defined for all statistical analyses involving significance as the 
last visit in which a subject was treated with the study drug. 
 
Sample Size Rational: 
The study was powered to allow achieving two goals: 
• To demonstrate the superiority of P2B001 0.6/0.75mg compared to its individual components 
in the primary endpoint, the change from baseline to Week 12/Treatment Termination in total 
UPDRS score: 

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- 
The power to meet the primary endpoint was estimated based on simulation runs assuming 
equal arms size of P2B001 0.6/0.75mg and its individual components as well as repeated 
UPDRS measurements at baseline, week 5, week 8 and week 12.  
- 
The expected STD of the change from baseline was assumed to be 6.0 UPDRS points. 
- 
The expected treatment effect of P2B001 0.6/0.75mg is 3 UPDRS points over rasagiline 
0.75mg and 2.25 UPDRS points over 0.6mg pramipexole. 
- 
Sequential correlations between changes from baseline will be 0.7 and 0.49 between these 
obtained at week 5 and at week 12. 
- 
Missing observations rate of 10% occurring at random. 
- 
The statistical model used in the simulation study was the Mixed Model for Repeated 
Measures (MMRM) (SAS® MIXED procedure with REPEATED sub-command) testing 
two contrasts: P2B001 0.6/0.75mg vs. rasagiline 0.75mg and P2B001 0.6/0.75mg vs. 
pramipexole 0.6mg at Week 12/Treatment Termination. 
- 
In order to consider the study as successful both tested contrasts have to be statistically 
significant at 5% two-tailed each.  
The simulation indicates that a total of  150 subjects to be included in each P2B001 0.6/0.75mg 
arm, rasagiline 0.75mg arm and pramipexole 0.6mg arm will provide 87.6% power to detect a 
statistically significant effect size favoring P2B001 0.6/0.75mg by 3 UPDRS points over 
rasagiline 0.75mg and 2.25 UPDRS points over pramipexole 0.6mg.   
• To demonstrate the superiority of P2B001 0.6/0.75mg over pramipexole ER in the first 
secondary endpoint, namely, the change from baseline to Week 12/Treatment Termination in 
the ESS: 
- 
The power to meet this secondary endpoint was estimated using the two-sample t-test for 
mean difference at a two-sided alpha of 5% (SAS® POWER procedure). 
- 
The expected STD of the change from baseline was assumed to be 3.0 ESS points. 
- 
The expected treatment effect of P2B001 0.6/0.75mg over pramipexole ER is 1.5 ESS 
points. 
- 
According to the gate keeping method for multiple endpoints while testing for the secondary 
endpoints, this secondary endpoint will be considered as met only in the case that both 
primary endpoint contrasts as well as the P2B001 0.6/0.75mg over pramipexole ER 
comparison in the change from baseline to Week 12/Treatment Termination in the ESS will 
be met at two-tailed alpha level of 5% each.  
This analysis indicates that a total of 150 subjects to be included in the P2B001 0.6/0.75mg arm 
and 75 subjects to be included in pramipexole ER arm, considering the above assumptions, will 
provide a power of 94.1% to detect a statistically significant effect size at the magnitude of 1.5 
ESS units or more at a two-sided alpha level of 5%. 
 
Sample Size Re-Assessment: 

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To examine whether the variance estimate used in power calculations for the primary endpoint was 
adequate, an assessment of the variance magnitude will be performed after at least 1/3 of the 
subjects complete the study treatment period. The EM algorithm of Gould and Shih 
(Communications in Statistics. A Theory and Methods, 21, 2833-2853, 1992), will be applied to 
estimate the variance of the change from baseline to Week 12/Treatment Termination in total 
UPDRS score, without breaking the blind. In the case that the variance estimate will be found to be 
larger than the one projected, the sponsor reserves the right to up-size the study via protocol 
amendment. 
 
Randomization: 
Randomization will take place following the completion of all screening procedures including 
subject approval by both site PI and the central EMC. 
Subjects will be randomized to treatment with P2B001 0.6/0.75 (approximately 150 subjects), or 
pramipexole 0.6 mg once daily (approximately 150 subjects), or rasagiline 0.75 mg once daily 
(approximately 150 subjects), or pramipexole ER titrated to therapeutic optimal dose 
(approximately 75 subjects) using a randomization scheme of 2:2:2:1, respectively, stratified by 
region. 
 
Overall Significance Level and Multiplicity Adjustment: 
The overall significance level for this study will be 5% using two-tailed tests. No interim analyses 
or futility analyses are planned for this study. 
The overall, experiment-wise type-I error rate of 5% will be preserved according to the below plan: 
1. The principal analysis of the primary endpoint is designed to demonstrate the efficacy of 
P2B001 0.6/0.75mg as compared to its individual components in the changes from baseline to 
Week 12/Treatment Termination. Accordingly, analysis will employ two contrasts: P2B001 
0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg 
once daily. The type-I error of 5% for multiple contrasts testing for the primary endpoint will 
be preserved by determining that the primary endpoint is met only if both comparisons will 
favor P2B001 0.6/0.75mg at a two-tailed alpha level of 5% each.     
2. Multiplicity adjustment for multiple endpoints testing for the secondary endpoints will utilize 
the gate keeping hierarchical method according to the following order and plan: 
- 
For the 1st secondary endpoint, namely, the P2B001 0.6/0.75mg vs. pramipexole ER contrast 
in the change from baseline to Week 12/Treatment Termination in the ESS, will be 
considered as met only if both primary endpoint contrasts as above defined and the P2B001 
0.6/0.75mg vs. pramipexole ER contrast in the change from baseline to Week 12/Treatment 
Termination in the ESS will all be met (total of 3 contrasts) at a two-tailed alpha level of 5% 
each.     

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- 
The 2nd secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the Total PDQ39 will be considered as met if all of the 3 previous tested 
contrasts (primary endpoint and 1st secondary endpoint) as well the two contrasts: P2B001 
0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 
0.75mg once daily in the 2nd secondary endpoint will all be met (total of 5 contrasts) at a 
two-tailed alpha level of 5% each. 
- 
The 3rd secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the ADL UPDRS (part II) score will be considered as met if all of the 
5 previous tested contrasts (primary endpoint, 1st and 2nd secondary endpoints) as well the 
two contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 
0.6/0.75mg vs. rasagiline 0.75mg once daily in the 3rd secondary endpoint will all be met 
(total of 7 contrasts) at a two-tailed alpha level of 5% each. 
- 
The 4th secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the motor UPDRS (part III) score will be considered as met if all of the 
7 previous tested contrasts (primary endpoint, 1st, 2nd and 3rd secondary endpoints) as well 
the two contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 
0.6/0.75mg vs. rasagiline 0.75mg once daily in the 4th secondary endpoint will all be met 
(total of 9 contrasts) at a two-tailed alpha level of 5% each. 
- 
The 5th secondary endpoint, namely, the CGI-S responder’s analysis at Week 12/Treatment 
Termination visit (change from baseline ≥1 CGI-S points) will be considered as met if all 
of the 9 previous tested contrasts (primary endpoint, 1st, 2nd, 3rd and 4th secondary endpoints) 
as well the two contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg once daily and, 
P2B001 0.6/0.75mg vs. rasagiline 0.75mg once daily in the 4th secondary endpoint will all 
be met (total of 11 contrasts) at a two-tailed alpha level of 5% each. 
 
Principal Analysis of the Primary Endpoint: 
The primary efficacy endpoint for this study is the change from baseline to Week 12/Treatment 
Termination in total UPDRS score (defined as sum of parts II and III, scores (0-160). The statistical 
model will be a Mixed Model for Repeated Measures (MMRM) (SAS® MIXED procedure with 
REPEATED sub-command). The model will include the following fixed effects: categorical week 
in trial by treatment interaction, country or geographical region (CGR), and baseline UPDRS score. 
The model will use the unstructured covariance structure and the REML estimation method and 
degrees of freedom will be adjusted using the Kenward-Roger method. Data from all three changes 
form baseline to post-baseline visits (weeks 5, 8 and 12) collected from all subjects randomized into 
the study will be used as response in the model. The differences between the P2B001 0.6/0.75mg 
arm as compared to its 2 individual components at Week 12/Treatment Termination will be 
estimated and tested using 2 contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg and, P2B001 

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0.6/0.75mg vs. rasagiline 0.75mg. The study primary endpoint will be considered as met only if 
both contrasts will favor P2B001 0.6/0.75mg at a two-tailed alpha level of 5% each. 
 
Statistical Analysis Plan (SAP) 
A more detailed SAP will be developed while the study is ongoing and prior to locking the 
database and un-blinding.  
 
If ever there is a discrepancy in the between the Protocol and the Statistical Analysis Plan, the 
methods defined in the SAP will have precedence. 
 
 
 
 
 

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3 INTRODUCTION 
3.1 Background  
Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The major motor 
symptoms include rigidity, tremor, and bradykinesia. Levodopa (L-DOPA) provides meaningful 
benefit for most patients, particularly in the early stages of the disease. However, chronic L-
DOPA treatment is associated with the development of motor complications (motor fluctuations 
and dyskinesia) in the majority of individuals.  Further, levodopa induced off time and 
dyskinesia are dose-related and seen with higher doses of L-DOPA (Olanow CW M. F., 2013) . 
To delay the introduction of L-DOPA and to permit the use of lower doses, many physicians 
choose to initiate therapy with a monoamine oxidase Type B (MAO-B) inhibitor, frequently 
rasagiline, a dopamine agonist, commonly pramipexole, or both (often in sequential order).  The 
use of these treatments prior to the introduction of L-DOPA can provide satisfactory clinical 
control in the early stages of the disease, enable lower doses of L-DOPA to be used when it is 
required and delay developing L-DOPA associated motor complications. 
Pramipexole is a non-ergot, specific and selective dopamine receptor agonist of the dopamine D2 
subfamily (Perez-Lloret S, 2010). Rasagiline is a selective and irreversible monoamine oxidase 
B (MAO-B) inhibitor (Youdim MB, 2001) . Thus, while pramipexole compensates for the lack 
of endogenous neurotransmitters by activating the postsynaptic dopamine receptor, rasagiline 
causes an enhancement of synaptic dopamine levels by inhibiting dopamine oxidative 
metabolism. 
Pramipexole has been shown to possess neurotropic activity in animal models (Imamura K, 
2008) (Li C, 2010). In the last decade, studies of rasagiline have shown that it also works 
through additional anti apoptotic mechanisms (Wu Y, 2015), and neurotropic effects (Azilect 
EPAR) that may contribute to its anti-parkinsonian benefit. Therefore, further compatibility of 
the mechanisms of these two agents may exist. 
While the use of alternative treatment prior to introduction of L-DOPA is now an acceptable 
approach (Olanow W, 2009), approved therapeutic doses of pramipexole and rasagiline have 
potential safety concerns and therapeutic limitations.  For example, therapeutic doses of 
dopamine agonists are typically associated with nausea, vomiting, constipation and orthostatic 
hypotension.  Further, pramipexole is also associated with a risk of impulse control disorders, 
peripheral edema, psychosis and excessive daytime sleepiness, and a risk of sudden onset sleep 
episodes in unintended situations such as while driving.  These side effects are more pronounced 
with higher dosages.  Rasagiline is largely well tolerated but has limited efficacy and also has 
potential safety concerns, particularly with respect to the risk of a hypertensive crisis with foods 
that are high in tyramine and as serotonin syndrome particularly when employed in high doses or 
in combination with selective serotonin reuptake inhibitors and other anti-depressants that are 
commonly prescribed in Parkinson’s disease.  Again, higher doses are associated with a greater 
risk of developing these adverse effects. 

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Pharma Two B’s therapeutic strategy is to develop a fixed-dose combination of low doses of 
agents with complementary mechanisms of action (ie, a dopamine agonist and a MAO-B 
inhibitor) in an attempt to obtain enhanced anti-Parkinsonian efficacy and a better safety profile 
in comparison to what can be achieved with higher doses of either agent alone, as the drugs are 
currently employed. 
Pharma Two B has investigated the effects of combining low doses of pramipexole and 
rasagiline in both animal models and PD patients.  Nonclinical data demonstrate that low doses 
of the MAO-B inhibitor rasagiline and the dopamine agonist pramipexole act synergistically 
with respect to behavioural effects and striatal dopamine.   
In animal studies, administering both agents in a slow infusion over 24 hours (mimicking 
extended-release) further improves their efficacy, presumably by allowing the agents to work 
together for a longer time, enhancing their mutual action.  The half-lives of the currently available 
pramipexole and rasagiline vary (T1/2 is 8-12 hours for pramipexole, and 1.5-3.5 hours for 
rasagiline) (Wright CE, 1997) (Thebalut JJ, 2004). Therefore, the P2B001 combination comprises 
an extended release (ER) profile for both pramipexole and rasagiline, which enables release 
throughout the day for both drugs, allowing for a longer time of mutual action.  
 
P2B001 is intended to offer a novel approach to PD treatment in that it would be: 
• 
a fixed-dose combination of the two agents; 
• 
an extended-release formulation of both pramipexole and rasagiline; and 
• 
a new low-dose regimen of the two agents intended to maximize efficacy while limiting 
known adverse effects of approved higher doses of the individual components. 
 
A Phase 2b clinical study (P2B001/001) in patients with early Parkinson’s disease testing the 
low-dose combinations of pramipexole (0.3 or 0.6 mg) and rasagiline (0.75 mg) in an extended-
release formulation has recently been completed and demonstrated that the combination provides 
highly significant and clinically meaningful benefits in comparison to placebo, with a good 
safety profile (Olanow CW K. K., 2017). The primary efficacy endpoint was the change from 
baseline to Week 12 in total UPDRS (I+II+III) score. The UPDRS data showed significant 
improvement at each time point relative to baseline (p<0.0001 at 4, 8, and 12 weeks) for both the 
0.3/0.75 mg and 0.6/0.75 mg dose combinations. The placebo-subtracted differences were 
statistically significant at 12 weeks, these were -4.67 points for 0.6/0.75 mg (p=0.0004) and -
3.84 points for 0.3/0.75 mg (p=0.0027).   
Out of the two above tested doses, the 0.6/0.75 mg dose was selected for the phase III study. 
Although between-group differences in efficacy were not statistically significant, there was 
consistent numerical benefit for this dose on total, motor and ADL UPDRS scores, PDQ39 and 
CGI-severity. 

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3.2 Preclinical Pharmacology Studies  
Several non-clinical pharmacology studies assessing the effects of the proposed drug 
combination have been conducted. When the combination of rasagiline and pramipexole were 
administered together at doses that individually produce only small changes in striatal dopamine 
levels in MPTP-lesioned animals, greater than additive recovery of dopamine levels were 
observed. Further, when the sustained-release dosage is mimicked, the effect is greater than 
when the same combination is administered as immediate release. This has been supported in a 
further study in which L-DOPA-induced contralateral turning and the stepping test in the 6-
OHDA-lesioned rat model showed greater than additive changes when rasagiline and 
pramipexole were administered in combination. 
3.3 Toxicology Studies 
A review of the pharmacological profiles of pramipexole and rasagiline revealed that both products 
are highly specific in their activities.  Rasagiline is highly specific for MAO-B ( Lecht S, 2007). 
Similarly, pramipexole demonstrated specificity for D2-D3 dopamine receptors (Summary Basis 
of Approval NDA 20667., 1997).  The nonclinical development programs for Mirapex and Azilect 
included full batteries of toxicity testing needed for approval of chronically administered drug 
products.  These studies identified few end organs for toxicity other than those predicted by the 
pharmacology of the two substances.  Toxicological interactions are not predicted by the available 
human and animal data.   
In addition, evaluation of adverse effects in the LARGO and PRESTO studies showed no 
indication of an increase in dopaminergic adverse effects in patients when rasagiline was added to 
dopamine agonist treatment.  Also, increases in adverse dopaminergic or other adverse effects have 
not been noted in clinical studies in which other MAO inhibitors (e.g., selegiline) have been used 
with pramipexole (Du F, 2005), (Hauser RA, 2010), (Rascol PB, 2010), (Hubble JP, 1995), 
(Shannon KM, 1997), (PSG, 1997), (Mirapex ER Label, 2010)  
The P2B001/001 phase 2b study did not show any new or unexpected adverse events and showed 
a decrease in most dopaminergic adverse events.  
 
3.4 Clinical Studies 
Pharma Two B Ltd. has conducted three clinical trials with its low-dose, extended-release, fixed 
dose formulation of pramipexole and rasagiline for the treatment of early Parkinson’s disease. 
The initial pharmacokinetic study (Study 10/10) was four arms, crossover, pharmacokinetic 
study in healthy, fasted young adults comparing immediate release rasagiline (Azilect®, 1 mg, 
commercial), ER pramipexole (Mirapex ER®, 0.75 mg, commercial), both commercial drugs 
taken together, and Pharma Two B’s proprietary P2B001 containing doses of rasagiline (1 mg) 
and pramipexole (0.75 mg), both ER.  Results indicated that no pharmacokinetic interactions 
occurred between the components when given together. The Cmax and AUC of each component 

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in the combination were either equal (in case of Pramipexole) or lower (in case of Rasagiline) 
compared to the Cmax and AUC of the drugs given alone, indicating that no safety issues 
resulting from increased exposure are expected. In this study, the availability of the drugs in the 
P2B001 is about 90% for pramipexole and about 80% for rasagiline relative to the commercial 
mono-therapies.  Furthermore, both drugs were present in plasma throughout the day and the 
high peaks associated with the commercial products were avoided with P2B001. The second 
study has recently been completed. This was a phase 2b, twelve-week multi-center, randomized, 
double-blind, placebo-controlled, parallel group study, to determine the safety, tolerability and 
efficacy of two doses of P2B001 in subjects with early Parkinson’s disease. The   study tested 
two low-dose, fixed-dose combinations of P2B001, once-daily containing pramipexole and 
rasagiline (0.6 mg/0.75 mg and 0.3 mg/0.75 mg) relative to an identical placebo capsule. The 
results demonstrated robust statistically significant and clinically meaningful improvement 
results compared to placebo in Parkinson’s disease symptoms with a favorable safety profile at 
two dosage strengths of the combination product. The primary efficacy endpoint was the change 
from baseline to Week 12 in total UPDRS (I+II+III) score. The UPDRS data showed significant 
improvement at each time point relative to baseline (p<0.0001 at 4, 8, and 12 weeks) for both the 
0.3/0.75 mg and 0.6/0.75 mg dose combinations. The placebo-subtracted differences were 
statistically significant at 12 weeks, these were -4.67 points for 0.6/0.75 mg (p=0.0004) and -
3.84 points for 0.3/0.75 mg (0.0027).  Adverse events of frequency ≥ 5% are listed in the table 
below.  
 

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Common Adverse Events (Frequency ≥5%) (P2B001/001) Number and % of Subjects 
 
Placebo 
(N=50) 
P2B001 0.3/0.75 
(N=50) 
P2B001 0.6/0.75 
(N=49) 
Diarrhea 
3 (6%) 
0 (0%) 
0 (0%) 
Nausea 
1 (6%) 
6 (12%) 
10 (20.4%) 
Fatigue 
1 (2%) 
1 (2%) 
4 (8.2%) 
Nasopharyngitis 
5 (10%) 
2 (4%) 
2 (4.1%) 
Dizziness 
4 (8%) 
2 (4%) 
5 (10.2%) 
Headache 
4 (8%) 
1 (2%) 
1 (2%) 
Somnolence 
0 (0%) 
4 (8%) 
8 (16.3%) 
Tremor 
3 (6%) 
3 (6%) 
4 (8.2%) 
Insomnia 
2 (4%) 
0 (0%) 
3 (6.1%) 
Orthostatic 
hypotension 
4 (8%) 
1 (2%) 
2 (4.1%) 
 
As for severity, most of the adverse events (frequency ≥5%) were mild.  Interestingly most of the 
somnolence reported for the 0.6/0.75 mg dose were mild (67%) while for the 0.3/0.75 mg dose 
most were moderate. A second pharmacokinetic study (Study P2B001/002a) was recently 
completed in healthy male and non-pregnant female volunteers, comparing the effect of food 
(high-fat meal versus fasting) on the bioavailability of pramipexole and rasagiline from a single 
oral dose of P2B001 Pramipexole/Rasagiline 0.6 mg/0.75 mg once daily capsule. Results indicated 
that food does not alter the peak or extent of absorption of both pramipexole and rasagiline from 
P2B001.  
 
3.5 Summary of Non-Clinical and Clinical Studies 
P2B001 is an oral fixed-dose, extended release product that combines pramipexole and rasagiline 
for the treatment of early Parkinson’s disease. The Pharma Two B product is novel in that it would 
be: 
• A fixed-dose combination of the two agents. 
• A low-dose regimen intended to maximize efficacy while limiting adverse effects. 
• The first product incorporating a extended release formulation of rasagiline.  
 

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Pharma Two B Ltd. has completed several studies characterizing P2B001 in a rodent model of 
PD, a phase 1 study with healthy volunteers and a phase 2b study with early PD patients, all 
demonstrated the therapeutic advantage of Pharma Two B’s proprietary extended release 
combination:  
• The nonclinical studies in rodents PD models suggest a therapeutic advantage of combining 
low doses of rasagiline and pramipexole and suggest further improvement when both are 
administered in a sustained fashion. 
• The Phase 1 study (Study 10/10) indicates the absence of a pharmacokinetic interaction 
between pramipexole and rasagiline when co-administered. Further, when administered 
at equivalent doses, the plasma profile of pramipexole from Pharma Two B’s extended 
release combination product mirrors that of Mirapex ER®. The plasma profile from 
Pharma Two B’s extended-release combination product differs markedly, as expected, in 
Cmax from that of immediate-release Azilect, but provides similar exposure. 
• The 12-week Phase 2B, multi-center, randomized, double-blind, placebo-controlled, parallel 
group study of P2B001 in subjects with early Parkinson’s disease (study 
P2B001/001) demonstrated statistically significant and clinically meaningful improvement 
compared to placebo in Parkinson’s disease symptoms with a favorable safety profile at two 
dosage strengths of the combination product (0.6 mg pramipexole/0.75 mg rasagiline and 0.3 
mg pramipexole/0.75 mg rasagiline). 
 
P2B001 at dose of 0.6 mg pramipexole/0.75 mg rasagiline will be used for further development 
of Pharma Two B’s product.  
4 STUDY OBJECTIVES 
 
Pharma Two B intends to show that: 
• P2B001 has superior efficacy as compared to each of its components. 
• P2B001 is safe and tolerable. 
• P2B001 has descriptively comparable efficacy as well as safety benefits as compared to 
pramipexole ER.  
4.1 Primary Objective  
 
• To determine the superiority of P2B001 0.6/0.75 mg as compared to its individual 
components in the change of total UPDRS score (defined as sum of parts II and III, scores 
(0-160).  
 

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4.2 Secondary Objectives  
• To determine the superiority of P2B001 0.6/0.75 mg as compared to pramipexole ER in the 
change of Epworth Sleepiness Scale (ESS) score.  
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components 
in the change of Total PDQ39 score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components 
in the change of ADL UPDRS (part II) score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components 
in the change of motor UPDRS (part III) score. 
• To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual components 
in the CGI-S responder’s analysis (change from baseline ≥1 CGI-S points).  
4.3 Exploratory Objectives: 
• To evaluate the superiority of P2B001 0.6/0.75 mg compared to its individual components in 
the following endpoints: 
- 
Change in each of the 8 PDQ39 subscales scores. 
- 
Change in the score of Health-Related Quality of Life (HRQOL) SF-12v2 questionnaire. 
- 
Clinical Global Impression of Improvement (CGI-I). 
 
• To evaluate the superiority of P2B001 0.6/0.75 mg over pramipexole ER with respect to the 
following outcome measures: 
- 
Proportion (%) of patients with ESS score >10.  
- 
Proportion (%) of patients with ESS Score <10 at baseline and ESS score >10. 
- 
3-Months rate of total number of adverse events. 
- 
Change in the differences in systolic and diastolic blood pressure measured during supine 
and standing positions.   
- 
Proportion (%) of patients with both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
3-Months rate of total number of both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
Proportion (%) of patients with symptomatic Orthostatic Hypotension. 
- 
3-Months rate of total number of symptomatic Orthostatic Hypotension. 
- 
Proportion (%) of patients with daytime sleepiness/drowsiness related AE’s.  
- 
Proportion (%) of patients with gastrointestinal (GI) adverse events  
- 
Proportion (%) of patients presenting neurological adverse events  
- 
Change in the score of Orthostatic Hypotension Symptoms Assessment (OHSA) question1. 

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• To descriptively evaluate the comparability of P2B001 0.6/0.75 mg with reference to the 
calibration arm (pramipexole ER) in total UPDRS score (defined as sum of parts II and III, 
scores (0-160). 
Note that no formal efficacy comparisons will be made between the calibration arm of 
pramipexole ER to the other three treatment arms.   
 
4.4 Safety & Tolerability Objectives 
 
The safety profile of the test product and comparators will be evaluated by changes in the safety 
parameters, including adverse events, concomitant medications, vital signs, laboratory 
parameters, physical and neurological examinations, ECGs, Questionnaire for Impulsive-
Compulsive Disorders in Parkinson's Disease- Rating Scale (QUIP-RS), Columbia Suicide 
Severity Rating Scale (CSSRS), Orthostatic Hypotension Symptoms Assessment (OHSA) 
question 1 and Epworth Sleepiness Scale (ESS). 
Tolerability will be assessed by percentage of subjects that complete the trial on treatment 
assigned. 
5 INVESTIGATIONAL PRODUCT 
 
The drug combination P2B001 is comprised of two drugs; pramipexole and rasagiline, both 
currently approved drugs and routinely used in standard therapy for early PD. Each active 
pharmaceutical ingredient (API) is formulated separately as extended-release pellets (i.e., inert 
sugar bead core layered with drug and covered with an extended release coating). The two types 
of pellets are packed into a capsule to provide the desired dose.  
 
Pramipexole is a non-ergot, specific and selective dopamine receptor agonist of the dopamine D2 
subfamily (Perez-Lloret S, 2010), currently marketed as immediate release and as extended 
release. Rasagiline is a selective and irreversible monoamine oxidase B (MAO-B) inhibitor 
(Youdim MB, 2001). Thus, while pramipexole compensates for the lack of endogenous 
neurotransmitters by activating the postsynaptic dopamine receptor, rasagiline causes an 
enhancement of synaptic dopamine levels by inhibiting dopamine oxidative metabolism. 
 
Pramipexole is currently marketed as immediate release and as extended release (ER). In this 
study the ER product will be used as a calibration arm. The starting dose of pramipexole ER is 
0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased 
gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 

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mg increments up to a maximum recommended dose of 4.5 mg per day (Summary Basis of 
Approval NDA 20667., 1997). 
 
Rasagiline is only marketed as immediate release. The recommended monotherapy dose of 
rasagiline is 1 mg once daily (  Azilect Label, 2010). 
5.1 Dosage 
 
The dosage for the three main study arms will be: 
• P2B001 (pramipexole dihydrochloride 0.6 mg/rasagiline 0.75 mg) once daily 
• Pramipexole dihydrochloride (0.6 mg) once daily 
• Rasagiline (0.75 mg) once daily 
 
The dosage for the calibration arm will be: 
• Pramipexole ER individually titrated to an optimal dose (1.5-4.5mg/day). 
 
The combination product (P2B001) and its individual components, pramipexole and rasagiline 
were produced by: Catalent Pharma solutions Somerset, USA address: 14 Schoolhouse Rd. 
Somerset, NJ 08873, USA. 
 
The pramipexole ER comparator and its placebo tablets were produced by: 
Dr. Reddy's Laboratories Limited, FTO UNIT 3, Survey No 41 Bachupally village, Qutubullapur 
Mandal Ranga Reddy District Telangana 500090 India 
 
5.2 Dose Modification 
 
Subjects may be allowed to miss a dose of study medication if:  
1) Subject develops an adverse event that the Investigator believes requires the subject’s dose to 
be held temporarily, or  
2) Subject loses their kit of study medication and a replacement kit is requested, in this situation 
the PI should request an emergency shipment to alert the distributor to ship the replacement kit 
urgently).  
During the pramipexole ER titration phase, the PI or sub-Investigator may modify (up or down) 
subject’s dose to either1.5, 3.0 or 4.5 mg of the pramipexole ER/identical placebo to reach the 
optimal tolerated therapeutic dose. Following the titration phase, after week 6, no modifications 
are allowed.  
If the subject experiences intolerable adverse events, dosing may be held temporarily or 
withdrawn (all treatments, including both capsules and tablets, please note that pramipexole 

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ER/matching placebo tablets need to be down titrated gradually (see down titration instructions 
in section 6.1). However, the subject will continue to be followed-up according to the protocol 
pre-planned schedule of activities  
No other dose modifications will be allowed in this study.  
5.3 Method of Administration & Meals 
 
Subjects will take the study medications (capsule and tablets) by mouth with a glass of water 
(8oz or 240ml). Study medication can be taken with or without food and efforts should be made 
to take the study medication at about the same time every day.  
6 STUDY DESIGN 
6.1 Overall Study Design and Plan Description 
 
This study is a phase 3, twelve-week, randomized, double-blind, double-dummy, 4-arm, parallel 
group, multi-center, multinational study to determine the efficacy, safety and tolerability of 
P2B001 in subjects with early Parkinson’s disease as compared to its individual components and 
compared to a calibration arm of pramipexole ER. 
 
Up to 525 eligible subjects with early untreated PD, who are not early terminated from the study 
during screening or baseline visits and are randomized to treatment with P2B001 0.6/0.75 or 
pramipexole 0.6 mg once daily, or rasagiline 0.75 mg once daily, or pramipexole ER titrated to 
optimal dose (1.5, 3.0 or 4.5mg) using a randomization scheme of 2:2:2:1, respectively. 
Randomization will take place following the completion of all screening procedures including 
subject approval by both site PI and the central EMC. Subjects will be recruited from 
approximately 70 sites in North America and Europe.  
 
Each subject will be asked to take one capsule and 1-3 tablets once daily. The capsules will 
contain either P2B001 0.6/0.75 mg or pramipexole 0.6 mg or rasagiline 0.75 mg or matching 
placebo. The tablets will contain either Pramipexole ER or matching placebo.  
 
Dosing Regimen: 
 
• P2B001 pramipexole dihydrochloride 0.6mg/Rasagiline 0.75 mg Once Daily + Placebo 
of Pramipexole ER. 
• Pramipexole dihydrochloride 0.6 mg Once Daily (PPX 0.6) + Placebo of Pramipexole 
ER. 

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• Rasagiline 0.75 mg Once Daily (RAS 0.75) + Placebo of Pramipexole ER. 
• Pramipexole ER individually titrated to optimal dose + Placebo of P2B001. 
 
Study Structure:  
• Up-titration phase  
• Maintenance phase  
• Down-titration phase 
• Safety follow-up phase.     
 
Up-Titration phase: A 3-6 week double blind, double dummy titration phase with pramipexole ER 
or matching placebo. During this phase subjects will also take 1 capsule of P2B001/RAS 
0.75/PPX0.6/Placebo which does not need titration. For the first 3 weeks the titration of the 
pramipexole ER will be increased by weekly increments up to a daily dose of 1.5 mg as follows: 
0.375, 0.75 and 1.5 mg. If needed, between weeks 3 and 6, the titration can continue to a daily 
dose of 3.0 mg or 4.5 mg of pramipexole ER or matching placebo or reduced to a minimum of 
1.5mg with the final level determined based on achieving satisfactory efficacy and tolerability. On 
completion of the dose-titration phase (end of week 6), the minimum therapeutic dose of 
Pramipexole ER 1.5 mg per day (or placebo) must be achieved by all the patients. The treatment 
with study medications of patients who cannot achieve this dosage will be discontinued, but the 
subject will be requested to continue with all the study visits. 
 
Maintenance phase: Once the final dose level has been reached for the pramipexole ER, the 
subject will continue at that dose, together with the once daily P2B001/RAS 
0.75/PPX0.6/Placebo capsule, until the end of Week 12.  
 
Down-titration phase: a 7-day gradual down titration of pramipexole ER or matching placebo. 
The down titration should be done by reducing the dose every two days by half (except for 
subjects taking 4.5 mg, these should reduce the dose to 3.0 mg and then continue to reduce by 
half every two days). There is no treatment with once daily P2B001/RAS 0.75/PPX0.6/Placebo 
capsules during this period.  
 
Safety follow-up phase: a 7 days period of no treatment of pramipexole ER and 14-day period of 
no treatment for the P2B001/RAS 0.75/PPX0.6/Placebo capsule.  
 
 
 

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Study design scheme: 
 
 
*Titration phase: Subjects can stop titration of pramipexole ER or placebo at 1.5 mg or can continue titration and increase the 
dose to 3.0 or 4.5 mg to optimal dose or decrease back to 3.0 or 1.5 mg. The dosage level achieved at the end of the titration 
phase (end of week 6) is then held constant during the maintenance phase ending at the end of week 12. 

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6.2 Rationale for Study Design, study population and Doses 
 
The study is designed to show the contribution of both active components, pramipexole and 
rasagiline, to the efficacy of the combination product P2B001 by comparing the efficacy 
between P2B001 and its individual components as the co-primary objectives. In addition, the 
study includes a calibration arm in order to characterize the benefits of P2B001 in respect to 
safety and efficacy of currently used therapeutic doses of pramipexole ER.  
 
Early Parkinson's disease patients are chosen for this study, since they are the patient population 
that most likely can benefit from the combination product. The use of the combination product 
can delay the beginning of treatment with L-DOPA and as consequence reduce and delay the risk 
of developing motor complications with L-DOPA treatment. 
 
The study was adequately powered to allow demonstration of the efficacy of P2B001 over its 2 
components by randomly allocating 150 subjects to each of P2B001 arms and its 2 components. 
Additional 75 subjects will also be randomized to treatment with pramipexole ER to allow 
characterization of the benefits of P2B001 with reference to pramipexole ER titrated to 
individual optimal doses.  
The dose of P2B001 chosen for this study is based on the results of the previous phase 2b dose 
ranging study (P2B001/001). Both doses of P2B001 that were tested (0.6 mg pramipexole/0.75 
mg rasagiline and 0.3 mg pramipexole/0.75 mg rasagiline) provided significant clinical benefits 
with a good safety profile. The 0.6 mg pramipexole/0.75 mg rasagiline dose was chosen because 
there was consistent numerical benefit for this dose on total, motor and ADL UPDRS scores, 
PDQ39 and CGI-severity assessments. Both doses were well tolerated with an adverse event 
profile similar to placebo, with the exception of somnolence and mild nausea, known adverse 
events of pramipexole. Slightly more cases of somnolence and nausea were reported for the 0.6 
mg pramipexole/0.75 mg rasagiline dose, but both doses did not show statistically significant 
differences from placebo in the ESS scale and the reports of nausea in both doses were mostly 
mild and transient. 
 
Subjects with mild to moderate renal impairment and subjects with mild hepatic impairment 
were included in the previous phase 2b study and were followed up with monthly renal and liver 
function tests to assure compliance with exclusion criteria 17 and 18 and these showed no 
significant changes. In the current study subjects with mild renal and or mild hepatic impairment  
will also be included with the same additional follow up to assure compliance with exclusion 
criteria 17 and 18. In case of worsening in a subject's liver or renal condition and the subject is 
not compliant with the above exclusion criteria, their participation in the study will be stopped. 

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Subjects with moderate renal impairment (creatinine clearance between 30 and 50 mL/min) will 
be excluded in the current study due to possible titration of pramipexole ER tablets to doses 
above the recommended dose in such patient populations, which is 2.25mg/day.   
7 STUDY POPULATION 
7.1 Number of Subjects 
Study population includes 525 eligible early stage untreated PD patients who are not early 
terminated from the study during screening or baseline visits.  Subject will be recruited from 
approximately 70 sites in North America and Europe. 
 
7.2 Subjects Enrolment  
All subjects enrolled must be eligible as per Inclusion/Exclusion Criteria. Personal interview 
including medical history, physical and neurological examination, and evaluation for trial 
eligibility will be done as specified in Schedule of Activities, Appendix I. 
 
7.3 Inclusion Criteria 
Subjects must meet all the inclusion criteria to be eligible: 
 
1. Subject is informed and given ample time and opportunity to think about his/her 
participation in this study and has given his/her written informed consent on an EC/IRB 
approved consent form. 
 
2. Subject is willing and able to comply with all study requirements (protocol, clinic visits, 
procedures and medication administration). 
 
3. Subject is male or female ≥35.0 years of age to ≤80.0 years of age at the time of 
enrollment 
 
4. Subject has Parkinson's disease consistent with the UK Brain Bank Criteria and must 
have bradykinesia with sequence effect.  If rest tremor does not exist must have 
prominent asymmetry of motor function. 
 
5. Subject with disease duration less than 3 years since diagnosis. 
 
6. Subject has a H&Y stage score of < 3. 
 

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7. Subject has a MMSE score ≥ 26. 
 
8. Women of child-bearing potential (WOCBP)* must use a reliable method of 
contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal 
contraceptive, double-barrier methods [such as condom plus diaphragm, condom plus 
spermicide foam, condom plus sponge], or intra-uterine devices) for the entire study 
duration, and must have a negative serum pregnancy test at Screening and negative urine 
pregnancy at baseline visit. 
 
9. Subject was approved by a central Eligibility Monitoring Committee (EMC) based on 
suitability for the study, and his/her eligibility was confirmed by EMC signature on the 
Randomization Authorization Form (RAF).  
*WOCBP are defined as any female who has experienced menarche and who is NOT 
permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months 
with no menses without an alternative medical cause. 
 
7.4 Exclusion Criteria 
Subjects are not permitted to enroll in the study if any 1 of the following criteria is met. 
 
1. Subject has previously participated in this study. 
 
2. Subject has participated in another study of an investigational medicinal product (IMP) or 
a medical device within the last 30 days or is currently participating in another study of 
an IMP or medical device. 
 
3. Subject has an atypical parkinsonian syndrome or secondary parkinsonism (e.g., due to 
drugs, toxins, metabolic disorders, encephalitis, cerebrovascular disease or degenerative 
disease). 
 
4. Subject has a history of psychosis or hallucinations within the previous 12 months. 
 
5. Subject has cognitive impairment in the judgment of the Investigator that excludes 
him/her from understanding consent or participating in the study. 
 
6. Subject has previous exposure to levodopa or a dopamine agonist for longer than 4 
weeks; if previous exposure was less than 4 weeks then it must not be within 2 months 
prior to the baseline visit. 

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7. Subject has previous exposure to a MAO-B inhibitor for longer than 4 weeks; if 
previous exposure was less than 4 weeks then it must not be within 3 months prior to 
the baseline visit. 
 
8. Subject who has taken anticholinergic drugs for PD or amantadine for longer than 4 
weeks; if previous exposure was less than 4 weeks then it must not be within 1 month 
prior to the baseline visit. 
 
9. Subject who is taking non-selective MAO inhibitors. 
 
10. Subject who is taking potent CYP1A2 inhibitors, e,g, Ciprofloxacin  
 
11. Subject who is taking antitussive agent dextromethorphan. 
 
12. Subject who is taking analgesic agents such as tramadol, meperidine, methadone and 
propoxyphene. 
 
13. Subject who is taking strong 3A4 inducers, e.g., St. John's Wort or cyclobenzaprine 
(tricyclic muscle relaxant).  
 
14. Subject who is taking dopamine antagonists, such as the neuroleptics (phenothiazines, 
butyrophenones, thioxanthenes) or metoclopramide. 
 
15. Marijuana or previous exposure to Marijuana during the last 30 days prior to the baseline 
visit or subject has a history of alcohol or drug abuse or dependence within the prior 12 
months, according to Investigator judgment, (alcohol intake is limited to 1 glass or shot 
per day during the whole study taken not less than 3 hours before or after dosing (see 
section 10.2). 
 
16. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant 
medication which, in the opinion of the Investigator, makes the subject unsuitable for 
study entry or potentially unable to complete all aspects of the study. 
 
17. Subject has severe or moderate renal impairment (creatinine clearance <50 mL/min) or 
on dialysis. 
 
18. Subject has moderate (Child-Pugh categorization B, score 7-9) or severe (Child-Pugh 
categorization C, score 10-15) hepatic impairment ( Lucey MR, 1997). 

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19. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response ('Yes') to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (CSSRS) at Screening. 
 
20. Subject has known hypersensitivity or intolerance to pramipexole or rasagiline or to any 
components or excipients of the test drug or placebo. 
 
21. Subject who has a history of neuroleptic malignant syndrome. 
 
22. Subject who is pregnant or breastfeeding. 
 
23. Subject, who, for any reason, is judged by the Investigator or the EMC to be 
inappropriate for this study, including a subject who is unable to communicate or 
cooperate with the Investigator or who has/had a clinically significant illness or abnormal 
physical examination that may compromise safety of the subject during the trial or affect 
ability of the subject to adhere to study procedures. 
 
A site will not be allowed to randomize subjects unless their diagnosis and suitability for the 
study has been confirmed and documented by both the Investigator and the EMC and they are 
deemed to be a satisfactory candidate by the EMC. 
 
7.5 Early Discontinuation Subjects 
A subject can leave the study at any time for any reason without consequences, upon request.  The 
protocol distinguishes between two types of early Terminations:   
• Early Treatment Termination (ETT) 
• Early Study Termination (EST) 
 
Early Treatment Termination (ETT) 
A subject who discontinued study medication for any reason before the end of week 12 will 
continue pre-planned study schedule of activities as follow up. The subject will be requested to 
undergo a treatment termination visit as described in section 9.2.11 
Please note that P2B001/PPX 0.6/RAS 0.75/Placebo capsules can be stopped immediately, while 
pramipexole ER/matching placebo tablets need to be gradually down titrated as described in 
section 6.1. 
The reasons for withdrawal could include the following: 

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• Subject withdrawal of consent to be treated with study medication(s) but still consenting to 
participate in study visits and activities 
• Request of the Investigator for any medical or other reason 
• Request of the primary care physician via the Investigator 
• Pregnancy  
• Non-compliance 
• Subject who cannot achieve the minimum therapeutic dose of pramipexole ER (or placebo) 
of 1.5 mg per day. 
• Major protocol violation 
• Adverse Event/Experience 
• Lack of Efficacy 
• Subjects who, according to the Investigator, need additional therapy that is excluded in the 
protocol for the treatment of the disease. 
• Any other reason relating to the patient's safety or integrity of the study data. 
 
If a subject suspect that she is pregnant, a urine test will be performed at the site. If the urine test 
is positive, study drug administration will be interrupted pending the results of a confirmatory 
blood/serum test. If the pregnancy is confirmed with a positive blood/serum test, then the subject 
will be permanently discontinued from study drug, but should participate in a Treatment 
Termination visit and continue with all the study visits as follow up visits up to and including 
safety follow up visit at week 14. The PI will follow the subject until she has given birth.  
 
On completion of the dose-titration phase (end of week 6), the minimum therapeutic dose of 
pramipexole ER 1.5 mg per day (or placebo) must be achieved by all the patients. The treatment 
with study medications of patients who cannot achieve this dosage will be discontinued, but the 
subject will be requested to continue with all the study visits. 
 
 
Early Study Termination (EST) 
A subject who requests to stop study participation for any reason before the end of week 12, 
including study treatment and study scheduled activities, will be requested to undergo a study 
termination visit as described in section 9.2.11, unless erroneously randomized or withdrew 
consent prior to first dose.  
 
The reasons for EST could include the following: 
•  Pregnancy 
• Adverse Event/Experience 

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• Subject withdrawal of consent and refusal to continue participation in study due to lack of 
efficacy or due to other reasons  
• Lost to follow-up/failure to return 
• Death 
• Erroneously randomized 
• Withdrew consent prior to first dose 
 
If there is a medical reason for withdrawal and the subject refuses to come to study visits after 
study medication was stopped, the subject will remain under the supervision of the PI as long as 
the PI deems medically necessary.  
 
7.6 Subject Replacement 
A subject who leaves the study at any time for any reason will not be replaced. 
8 ASSESSMENTS 
8.1 Schedule of Activities 
See Appendix I for a table describing activities performed at each visit. 
8.2 Evaluation of Pramipexole ER (or Placebo) Dose 
 The subject will be required to visit the clinic at the end of week 3 and 5 (visit 3 and 4) and be 
available for a phone call at the end of week 4 for titration evaluation; to assess the tolerability 
and efficacy of the pramipexole ER (or placebo) and the possible need for changing the 
pramipexole ER dose.  
8.3 Safety and Tolerability 
8.3.1 Physical and Neurological Exams 
A complete physical exam (consisting of a review of all body systems) and neurological exam 
(including evaluation of mental status; motor function; balance and coordination; sensory 
function; reflexes and cranial nerves) at visit 1 will be conducted by the study neurologist 
(primary Investigator or sub-Investigator). On visit 7 and unscheduled visits a symptom-directed 
physical and neurological exam will be performed by the study neurologist.  
 
8.3.2 Safety Laboratory Tests – see Appendix II 
Hematology, chemistry and urinalysis tests will be performed as general measures of health.  
Eurofins Scientific will be responsible for shipment, storage, and testing of all laboratory 
samples.  Instructions will be included in the laboratory manual. 
 

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8.3.3 ECG 
12-lead ECGs will be performed to evaluate the cardiovascular system on the screening and 
baseline visits and on visit 7.  
 
8.3.4 Vital Signs  
Vitals signs will be measured at all visits except for Visit 3. Blood pressure and pulse will be 
recorded after resting supine for 5 minutes and standing after at least 3 minutes.  Orthostatic 
hypotension is defined as a reduction of systolic blood pressure of at least 20 mm Hg or 10 mm 
Hg in diastolic blood pressure within 3 minutes of quiet standing (Aronow WS, 2011). Height 
will be measured at screening only and weight will be measured at all visits.   
8.3.4.1 Orthostatic Hypotension Evaluation 
 
1. On baseline and visits 4, 5 and 6, subjects that have OH according to the description 
above (section 8.3.4) will be asked to answer one question of the orthostatic hypotension 
activity scale (OHAS) which inquires about dizziness, lightheadedness, feeling faint or 
feeling as though you might pass out. The answer is a scale from 0 to 10 where 0 is none 
and 10 is the worst possible.  
2. Change in the differences in systolic and diastolic blood pressure measured during supine 
and standing positions.   
 
8.3.5 Concomitant Medications  
Concomitant medication logs will be completed at the Screening visit and will be updated at 
each subsequent visit.  The logs will include the medication taken by the subject over the past 3 
months.  A separate log will record anti-PD medications that were previously used. 
 
 
8.3.6 Adverse Events 
Adverse events will be recorded after the signing of the informed consent of enrolled subjects 
throughout the study and shall be reviewed and updated at each subsequent visit and during any 
phone contact with the subject. AEs for screen failure subjects will be captured only in the 
source documents and not in the eCRF. 
 
8.3.7 Sleepiness 
Sleepiness will be evaluated at baseline and at end of weeks 5, 8 and 12/Treatment Termination 
visit (visits 4, 5 and 6) using the Epworth Sleepiness Scale (ESS, see Appendix III).  
 
8.3.8 Impulsive-Compulsive Disorders  

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The questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease, (QUIP-Rating 
Scale Appendix VI), will be used on the baseline visit and at end of weeks 3, 5, 8, 12/Treatment 
Termination visit and end of week 14 (visits 3, 4, 5, 6 and 7).  The answers for all questions are 
based on current behaviors and behaviors occurred in the past 4 weeks.  
8.3.9 Suicidality 
Columbia Suicide Severity Rating Scale (CSSRS, see Appendix VIII) will be used. Baseline / 
screening version of the CSSRS will be used at screening visit. This version assesses suicidality 
in a patient’s lifetime and during the past six months. The Since Last Visit (SLV) version of the 
CSSRS will be used at all consequent visits. This version assesses suicidality since the patient’s 
last visit.  Efforts must be made to ensure that the same trained team member completes this 
questionnaire for each subject.   
A subject with any suicidal ideation that answered YES to questions 4 or 5 in the CSSRS 
questionnaire will be referred to a mental health professional. 
CSSRS-SLV  will be used on the baseline visit and at end of weeks 3, 5, 8, 12/Treatment 
Termination visit and end of week 14 (visits 3, 4, 5, 6 and 7).   
8.4 Efficacy 
Efforts must be made to ensure that the same Investigator completes the UPDRS, CGI-S and 
CGI-I scales at all visits that these scales are done.   
8.4.1 UPDRS – see Appendix IX 
The UPDRS assesses motor and functional abilities of the subjects.  The total UPDRS is defined 
for this study as the sum of Parts II and III (Activities of Daily Living and Motor sections). 
These will be completed by history and examination. UPDRS II and III will be performed at 
baseline visit and at end of weeks 5, 8 and 12/Treatment Termination (visits 4, 5, and 6). UPDRS 
part III will be completed also at screening visit to support diagnosis and the score will be 
included in the RAF.  
The UPDRS part III evaluation will be conducted by a trained neurologist or other senior trained 
research staff with at least 10 years’ experience in conducting the UPDRS. All attempts will be 
made to ensure that the same trained research staff member performs the UPDRS part III at all 
visits for each subject and at approximately the same time of the day and time following 
administration of medication.  The UPDRS part II will be completed by a trained neurologist or 
other trained research staff member as delegated by the Site PI. For consistency efforts must be 
made to ensure that the same trained research staff member will do the UPDRS part II at all 
required visits for all subjects. 
8.4.2 Clinical Global Impression - severity (CGI-S) - Appendix IV 
This scale will be completed by the Investigator at baseline and at end of week 12/Treatment 
termination (visit 6). The scale rates the subject’s overall well-being, including the Parkinson’s 

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disease symptoms over the week before the visit.  The CGI scale refers to the global impression 
of the subject and requires clinical experience with the syndrome under assessment. The CGI-S 
scale is a 7-point scale that requires the clinician to rate the severity of the subject's illness at the 
time of assessment, relative to the clinician's past experience with patients who have the same 
diagnosis. Considering total clinical experience, a subject is assessed on severity of illness at the 
time of rating using a nominal scoring system with:  1, normal, not at all ill; 2, borderline ill; 3, 
mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Efforts must be 
made to ensure that the same neurologist performs the CGI-S at all visits. 
8.4.3 Clinical Global Impression of Improvement (CGI-I) – Appendix XIV 
This scale will be completed by the Investigator at end of weeks 5, 8 and 12/Treatment 
Termination (visits 4, 5 and 6). The scale rates the subject’s overall well-being, including the 
Parkinson’s disease symptoms over the week before the visit.   
The CGI-I scale is a 7-point scale that requires the clinician to rate the improvement of the 
subject's illness relative to the baseline visit using a nominal scoring system with:  1, very much 
improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, 
much worse; or 7, very much worse. Efforts must be made to ensure that the same neurologist 
performs the CGI-I at all visits. 
8.4.4  Quality of Life PDQ39 – Appendix X 
This is a PD specific health-related quality of life scale that will be performed at baseline visit 
and at end of week 12/Treatment Termination (visit 6). There are 39 questions in the PDQ-39, 
with 8 discrete scales: 
• 
mobility (10 items)  
• 
activities of daily living (6 items)  
• 
emotional well-being (6 items)  
• 
stigma (4 items)  
• 
social support (3 items)  
• 
cognitions (4 items)  
• 
communication (3 items)  
• 
bodily discomfort (3 items)  
Subjects are asked to think about their health and general well-being and to consider how often 
in the last month they have experienced certain events (e.g. difficulty walking 100 yards). 
Subjects are asked to indicate the frequency of each event by selecting one of 5 options (Likert 
Scale): ever/occasionally/sometimes/often/always or cannot do at all. 
8.4.5 Health-Related Quality of Life (HRQOL) SF-12v2 questionnaire – Appendix 
VII 
The HRQOL SF-12v2 questionnaire assesses the physical and mental health of the patient using 
12 questions related to eight aspects of health (physical and social functioning, role limitation 

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due to physical limitation, vitality, role limitation due to emotional problems, bodily pain, mental 
and general health). This questionnaire will be filled in on the baseline visit and at end of week 
12/Treatment Termination (visits 2, and 6).  
8.5 Compliance 
8.5.1 Study Compliance 
At each study visit the Investigator and/or site coordinator will assess the subject’s compliance 
with the prescribed regimen for the study medication using pill counts.  This will include checks 
of protocol compliance and use of study drug in order to assess the reliability of subject-
generated data.  Subjects who fail to comply with the study requirements may be withdrawn 
from the study, following consultation with the sponsor.  
The Investigator and clinical staff will make all efforts to ensure all enrolled subjects attend all 
study visits. If a subject missed a visit all efforts will be made to reschedule the visit within the 
time frame allowed in this protocol, which is 28±2 days from the previous visit.  In case the 
subject cannot complete the visit in the appropriate time, the subject will continue to the next 
routine visit. If safety issues arise, an unscheduled visit may be done. 
The Investigator and clinical staff will make all efforts to ensure all subjects’ efficacy and safety 
scales are fully completed at each visit. If it is discovered that data is missing from these scales 
after they were initially completed, the Investigator or a member of the clinical staff can contact 
the subject, up until the following routine visit, to obtain this missing data. If missing data is not 
collected by the time of the following routine subject visit, no additional follow-up will be 
permitted, and this data will be considered missing. Details regarding the collection of this 
missing data (including time, date, data points collected and who collected them) will be 
documented in the source documents and the eCRF. 
8.6 Screening Evaluations 
 
The following scales or tests will be used for screening evaluations: 
• UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria – (Appendix XI) 
will be used to confirm the Parkinson’s disease diagnosis. 
• Modified Hoehn & Yahr Stage (Appendix XII) The scale should be completed with the 
Investigator rating PD symptoms to confirm that the subject meets inclusion criteria 
related to stage of disease.   
• Mini-Mental State Examination (MMSE) (Appendix XIII) MMSE, a 30 points 
questionnaire, will be completed to evaluate the subject for cognitive abilities necessary 
for study participation.  
• Columbia Suicide Severity Rating Scale - baseline, CSSRS-BL, (Appendix VIII)  
• UPDRS part III (Appendix IX) 

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9 STUDY CONDUCT 
9.1 Study Period 
 
The study duration per subject is 14 weeks in addition to up to 28 days for screening. The whole 
study duration is expected to be approximately 
24
-
18
 months. 
9.2 Study Procedures 
 
9.2.1 Detailed Study Plan 
 
A detailed Schedule of Activities is provided in Appendix I. 
The study includes 7 visits. The first visit will allow screening of potential subjects that will 
participate in the study.  This period of time between the screening visit and enrollment of a 
subject to the study is named the screening phase. The treatment phase is when subjects are 
receiving treatment with the study drugs. During the treatment phase, subjects’ condition will be 
evaluated every 
5
-
3
 weeks (visits 2-6). The first 6 weeks of the treatment period will include a 
titration of the Pramipexole ER dose or its placebo to optimal dose (titration phase). One capsule 
a day of P2B001/PPX 0.6/RAS 0.75/Placebo will be taken at this time without any need for 
titration. This will be followed by a maintenance phase ending at the end of week 12. The safety 
follow up phase will start after week 12 which will include a week (week 13) of no treatment of 
the P2B001 or its components and a down-titration of pramipexole ER or its placebo. Week 14 
will include no treatment at all. The end of the study drug treatment and a follow up safety visit 
will be performed at the end of week 14 (visit 7).  
 
9.2.2 Visit 1 - Screening Visit  
 
Prior to performing any study activity, the subject will be thoroughly informed on all aspects of 
the study. The subject will be requested to sign an Ethics Committee/investigational Review 
Board (EC/IRB) approved informed consent form, after which a unique subject number will be 
assigned to the subject.  
Adverse events will be recorded after the signing of the informed consent of enrolled subjects. 
Subjects will be assessed for study eligibility by the Investigator at the screening visit.  
Subject eligibility will be assessed based on clinical procedures: 
- 
Medical history – Complete medical history including PD history 
- 
Complete physical and neurological examination  
- 
Vital signs (HR, BP RR and temperature), height, weight, and ECG 
- 
Previous and concomitant drug history (record of drugs used 3 months prior to study) 

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- 
Laboratory tests, including hematology, chemistry, urinalysis, coagulation and a 
serum pregnancy test for women of childbearing potential (see Appendix II) 
- 
Mini Mental State Exam (MMSE)  
- 
Modified H&Y staging 
- 
UPDRS part III 
- 
UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria 
- 
CSSRS-BL 
After completion of all the testing for the assessment of eligibility, it will be decided by the 
Investigator whether the subject is eligible for the study. For a subject to be eligible all the 
inclusion criteria must be met and none of the exclusion criteria must apply. Therefore, all the 
results from the screening procedures must be available before determining a subject’s 
eligibility. Subjects found eligible will be further reviewed by a central eligibility monitoring 
committee (see 16.4.2).  The maximal interval between the screening and baseline visits is 28 
days that can be extended up to 35 days, however, additional Sponsor approval will be required. 
Extension beyond 35 days and up to 90 days may be approved but will require a new collection 
of screening laboratory samples at an unscheduled visit prior to baseline. Subjects that are screen 
failures may rescreen for the study. If the rescreening visit is within 28 days (or 35 days with 
sponsor approval) of the original blood testing, the screening number remains the same and the 
blood draw does not need to be repeated, unless it is the reason for the screening failure. 
Subjects complying with inclusion/exclusion criteria will be randomly assigned to one of the 
four treatment groups by a central website-based computer program using Randomization Trial 
Supply Management (RTSM). A randomization form must be completed via the RTSM as soon 
as possible after subject eligibility was confirmed in order to trigger shipment of investigational 
product for this subject.   
9.2.3 Visit 2 - Baseline 
The time between visit 1 (screening), and visit 2 (baseline), will be no less than 24 hours and no 
more than 28 days (or up to 90 days with sponsor approval). In this visit a medication kit will be 
dispensed to him/her together with a leaflet of instructions for use. The subject will be given an 
emergency contact card with 24-hour contact numbers. The subject will be instructed to keep the 
contact card with him/her at all times. 
The following activities will be performed: 
- 
Dispensation of study medication kit 
- 
Vital signs (HR, BP RR and temperature), weight and ECG 
- 
Urine pregnancy test for women of childbearing potential 
- 
Concomitant medications  
- 
Adverse events review 
- 
Inclusion/Exclusion criteria review 
- 
Study drug dispensing and dosing instructions  

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- 
UPDRS II and III questionnaire 
- 
CSSRS- SLV questionnaire 
- 
CGI-S questionnaire 
- 
PDQ39 questionnaire 
- 
ESS questionnaire 
- 
QUIP-RS questionnaire 
- 
HRQOL SF-12v2  
- 
Orthostatic hypotension scale question 1 for subjects with OH 
 
The treatment should be started according to the dosing instructions the day after the baseline 
visit. 
9.2.4 Visit 3 
At the end of week 3 ±2 days subjects will be required to visit the clinic for titration evaluation 
regarding their satisfaction and tolerability with the 1.5 mg dose of Pramipexole ER (or placebo). 
The dose may remain 1.5 mg or be increased to 3.0 mg. Additionally, the subject will continue to 
take 1 capsule a day of P2B001/PPX 0.6/RAS 0.75/placebo.  The following activities will be 
performed: 
- 
On-site evaluation of Pramipexole ER (or placebo) dose. 
- 
Concomitant medications 
- 
Adverse events review 
- 
CSSRS-SLV questionnaire 
- 
QUIP-RS questionnaire 
9.2.5 Week 4 Phone Call 
At the end of week 4 a phone call to the subject will be conducted by the PI or sub-Investigator 
regarding the subject’s satisfaction and tolerability of the treatment and the possible need for 
increase of the dose. During this phone call a review of adverse events and concomitant 
medications will also be done. In addition, if the PI or sub-Investigator deem necessary, an 
unscheduled visit for a titration evaluation may be conducted at this time.  
9.2.6 Visit 4 
Visit 4 will take place 5 weeks after the baseline visit ±2 days. The following activities will be 
performed: 
- 
Evaluation of the pramipexole ER/placebo dose which may be changed if 
necessary only until the end of the next week, week 6. 
- 
Vital signs (HR, BP RR and temperature) and weight 
- 
Concomitant medications 
- 
Adverse events review 

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- 
Study drug accountability 
- Collection of the titration kit, (Weeks 1-4) 
- 
UPDRS II, III 
- 
CSSRS-SLV questionnaire 
- 
QUIP-RS questionnaire 
- 
ESS questionnaire 
- 
CGI-I questionnaire 
- 
Orthostatic hypotension scale question 1 for subjects with OH 
- 
Laboratory tests for hepatic or renal function for subjects with 
mild hepatic failure or mild kidney failure respectively. 
 
9.2.7 Visit 5 
Visit 5 will take place 8 weeks after the baseline visit and start of medication treatment ±2 days. 
The following activities will be performed: 
- 
Vital signs (HR, BP RR and temperature) and weight 
- 
Concomitant medications 
- 
Adverse events review 
- 
Study drug accountability 
- Collection of the maintenance kit  (Box 1 of 2, weeks 5-8) 
- 
UPDRS II, III 
- 
CSSRS-SLV questionnaire 
- 
QUIP-RS questionnaire 
- 
ESS questionnaire 
- 
CGI-I questionnaire 
- 
Orthostatic hypotension scale question 1 for subjects with OH 
- 
Laboratory tests for hepatic or renal function for subjects with 
mild hepatic failure or mild kidney failure respectively. 
9.2.8 Visit 6 – Treatment Termination 
Visit 6 will be performed at the end of the treatment phase, 12 weeks ±2 days after the baseline 
visit. The following activities will be performed: 
- 
Vital signs (HR, BP RR and temperature), weight  
- 
Concomitant medications  
- 
Adverse events review 
- 
Study drugs accountability 
- 
Collection of maintenance kit (Box 2 of 2 Weeks 9-12) 
- 
UPDRS II and III questionnaire 
- 
CSSRS-SLV questionnaire 

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- 
CGI-S questionnaire 
- 
CGI-I questionnaire 
- 
PDQ39 questionnaire 
- 
ESS questionnaire 
- 
QUIP-RS questionnaire 
- 
HRQOL SF-12v2  
- 
Orthostatic hypotension scale question 1 for subjects with OH 
9.2.9 Visit 7 – Safety Follow Up 
A  follow up safety visit will be performed 2 weeks ±2 days after the termination visit. Safety 
parameters will be evaluated, as follows: 
- 
Symptom-directed physical and neurological examination  
- 
Vital signs (HR, BP RR and temperature), weight and ECG 
- 
Concomitant medications  
- 
Adverse events review 
- Study drugs accountability 
- 
Collection of down titration kit (week 13)  
- 
Laboratory tests, including hematology, chemistry , urinalysis and a serum     
pregnancy test for women of childbearing potential (see Appendix II) 
- 
CSSRS-SLV questionnaire 
- 
QUIP-RS questionnaire 
 
9.2.10 Unscheduled Visits 
If needed, an unscheduled visit may take place. 
 
Unscheduled visit for titration follow-up 
During the titration phase an unscheduled visit may be conducted to assess the need to raise or 
lower the dose of pramipexole ER/or placebo. In addition to the dose evaluation, a review of 
adverse events and concomitant medications will be conducted. No other study activities will be 
performed at this visit unless safety considerations arise (see next section).  
 
Unscheduled visit for other reasons 
An unscheduled visit may take place at any time during the study (e.g. PD symptoms or an AE 
that warrant personal evaluation). The following activities will be performed: 
- 
Vital signs (HR, BP RR and temperature) and weight 
- 
Concomitant medication 
- 
Adverse events review 
- 
Symptom-directed physical and neurological examination 

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- 
Completion of any uncompleted efficacy or safety scales, as needed 
 
The date and reason for the visit and any data generated will be documented in the eCRF.  
9.2.11 Early Treatment/Study Termination Visit  
Subjects who terminate treatment/study early (following first dose and prior to visit 6) according 
to criteria in section 7.5 will be requested to undergo a treatment/study termination visit. The 
treatment termination visit can be conducted as part of the next scheduled study visit if it is 
within 5 days of treatment termination. If the next scheduled visit is more than 5 days away it is 
preferable, if possible, to schedule an “unscheduled” visit as soon as possible. All efforts should 
be made to schedule the early treatment/study termination visit as close to the treatment/study 
termination as possible. All activities listed in the treatment termination (visit 6) and safety 
visits (visit 7) will be performed at this visit. The entire study medication kit with all boxes and 
bottles left should be returned. The date and reason for the ETT and any data generated from the 
ETT visit will be documented in the eCRF.  
 
Subject will be requested to continue all study schedule activities as in section 9.2.11.1. If a 
subject refuses to take part in the scheduled study visits and activities it will be documented as 
early study termination and the Investigator shall only follow up on any safety issues if needed.  
9.2.11.1 Follow-up visits of subjects that have terminated the study treatment early 
ETT subjects will be requested to continue with all study visits and activities as planned, for 
follow up, without taking any study medication. During these visits, all questionnaires and 
assessments will continue as planned for follow up. Accountability will be omitted since study 
drug was returned at the ETT visit.  
 
Subjects may take rescue therapy during the follow-up visits; this will be documented in the 
concomitant medication list.  
 
ETT subjects that decided later to stop their participation in the study will be requested to 
undergo a study termination visit. All activities listed in the treatment termination (visit 6) 
and safety visits (visit 7) will be performed at this visit. 
10 CONCOMITANT MEDICATIONS 
All concomitant medication that the subject is taking from the screening visit should be recorded 
on the concomitant medications log.  In addition, any changes in concomitant medication or new 
medications added, including as a result of an inter-current illness must be recorded in the case 
report forms. A separate log will record anti-PD medications taken prior to enrollment. 

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10.1 Prohibited Medication 
Subjects must not receive concomitant therapy with any of the following: 
• Other investigational therapy (washout period 30 days prior to study entry, baseline visit) 
• Previous MAO-B inhibitors, selegiline or rasagiline, for longer than 4 weeks or within 
the previous 3 months prior to baseline visit. 
• Previous levodopa or dopamine agonists, for longer than 4 weeks or within the previous 2 
months prior to baseline visit.  
• 
Previous anticholinergic drugs for PD (such as benztropine, orphenadrine 
hydrochloride, biperiden, ethopropazine, procyclidine, trihexyphenidyl) or amantadine 
for longer than 4 weeks; if previous exposure was less than 4 weeks then it must not be 
within 1 month prior to the baseline visit.  
• Subjects can take peripheral anticholinergic drugs (such as oxybutynin, orphenadrine 
citrate, tiotropium bromide etc..) if they are stable on low dose for at least 4 weeks 
prior to study entry, and without (or with minor) cognitive effects; however, once 
enrolled into the study use of new peripheral anticholinergic drugs is prohibited. 
Patients should be followed very closely for possible cognitive side effects. 
• Non selective MAO inhibitors, such as phenelzine or tranylcypromine 
• Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones,       
thioxanthenes) or metoclopramide. 
• Ciprofloxacin or other CYP1A2 inhibitors: may affect rasagiline plasma concentrations. 
• Antitussive agent Dextromethorphan.: co-administration with rasagiline may lead to 
psychosis. 
• Analgesic agents such as tramadol, methadone, meperidine and propoxyphene due to risk 
of serotonin syndrome. 
• St. John's Wort or cyclobenzaprine (tricyclic muscle relaxant).  
• Marijuana or previous exposure to Marijuana during the last 30 days prior to the 
baseline visit. 
 
Care should be taken to avoid or minimize use of sympathomimetic medications, including 
nasal, oral and ophthalmic decongestants and cold remedies due to possible hypertensive 
reactions.  
Care should be taken when giving study drugs with sedating medications (e.g. Diphenhydramine, 
Doxylamine Succinate and other first generation antihistamines) due to possible additive 
sedative effects with pramipexole.  
 
Special attention should be given to symptoms and signs of serotonin syndrome, when an 
antidepressant is administered concomitantly with the study medication. Subjects who are taking 

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tricyclic or tetracyclic antidepressants, SSRIs, SNRIs or triazolopyridine antidepressants will be 
closely followed up by the PI for signs of serotonin syndrome, including:  
agitation or restlessness, confusion, rapid heart rate and high blood pressure, dilated pupils, 
loss of muscle coordination or twitching muscles, muscle rigidity, heavy sweating, diarrhea, 
headache, shivering or goose bumps. At each periodic meeting, the DSMB will review adverse 
events and vital signs reported for subjects taking antidepressants concomitantly. Severe or 
serious adverse events for such subjects will be reported to the DSMB within 48 hours of receipt 
of the report by the sponsor. 
 
 
10.2 Dietary Restrictions 
Alcohol may increase symptoms of drowsiness or sudden onset of sleep that can be caused by 
pramipexole. Subject will be requested to limit alcoholic consumption to one glass of wine or 
one shot a day, and not within three hours before or after taking the study medication.  
Dietary tyramine restriction is not ordinarily required with recommended doses of rasagiline. 
However, certain foods (e.g. aged cheeses, such as stilton cheese) may contain very high 
amounts (i.e. 150 mg) of tyramine and could potentially cause a hypertensive "cheese" reaction 
in subjects taking rasagiline, even at recommended doses, due to mild increased sensitivity to 
tyramine. 
10.3 Rescue Therapy 
No rescue therapy will be allowed during the treatment phase and the two weeks afterwards up 
until the safety follow up visit. If needed by the subject for adequate treatment of subject’s 
Parkinson's symptoms and according to the Investigator’s judgment the study medication will be 
discontinued and a rescue medication may be administered. This will be recorded on the 
concomitant medications log and in the reasons for treatment termination. Subject, who stopped 
taking study treatment prior to Visit 6, should return to the site for an Early Treatment 
Termination (ETT) visit as soon as possible. ETT subjects will be requested to continue with 
study visits and activities as planned, for follow up, without taking any study medication.    
11 LABORATORIES 
11.1 Safety Laboratory Tests 
The safety laboratory tests (chemistry, hematology, coagulation and urinalysis see Appendix II), 
conducted at screening, safety follow up visit, and additional liver function or kidney function 
tests, as needed, will be carried out by the Eurofins Central Laboratory EU, 
Bergschot 71, 4817 PA Breda, Netherlands for sites in Europe and Eurofins Central Laboratory 
US 2430 New Holland Pike, Lancaster, PA 17601 for sites in USA and Canada.  

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The tests will be done according to Eurofins Central Laboratory written Standard Operating 
Procedures. Any value outside the normal range will be flagged for the attention of the Investigator 
or designee at the site. The Investigator or designee will indicate whether or not the value is of 
clinical significance. 
Any clinically important abnormal laboratory values noted at the Screening visit will be recorded 
as medical history. In addition, in order for the Sponsor to collect additional information about 
clinically important laboratory abnormalities, at minimum, the following laboratory 
abnormalities should be captured from Baseline and onwards on the AE pages of the eCRF as 
appropriate: 
• Any laboratory test result that meets the criteria for an AE or SAE; 
• Any laboratory abnormality that requires the subject to have study drug discontinued or 
interrupted; 
• Any laboratory abnormality that requires the subject to receive specific corrective therapy. 
All clinically important abnormal laboratory tests occurring during the study will be repeated in 
appropriate intervals until: (1) the value returns to Baseline, (2) the value is judged to be 
clinically acceptable by the Investigator and the Sponsor, (3) a diagnosis that explains the 
abnormal laboratory is made or (4) subject is lost to follow-up. When possible, the Investigator 
should report the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin.) 
The central laboratory will perform all clinical laboratory tests. Detailed shipping/handling 
instructions of laboratory supply will be provided in a separate laboratory manual. 
11.2 Vital Signs, Height and Weight 
Respiration rate (RR per minute) and temperature will be measured, with the subject in the 
seated position for at least 5 minutes, at the visits specified in the Schedule of Activities.  
Orthostatic measurements (lying and standing BP and 30 seconds of radial pulse) can be 
measured manually or using an automated BP machine and will be measured at every clinic visit, 
except visit 3 that is done for titration evaluation of Pramipexole ER or matching placebo. The 
subject’s BP and HR will be measured after the subject has been lying for approximately 5 
minutes. The subject will be instructed to rise to a standing position, and a BP measurement will 
be taken after the subject has been standing for 3 minutes. HR will be determined for a period of 
30 seconds. 
 
All BP and HR measurements will be taken using the writing arm of each subject. 
 
Additional vital signs will be obtained at the discretion of the Investigator if clinically significant 
signs or symptoms occur. 
 

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The subject’s weight will be measured at every clinic visit except visit 3 that is done for titration 
evaluation of Pramipexole ER or matching placebo. The subject’s height will only be measured 
at the Screening visit. 
11.3 Electrocardiograms (ECG)  
A standard 12-lead ECG will be performed at Screening, Baseline and Week 14/ETT. Additional 
ECGs will be performed if clinically indicated. ECGs will be conducted after approximately 5 
minutes supine or recumbent rest using a standard ECG machine equipped with computer-based 
interval measurements.  
The Investigator is responsible for evaluating the ECG interpretation in relationship to clinical 
signs and symptoms and reaching a medical decision regarding the subject’s medical status. The 
ECG findings should be assessed by the Investigator as normal, abnormal not clinically 
significant (NCS), or abnormal clinically significant (CS), as appropriate. All abnormalities, 
whether assessed as clinically significant or not, will be recorded. The ECG tracing should be 
initialed and dated by the Investigator.  
12 STUDY DRUGS SUPPLY 
12.1 Drug Manufacturing 
Capsules of P2B001, its individual components (pramipexole and rasagiline) and matching 
placebo were manufactured by Catalent Pharma solutions Somerset, USA, address: Schoolhouse 
Rd. 14 Somerset, NJ 08873, USA.  
Pramipexole ER tablets and matching placebo were purchased from Dr. Reddy's Laboratories 
Limited, FTO UNIT 3,  Survey No 41 Bachupally village Qutubullapur Mandal 
Ranga Reddy District Telangana 500090 India 
 
All bottle closures are tamper proof and child resistant.  
12.2 Treatment Assignment and Randomization  
All subjects will be assigned a unique subject number at the screening visit (visit 1). The subjects 
found to be eligible for the study by both PI and the EMC will be randomized as soon as possible 
in order to trigger shipment of investigational medication to the subject. At randomization, the 
subject will be given a unique randomization number which will be entered into the database but 
not used for subject follow-up. The same unique subject number allocated in the screening visit 
will continue to be the subject ID number for the rest of the study. 
The randomization will be managed by a cloud-based Randomization and Trial Supply 
Management (RTSM) system of Medidata-Balance using a randomization list comprised of 
permuted blocks, with stratification by region. Allocation will be to the next available record in 

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the randomization list which corresponds to the appropriate stratum. Medication will be assigned 
based on the treatment group allocated at randomization. 
Study files will keep track of subject number and medication kit number. In case of medication 
kit loss or the patient ran out of drug for any reason the site can get a replacement medication kit 
by contacting the RTSM in order to get the appropriate medication kit number. 
12.3 Packaging and Labeling 
The study medication will be packed and labeled by Almac Group limited, 25 Fretz Road, 
Souderton, PA 18964, USA. 
The study kit will include an outer box containing 4 inner boxes;  
• Weeks 1-4 box containing three bottles:  one bottle of capsules of either P2B001/RAS 
0.75/PPX 0.6/placebo once daily (33 capsules) (bottle C, labeled with a blue stripe), one 
bottle with tablets of either Pramipexole ER 0.375 mg or matching placebo (30 tablets), 
(bottle A, labeled with a yellow stripe) and one bottle with either Pramipexole ER 1.5 mg or 
matching placebo (30 tablets), (bottle B, labeled with a pink stripe). 
• Two identical boxes for weeks 5-12. Each box containing 4 bottles:  one bottle of capsules of 
either P2B001/RAS 0.75/PPX 0.6/Placebo (33 capsules) and 3 identical bottles with 
Pramipexole ER 1.5 mg or matching placebo tablets (30 tablets each). 
• Week 13 One box containing two bottles: one bottle of tablets of either Pramipexole ER 
0.375 mg or matching placebo (30 tablets) and one bottle of tablets of either Pramipexole ER 
1.5 mg or matching placebo 
 
For subject’s convenience the bottles are labeled with different colored stripes. The bottle of 
P2B001/RAS 0.6/PPX 0.75/placebo is labeled with a blue stripe named bottle C. The bottle of 
Pramipexole ER 0.375 mg/matching placebo is labeled with a yellow stripe named bottle A and 
the bottle of Pramipexole ER 1.5 mg/matching placebo is labeled with a pink stripe named bottle 
B. 
The whole study kit with the 4 inner boxes will be dispensed to the subject on visit 2. No further 
dispensing is needed on other visits. The subject will be requested to bring the used inner box 
with him/her for the next visit as follows:  
• Visit 4: return of box weeks 1-4. 
• Visit 5: return of box used during weeks 5-8 (1 out of 2 Week 5-12). 
• Visit 6: return of box used during weeks 8-12 (2 out of 2 Week 5-12). 
• Visit 7: return of box week 13 
 
Since this product is intended for once daily dosing, there is no need for the subject to carry the 
medication with him/her throughout the day, therefore, the subject will be instructed to keep the 

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bottles with the kit box throughout the study. The outer box and each inner box will tamper 
evident sealed. 
 
The master English version of the labels on the bottles will include at least the following 
information as follows:   
 
Label for P2B001 /RAS 0.75mg / PPX 0.6mg / placebo bottle: 
• Study number: P2B001/003 
• Kit number 
• Subject number  
• Subject initials 
• Site number 
• Contents: 33 capsules, containing: Pramipexole / Rasagiline once daily 0.6/0.75 mg or 
Pramipexole 0.6 mg or Rasagiline 0.75 mg or placebo (Exp: mm/yyyy) 
• Storage conditions: 59⁰F - 77⁰F (15⁰C - 25⁰C). 
• Protect from exposure to high humidity. 
• Take 1 capsule by mouth with a glass of water (8oz or 240ml), do not chew, crush or cut. 
For further dosing instructions see “dosing instruction leaflet” provided by the clinical 
staff. 
• Packaging batch number 
• Caution: new Drug Limited by Federal (or United States) law to Investigational use / for 
clinical trial use only/ Investigational drug. To be used by qualified investigators only.  
• Keep out of the reach of children. 
• Do not remove or ingest moisture resistant bags or canisters from the bottle. 
• Return all empty, partially used or unused bottles from the current box to the clinic for 
accountability. 
• Sponsor name and location    
 
Label for Pramipexole ER tablets 1.5 mg / matching placebo bottle: 
• Study number: P2B001/003 
• Kit number 
• Subject number 
• Subject initials 
• Site number 
• Bottle # ____ out of _______ 
• Contents: 1 x 30 tablets, containing Pramipexole 1.5 mg or placebo (exp: mm/yyyy) 
• Storage conditions: 59⁰F - 77⁰F (15⁰C - 25⁰C). 

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• Take caplet/s by mouth with a glass of water (8oz or 240ml), do not chew, crush or cut. 
For further dosing instructions see “dosing instruction leaflet” provided by the clinical 
staff. 
• Packaging batch number 
• Caution: new Drug Limited by Federal (or United States) law to Investigational use / for 
clinical trial use only/Investigational drug. To be used by qualified investigators only.  
• Keep out of the reach of children. 
• Do not remove or ingest moisture resistant bags or canisters from the bottle. 
• Return all empty, partially used or unused packages from the current box to the clinic for 
accountability. 
• Sponsor name and location  
• Protect from exposure to high humidity. 
• Please keep the bottles with the kit box together at all times.  
 
Label for Pramipexole ER tablets 0.375 mg / matching placebo bottle: 
• Study number: P2B001/003 
• Kit number 
• Subject number 
• Subject initials 
• Site number 
• Contents: 1 x 30 tablets, containing Pramipexole 0.375 mg or placebo (exp: mm/yyyy) 
• Storage conditions: 59⁰F - 77⁰F (15⁰C - 25⁰C). 
• Take tablet/s by mouth with a glass of water (8oz or 240ml), do not chew, crush or cut. 
For further dosing instructions see “dosing instruction leaflet” provided by the clinical 
staff.  
• Packaging batch number 
• Caution: new Drug Limited by Federal (or United States) law to Investigational use / for 
clinical trial use only/Investigational drug. To be used by qualified investigators only. 
• Keep out of the reach of children. 
• Do not remove or ingest moisture resistant bags or canisters from the bottle. 
• Return all empty, partially used or unused packages from the current box to the clinic for 
accountability. 
• Sponsor name and location  
• Protect from exposure to high humidity 
• Please keep the bottles with the kit box together at all times. 
 

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The following information will be included on the Inner boxes label (up titration box, 
maintenance box and down titration box): 
 
• Study number: P2B001/003  
• Box type (either weeks 1-4, Weeks 5-12, Weeks 13)                  
• Kit number 
• Subject number 
• Subject initials 
• Investigator name    
• Site number 
• Contents (one or more of the following, as relevant):  
o 33 capsules, containing: Pramipexole / Rasagiline once daily 0.6/0.75 mg or 
Pramipexole 0.6 mg or Rasagiline 0.75 mg or placebo. (Exp: mm/yyyy) 
o 30 tablets, containing Pramipexole 1.5 mg or placebo (Exp: mm/yyyy) 
o 30 tablets, containing Pramipexole 0.375 mg or placebo (Exp: mm/yyyy) 
• Storage conditions: 59⁰F - 77⁰F (15⁰C - 25⁰C). Take by mouth with a glass of water (8oz 
or 240ml), do not chew, crush or cut. For further dosing instructions see “dosing 
instruction leaflet” provided by the clinical staff. 
• Packaging batch number 
• Caution: new Drug Limited by Federal (or United States) law to Investigational use / for 
clinical trial use only/Investigational drug. To be used by qualified investigators only. 
• Keep out of the reach of children. 
• Return all empty, partially used or unused packages from the current box to the clinic for 
accountability. 
• Sponsor name and location    
• Protect from exposure to high humidity 
• Please keep the bottles with the kit box together at all times. 
 
The following information will be included in the Outer box label: 
 
• Study number: P2B001/003                   
• Kit number 
• Earliest expiry date 
• Subject number 
• Subject initials 
• Investigator name    
• Site number 

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• Kit content 
• Storage conditions: 59⁰F - 77⁰F (15⁰C - 25⁰C). 
• Packaging batch number 
• Caution: new Drug Limited by Federal (or United States) law to Investigational use / for 
clinical trial use only/Investigational drug. To be used by qualified investigators only. 
• Keep out of the reach of children. 
• Sponsor name and location   
• Protect from exposure to high humidity 
• Take by mouth with a glass of water (8oz or 240ml), do not chew, crush or cut. 
• For further dosing instructions see "dosing instruction leaflet" provided by the clinical 
staff. 
 
Specific information or language required for sites in Canada and Europe will be included 
according to local regulations of each country. The kit label to Canadian sites will include at 
least a French translation. The kit label to the European sites will include the relevant translation 
per the main language of the European country 
12.4 Distribution and Shipment 
Study drugs will be shipped to the study site, under the sponsor’s responsibility. 
The study drugs will be shipped and stored in room temperature between 15° and 25°C (59°F-
77°F). Protect from exposure to high humidity and light.  
All study drugs and materials will be packed in appropriate storage boxes.  
If, upon arrival at the investigational site, the study drugs appear to be damaged, the sponsor 
should be contacted immediately. 
Each shipment of study drugs for the study will contain a shipment form describing the content 
of shipment. This form will assist in maintaining current and accurate inventory records. When a 
shipment is received, the site Investigator/coordinator/pharmacist or depot will acknowledge 
receipt of the study drugs by signing the relevant shipping documents. 
12.5 Storage, Dispensing and Return 
The study drugs will be kept in a secure, limited-access, controlled storage area.  
Only authorized personnel will have access to the study drugs. The study site personnel at each 
site will be responsible for correct storage and handling of the study drugs. Drug storage 
temperature will be monitored and recorded on a daily basis. 
The study drugs will be dispensed by the study site pharmacist or by other authorized personnel. 
All unused capsules/tablets and all full, empty or partially empty bottles will be returned to the 
sponsor by the site monitor after a full reconciliation of the site’s study drug inventory against 
the site’s drug accountability records has been performed. 

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The retest dates will be managed by the Randomization Trial Supply Management (RTSM) 
system. 
12.6 Verification of Compliance with Treatment Regimen 
Subjects will be instructed to bring the last medication box used (open and unopened bottles) 
with them to visits 4, 5, 6 and 7 for compliance and accountability checks. During each study 
visits, (visits 4-7), the Investigator and/or site coordinator will assess the subject’s compliance 
with the prescribed regimen for the study medication. This will include checks of protocol 
compliance and use of study drug in order to assess the reliability of subject-generated data.  
Subjects who fail to comply with the study requirements may be withdrawn from the study, 
following consultation with the sponsor.  
Compliance with the dosing regimen will be determined by performing study drug accountability 
of returned study drugs used and unused. The number of used, unused and lost capsules will be 
recorded in the study drug accountability records and the eCRF by site personnel at every post 
randomization visit.  
A subject will be considered non-compliant if he/she misses more than 4 doses of study 
medication within a 28 day period (less than 85% compliance). Examples of reasons for missing 
a dose are 1) if a subject develops an adverse event that the Investigator believes requires the 
subject’s dose to be held, or 2) if a subject loses their kit of study medication and a replacement 
kit is requested, which should arrive at the site within 1-2 days (3-4 days if a weekend is 
involved). 
12.7 Accountability 
For study drug accountability, the subject will be requested to bring for visits 4-7, all empty, 
partially used or unused bottles from the box used during the previous month.  During these 
visits (visits 4, 5, 6/ETT and 7) the site staff will count the remaining capsules and tablets that 
the subject brought with him and document the results in accountability records. Only the opened 
box that was used during the last visit will be brought for the accountability. Accountability of 
the entire study medications kit (with all boxes and bottles left) will be done at ETT visit for 
ETT subjects.  
The Investigator is responsible for the control of study drugs under investigation. Adequate 
records of the receipt and disposition of the study drug must be maintained. 
Study drugs accountability records should contain the following information: 
▪ Shipment number, kit numbers, batch number, number of kits and date 
received for all shipments of study drug received by the site  
▪ Subject number, medication kit number, the date, batch number, and 
quantity of study drug dispensed to AND returned by the subject 
(when applicable) 

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▪ Kits numbers, batch number, number of kits (un-dispensed study 
drug) or number of capsules/tablets (returned study drug) for all study 
drug returned to the Sponsor 
During each site visit, the monitor will review all study drugs accountability records and study 
drug inventory on-site.  
 
12.8 Study End 
Once the study site has been closed out by the monitor all remaining unused and partially used 
drug supplies must be returned to the sponsor. Once this has been done, the corresponding 
accountability records must be kept at the study sites and a photocopy of these records will be 
sent to the sponsor. 
12.9 Blinding  
Blinding will be maintained during the whole course of the study. The Investigators, study 
coordinators, and their staff at the study site, the sponsor’s personnel and the personnel involved 
in subject assessment, monitoring, analysis and data management will all be blinded to the 
subject assignment.  Specific, independent, unblinded study personnel from the CRO will be 
available to provide the DSMB with periodic reports.  
12.9.1 Emergency Code Breaking  
Emergency code breaking will be managed by the IWR/IVR system. The randomization code 
may be broken by the Investigator when urgent action is required for the clinical management of 
the patient. Typically, code breaks will occur only in emergency situations which may include 
the management of a serious adverse event. If possible, the sponsor, or designee, should be 
contacted to discuss the case before the code is broken.   
If it becomes necessary to break the code during the study, the name of the person who breaks 
the code, the date, time and reason will be recorded in the RTSM. The reason for the break of the 
code should also be documented in the eCRF. The Investigator should promptly document and 
explain to the Sponsor, or designee, any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event) of the investigational product.  
13 SAFETY/ADVERSE EVENTS 
13.1 Adverse Events definition 
An adverse event is any untoward medical occurrence in a clinical investigation subject who is 
administered a medicinal product whether or not considered related to the medicinal product. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease (new or exacerbated), temporally associated with the 

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use of a medicinal product, whether or not considered related to the product. Pre-existing signs 
and symptoms should not be considered AEs unless they worsen unexpectedly post-study drug 
administration. In addition, any study procedure-related AE that occurs after study participants 
have signed the Informed Consent Form (ICF) and prior to administration of the first dose of 
study drug will be recorded as an AE. Any adverse event that occurs post-study drug 
administration will be considered a treatment-emergent AE. Any adverse event that occurs prior-
study drug administration will be considered a baseline-emergent AE. Again, all events should 
be entered whether or not the event is considered to be related to the study drug. 
The date of onset, a description of the AE, severity, seriousness, action taken, relationship to the 
study drugs (causality), outcome of the event and date of resolution will be recorded. The final 
study report will include all of these details for each AE as well as the calculated duration. 
The Investigator will assess the severity of the AE as: 
▪ mild: AE which is easily tolerated 
▪ moderate:  AE sufficiently discomforting to interfere with daily 
activity. 
▪ severe:  AE which prevents normal daily activities. 
 
The Investigator will assess the causality of the AE as (see section 13.2): 
▪ unrelated  
▪ possibly related 
▪ probably related 
13.2 AE Causality Definitions 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated 
This category applies to those AEs which, 
after careful consideration, are clearly due to 
extraneous causes (disease, environment, etc.) 
 
Possibly 
This category applies to those AEs for which, 
after careful medical consideration at the time 
they are evaluated, a connection with the test 
drug administration appears unlikely but 
cannot be ruled out with certainty. 
An AE may be considered possibly related if or 
when (at least two of the following): 
• 
It follows a reasonable temporal sequence 
from administration of the drug. 
• 
A causal relationship to the experimental 
treatment cannot be reasonably excluded 
and an alternative explanation (e.g., 
concomitant medication or concomitant 
disease) cannot be excluded or reasonably 
suggested as causing the AE. 
• 
It follows a known pattern of 
response to the test drug. 
Probably 
This category applies to those AEs which, 
after careful medical consideration at the time 
An AE may be considered probably related if or 
when (at least three of the following): 

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TERM 
DEFINITION 
CLARIFICATION 
they are evaluated, are felt with a high degree 
of certainty to be related to the test drug. 
• 
It follows a reasonable temporal sequence 
from administration of the drug. 
• 
It could not be reasonably explained by the 
known characteristics of the subject’s clinical 
state, environmental or toxic factors or other 
modes of therapy administered to the subject. 
• 
It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does not 
disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists. 
• 
It follows a known pattern of response to the 
test drug. 
 
In case of an AE, the Investigator will initiate appropriate treatment according to his medical 
judgment and will decide whether to withdraw the subject from the study.  Subjects should be 
followed clinically until all parameters (including laboratory tests) have either returned to 
normal, or are otherwise explained. 
 
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it: 
• results in subject’s withdrawal by the Investigator 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• is considered by the physician to be of clinical significance 
All adverse events will be recorded in the source documents for all study subjects from the 
signing of the ICF until the subject has completed the study (i.e., following completion of Visit 7 
(week 14) or screen fails or prematurely discontinues from the study, whichever occurs first.  
For randomized subjects all adverse events will be recorded in the eCRF. For screen failure 
subjects, adverse events will be captured only in the source documents and not in the eCRF. 
13.3 Reporting Orthostatic Hypotension as AE  
Only the following instances of orthostatic hypotension need to be recorded as an adverse event: 
• Any drop in systolic or diastolic blood pressure that the PI deems is clinically significant. 
The decision could be based on observations during the visit or if a subject complains of 
symptoms related to orthostatic hypotension, however, this is left ultimately to the 
judgment of the PI.   
• A drop of over 30 mm Hg in systolic or 20 mm Hg in diastolic blood pressure should 
automatically be considered as clinically significant, even if asymptomatic, and thus 
should be captured as an adverse event. 

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13.4 Serious Adverse Event (SAE) 
An SAE is defined as an AE that results in any of the following outcomes:  
▪ death 
▪ life-threatening 
▪ requires inpatient hospitalization or prolongs hospitalization 
▪ persistent or significant disability/incapacity 
▪ a congenital abnormality or birth defect 
▪ an important medical event which requires medical intervention to 
prevent the above outcomes. 
Important medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an adverse event will normally be considered serious by this criterion. 
13.5 SAE Reporting 
Any AE meeting the definition of serious, occurring after signing of informed consent or during 
30 days after the last dose administration and, from then on, only if the study treatment is 
assessed as “suspected” with regard to causality, must be recorded on the SAE Report Form 
provided by PRA Health Science. The SAE must be reported within 24 hours from the 
Investigator’s knowledge of its occurrence to: 
Sites in Europe: 
PRA Drug Safety Centre Email (EAPA): MHGSafety@prahs.com  
PRA Drug Safety Centre Fax (EAPA): + 44 (0) 1792 525 720 
PRA Safety Helpline EAPA: +49 621 8782 154  
Sites in USA and Canada: 
PRA Drug Safety Centre Email (NA): CHOSafety@prahs.com 
PRA Drug Safety Centre Fax (NA): 1-888-772-6919 
PRA Safety Helpline NA: 1-800-772-2215 
 
 
The Investigator must be prepared to supply the sponsor with the following information: 
a) Investigator name and center number 
b) Subject ID number 
c) Medication kit number 
d) Subject initials 
e) Subject demographics 
f) 
Clinical Event 
g) description 

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h) date of onset 
i) 
severity 
j) 
treatment (including hospitalization) 
k) relationship to study drug (causality) 
l) 
action taken regarding study drug 
m) if the SAE was Fatal or Life-threatening 
cause of death (whether or not the death was related to study drug) 
autopsy findings (if available) 
n) Medical History case report form (copy) 
o) Concomitant Medication case report form (copy) 
p) Any relevant laboratory reports 
Follow-up information or new information about any SAE should be forwarded by the site to 
PRA Health Science Safety within 24 hours of the information becoming available. This 
information should be sent to the sponsor’s appointed safety monitor. 
The clinical site will be responsible for notifying their IRB and the subject’s General Practitioner 
of all SAEs that occur at their site.  
The sponsor/CRO will submit a summary of the clinical course of the SAEs to the authorities, 
according to regulations.  
Subjects who have had an SAE must be followed clinically until all parameters (including 
laboratory) have either returned to normal, stabilized or are otherwise explained. 
 
Overdose:  
Taking more than 1 capsule per day and/or more than 4.5 mg of pramipexole ER or matching 
placebo is considered an overdose. Cases of overdose, whether accidental or intentional, that 
result in serious adverse reactions are to be reported as an SAE within one business day after the 
Investigator becoming aware of the overdose.  The overdose should be reported on the standard 
SAE report form and sent to PRA Safety using the information below.  
Sites in Europe: 
PRA Drug Safety Centre Email (EAPA): MHGSafety@prahs.com  
PRA Drug Safety Centre Fax (EAPA): + 44 (0) 1792 525 720 
PRA Safety Helpline EAPA: +49 621 8782 154  
Sites in USA and Canada: 
PRA Drug Safety Centre Email (NA): CHOSafety@prahs.com 
PRA Drug Safety Centre Fax (NA): 1-888-772-6919 
PRA Safety Helpline NA: 1-800-772-2215 
 
All cases of overdoses, even if not associated with adverse reactions, shall be recorded within 
EDC, including symptoms, corrective treatment and outcome of overdose. 
 

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13.6 Pregnancy 
Should a pregnancy occur, it must be reported and recorded on a pregnancy report form. 
However, pregnancy is not regarded as an AE for the purposes of this protocol, unless there is a 
suspicion that the study drug may have interfered with the effectiveness of a contraceptive 
medication.  
The outcome of all pregnancies (i.e., spontaneous miscarriage, elective termination, normal birth 
or congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are to be considered SAEs. Spontaneous 
miscarriages should also be reported and handled as SAEs. Elective abortions without 
complications will not be regarded as AEs. 
13.7 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Adverse reactions are all untoward and unintended responses to the investigational product 
related to any dose administrated. Unexpected adverse reaction is those of which the nature, or 
severity, is not consistent with the applicable product information.  
All SUSARs should be reported to the authorities.  
Investigators will also be notified of all unexpected, serious, drug-related events (i.e., 7- or 15-
day expedited safety reports) that occur during the clinical trial; those events will be reported to 
the site in a blinded fashion. Each site is responsible for notifying its IRB of these expedited 
safety reports, in accordance with applicable site practices. 
14 DATA MANAGEMENT AND QUALITY ASSURANCE 
14.1 Handling of Data 
An Electronic Data Capture (EDC) system to collect subject electronic Case Report Form 
(eCRF) information will be used. All the information collected during the study will be recorded 
in the eCRF identified by subject initials and subject ID number, for each subject enrolled, 
including those removed for any reason after administered the first dose. It is the responsibility 
of the Investigator and Co-Investigator to ensure that the eCRFs are properly and completely 
filled in. 
Central data management will be performed by PRA. Internet-based remote data capture will be 
used for entering, managing, and validating data from centers. The following regulation will be 
followed: 
• 
FDA 21CRF part 11 rule 
• 
ICH, Good Clinical Practice, Consolidated guideline 
• 
FDA Guidance for Industry “Computerized system used in clinical trials. 
• 
EU Directives 

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14.2 Coding of Adverse Events, Drugs and Diseases 
All AEs will be coded using the Medical Dictionary for Regulatory Activities Terminology 
(MedDRA) latest version.  Concomitant medications will be coded according to the WHO drug 
dictionary. 
14.3 Data Quality Assurance 
All aspects of the study will be carefully monitored with respect to Good Clinical Practices 
(GCP) and SOPs for compliance with applicable government regulations. The study monitor will 
be an authorized individual designated by the Sponsor. The study monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the PI.  Study monitoring will be conducted according to a monitoring plan.  
15 STATISTICAL METHODOLOGY 
This study is a phase 3, twelve-week, multi-center, multinational, randomized, double-blind, 
double-dummy, parallel group study. Up to 525 eligible subjects with early untreated Parkinson’s 
disease (PD) who are not early terminated from the study during screening or baseline visits and 
are randomized to treatment with P2B001 0.6/0.75 (150 subjects), or pramipexole 0.6 mg once 
daily (150 subjects), or rasagiline 0.75 mg once daily (150 subjects), or pramipexole ER titrated 
to therapeutic optimal dose (75 subjects) using a randomization scheme of 2:2:2:1, respectively.   
Randomization will take place following the completion of all screening procedures including 
subject approval by both site PI and the central EMC.  
This study is powered to demonstrate the superiority of (i) P2B001 0.6/0.75mg as compared to its 
individual components in the change from baseline to Week 12/Treatment Termination in Total 
UPDRS score and, (ii) to demonstrate the superiority of P2B001 0.6/0.75mg over pramipexole ER 
in the change from baseline to Week 12/Treatment Termination in the ESS.  
Treatment with pramipexole ER will serve as a calibration arm to better characterize P2B001 
against currently used therapy. Therefore, with the exception of change from baseline to Week 
12/Treatment Termination in the ESS, only descriptive statistics and no formal significance testing 
will be made between the pramipexole ER arm and the other three study arms. 
Week 12/Treatment Termination is defined for all statistical analyses involving significance 
testing as the last visit in which a subject was treated with the study drug. 
15.1 Sample Size Rationale 
The study was powered to allow achieving two goals: 
• To demonstrate the superiority of P2B001 0.6/0.75mg compared to its individual components 
in the primary endpoint, the change from baseline to Week 12/Treatment Termination in total 
UPDRS score: 

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- 
The power to meet the primary endpoint was estimated based on simulation runs assuming 
equal arms size of P2B001 0.6/0.75mg and its individual components as well as repeated 
UPDRS measurements at baseline, week 4, week 8 and week 12.  
- 
The expected STD of the change from baseline was assumed to be 6.0 UPDRS points. 
- 
The expected treatment effect of P2B001 0.6/0.75mg is 3 UPDRS points over rasagiline 
0.75mg and 2.25 UPDRS points over 0.6mg pramipexole. 
- 
Sequential correlations between changes from baseline will be 0.7 and 0.49 between these 
obtained at week 4 and at week 12. 
- 
Missing observations rate of 10% occurring at random. 
- 
The statistical model used in the simulation study was the Mixed Model for Repeated 
Measures (MMRM) (SAS® MIXED procedure with REPEATED sub-command) testing 
two contrasts: P2B001 0.6/0.75mg vs. rasagiline 0.75mg and P2B001 0.6/0.75mg vs. 
pramipexole 0.6mg at Week 12/Treatment Termination. 
- 
In order to consider the study as successful both tested contrasts have to be statistically 
significant at 5% two-tailed each.  
The simulation indicates that a total of 150 subjects per group treated with P2B001 0.6/0.75mg, 
rasagiline 0.75mg arm or pramipexole 0.6mg will provide 87.6% power to detect a statistically 
significant effect size favoring P2B001 0.6/0.75mg by 3 UPDRS points over rasagiline 0.75mg 
and 2.25 UPDRS points over pramipexole 0.6mg.   
• To demonstrate the superiority of P2B001 0.6/0.75mg over pramipexole ER in the first 
secondary endpoint, namely, the change from baseline to Week 12/Treatment Termination in 
the ESS: 
- 
The power to meet this secondary endpoint was estimated using the two-sample t-test for 
mean difference at a two-sided alpha of 5% (SAS® POWER procedure). 
- 
The expected STD of the change from baseline was assumed to be 3.0 ESS points. 
- 
The expected treatment effect of P2B001 0.6/0.75mg over pramipexole ER is 1.5 ESS 
points. 
- 
According to the gate keeping method for multiple endpoints while testing for the 
secondary endpoints, this secondary endpoint will be considered as met only in the case 
that both primary endpoint contrasts as well as the P2B001 0.6/0.75mg over Pramipexole 
ER comparison in the change from baseline to Week 12/Treatment Termination in the ESS 
will be met at two-tailed alpha level of 5% each.  
This analysis indicates that a total of 150 subjects per group treated with P2B001 0.6/0.75mg 
and 75 subjects treated with pramipexole ER arm, considering the above assumptions, will 
provide a power of 94.1% to detect a statistically significant effect size at the magnitude of 1.5 
ESS units or more at a two-sided alpha level of 5%. 
15.2 Sample Size Re-Assessment 

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To examine whether the variance estimate used in power calculations for the primary endpoint 
was adequate, an assessment of the variance magnitude will be performed after at least 1/3 of the 
subjects complete the study treatment period. The EM algorithm of Gould and Shih 
(Communications in Statistics. A Theory and Methods, 21, 2833-2853, 1992), will be applied to 
estimate the variance of the change from baseline to Week 12/Treatment Termination in total 
UPDRS score, without breaking the blind. In the case that the variance estimate will be found to 
be larger than the one projected, the sponsor reserves the right to up-size the study via protocol 
amendment. 
15.3 Randomization 
Randomization will take place following the completion of all screening procedures including 
subject approval by both site PI and the central EMC. 
Up to 525 eligible subjects with early untreated Parkinson’s disease (PD) who are not early 
terminated from the study during screening or baseline visits and are randomized to treatment  
with P2B001 0.6/0.75 (approximately 150 subjects), or pramipexole 0.6 mg once daily 
(approximately 150 subjects), or rasagiline 0.75 mg once daily (approximately 150 subjects), or 
pramipexole ER titrated to therapeutic optimal dose (approximately 75 subjects) using a 
randomization scheme of 2:2:2:1, respectively.  
15.4 Data Analyses Sets 
The following data analysis sets are defined for this study: 
• Intention-to-Treat Analysis Set (ITT): The ITT Analysis Set will include all eligible and 
randomized subjects who are not early terminated from the study during screening or 
baseline visits according to the treatment group to which they are originally randomized 
to. The Intention-to-Treat (ITT) analysis set will serve as the principal analysis set for 
efficacy assessments 
• 
Modified Intention-to-Treat Analysis Set (mITT): The mITT Analyses Set is a subset of 
the ITT Analysis Set including subjects who have at least one post-baseline UPDRS 
assessment and have taken at least one study drug dose according to the treatment group to 
which they are originally randomized to.  
• 
Completers Analysis Set (CO): The completers analysis set (CO) will consist of all subjects 
who complete the 12 weeks of the study according to treatment actually administered. 
• 
Per Protocol Analysis Set (PP): The per-protocol analysis set (PP) will consist of all subjects 
included in the CO analysis set without any major protocol violations according to treatment 
actually administered. 
• 
Safety Analysis Set (ST): The safety analysis set (ST) will consist of all subjects who have 
been randomized and received at least one study drug according to treatment actually 
administered. The safety analysis set (ST) will serve as the principal analysis set for safety 
assessments. 

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15.5 Overall Significance Level and Multiplicity Adjustment: 
The overall significance level for this study will be 5% using two-tailed tests. No interim analyses 
or futility analyses are planned for this study. 
The overall, experiment-wise type-I error rate of 5% will be preserved according to the below plan: 
1. The principal analysis of the primary endpoint is designed to demonstrate the efficacy of 
P2B001 0.6/0.75mg as compared to its individual components in the changes from baseline to 
Week 12/Treatment Termination. Accordingly, analysis will employ two contrasts: P2B001 
0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg 
once daily. The type-I error of 5% for multiple contrasts testing for the primary endpoint will 
be preserved by determining that the primary endpoint is met only if both comparisons will 
favor P2B001 0.6/0.75mg at a two-tailed alpha level of 5% each.     
2. Multiplicity adjustment for multiple endpoints testing for the secondary endpoints will utilize 
the gate keeping hierarchical method according to the following order and plan: 
- 
For the 1st secondary endpoint, namely, the P2B001 0.6/0.75mg vs. Pramipexole ER 
contrast in the change from baseline to Week 12/Treatment Termination in the ESS, will 
be considered as met only if both primary endpoint contrasts as above defined and the 
P2B0011 0.6/0.75mg vs. pramipexole ER contrast in the change from baseline to Week 
12/Treatment Termination in the ESS will all be met (total of 3 contrasts) at a two-tailed 
alpha level of 5% each.     
- 
The 2nd secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the Total PDQ39 will be considered as met if all of the 3 previous 
tested contrasts (primary endpoint and 1st secondary endpoint) as well the two contrasts: 
P2B001 0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. 
rasagiline 0.75mg once daily in the 2nd secondary endpoint will all be met (total of 5 
contrasts) at a two-tailed alpha level of 5% each. 
- 
The 3rd secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the ADL UPDRS (part II) score will be considered as met if all of the 
5 previous tested contrasts (primary endpoint, 1st and 2nd secondary endpoints) as well the 
two contrasts: P2B001 0.6/0.75mg vs. Pramipexole 0.6mg once daily and, P2B001 
0.6/0.75mg vs. rasagiline 0.75mg once daily in the 3rd secondary endpoint will all be met 
(total of 7 contrasts) at a two-tailed alpha level of 5% each. 
- 
The 4th secondary endpoint, namely, the change from baseline to Week 12/Treatment 
Termination visit in the motor UPDRS (part III) score will be considered as met if all of 
the 7 previous tested contrasts (primary endpoint, 1st, 2nd and 3rd secondary endpoints) as 
well the two contrasts: P2B001 0.6/0.75mg vs. Pramipexole 0.6mg once daily and, P2B001 
0.6/0.75mg vs. rasagiline 0.75mg once daily in the 4th secondary endpoint will all be met 
(total of 9 contrasts) at a two-tailed alpha level of 5% each. 

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- 
The 5th secondary endpoint, namely, the CGI-S responder’s analysis at Week 12/Treatment 
Termination visit (change from baseline ≥1 CGI-S points) will be considered as met if all 
of the 9 previous tested contrasts (primary endpoint, 1st, 2nd, 3rd and 4th secondary 
endpoints) as well the two contrasts: P2B001 0.6/0.75mg vs. Pramipexole 0.6mg once daily 
and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg once daily in the 4th secondary endpoint 
will all be met (total of 11 contrasts) at a two-tailed alpha level of 5% each. 
15.6 
Study Population Summary 
The ITT analysis set will be used to describe study population. Descriptive statistics of these data 
will be provided by treatment group and overall.  
15.6.1 Subject Disposition 
Data from subjects who are randomized, subjects who are randomized regardless of treatment 
(ITT), mITT, CO, PP and ST analysis sets, subjects who have reached the End of Study visit 
according to study plan, subjects who early discontinued treatment or study follow-up will be 
summarized. Data from subjects who early discontinued study IP treatment or study follow-up will 
also be displayed by discontinuation reason using descriptive statistics. The denominator for 
calculating the percentages will be the set of ITT. This summary table will also describe all subjects 
screened into the study. 
15.6.2 Study Inclusion and Exclusion Criteria 
Although it is expected that all subjects randomized into the study will meet all study inclusion 
and exclusion criteria there might be some subjects that will be granted waivers allowing them to 
be enrolled into the study. The number and proportion (%) of the ITT analysis set subjects who 
failed to meet study inclusions/exclusion criteria will be reported broken down by criteria. 
15.6.3 Demographics and Baseline Characteristics 
Demographics and baseline data will be displayed for the ITT analysis set. Subject demographic 
and baseline characteristics, including baseline prognostic factors will be examined to assess the 
comparability of the treatment groups. For continuous variables, descriptive statistics (number [n], 
mean, standard deviation (SD), standard error, median, minimum, and maximum) will be 
provided. For categorical variables, subject counts and percentages will be provided. Categories 
for missing data will be presented.  
Summary statistics of these parameters will also be provided when broken down by geographical 
region, and by US/Non-US sub-populations. 
15.6.4 Medical History 
The incidence (no. of patients) of past medical conditions will be provided when broken down by 
System Organ Class (SOC) and Preferred Term (PT) according to MedDRA dictionary. Subjects 

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with at least 1 past medical condition in each SOC/PT category will be summarized using 
descriptive statistics. Subjects will be counted only once in each category. 
15.6.5 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the WHODRUG dictionary. The 
incidence of prior medications and separately those consumed concomitantly; from the day of 1st 
study IP administration and onwards, will be summarized using descriptive statistics by 
Therapeutic Main Group (ATC Level 2) and dictionary Preferred Term.  
Subjects will only be counted once in each Therapeutic Main Group, and only once in each 
Preferred Term category. 
15.6.5.1 Pre-Study Medications 
Analyses will include only coded medications that were initiated one day or more prior to the 1st 
administration of study IP. Medications in which start date will not be reported in the database will 
also be considered as pre-study medications.  
Incidence table including subject counts (no. of subjects) and percentages broken down by 
Therapeutic Main Group and Preferred Term as well as by treatment group will be generated. 
Summary statistics of pre-study medications will also be provided when broken down by US/Non-
US sub-populations. 
15.6.5.2 Concomitant Medications 
Analyses will include only coded medications that were consumed after 1st study IP administration. 
Medications in which start date will not be reported in database will also be considered as 
concomitant medications. Medications lacking stop date will be considered as ongoing for the 
purpose of analysis. 
Incidence table including subject counts (no. of subjects) and percentages broken down by 
Therapeutic Main Group and Preferred Term as well as by treatment group will be generated. 
Summary statistics of concomitant medications will also be provided when broken down by 
US/Non-US sub-populations. 
15.6.5.3 Disallowed Medications Use 
The following medications are disallowed:  
• 
Other investigational therapy (washout period 30 days prior to study entry, baseline visit) 
• 
Previous MAO-B inhibitors, selegiline or rasagiline, for longer than 4 weeks or within the 
previous 3 months prior to baseline visit. 
• 
Previous levodopa or dopamine agonists, for longer than 4 weeks or within the previous 2 
months prior to baseline visit.  
• 
Previous anticholinergic drugs for PD (such as benztropine, orphenadrine hydrochloride, 
biperiden, ethopropazine, procyclidine, trihexyphenidyl) or amantadine for longer than 4 

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weeks; if previous exposure was less than 4 weeks then it must not be within 1 month 
prior to the baseline visit.  
• 
Subjects can take peripheral anticholinergic drugs (such as oxybutynin, orphenadrine 
citrate, tiotropium bromide etc..) if they are stable on low dose for at least 4 weeks prior to 
study entry, and without (or with minor) cognitive effects; however, once enrolled into the 
study use of new peripheral anticholinergic drugs is prohibited. Patients should be 
followed very closely for possible cognitive side effects. 
• 
MAO inhibitors, such as phenelzine or tranylcypromine 
• 
Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones,    
thioxanthenes) or metoclopramide. 
• 
Ciprofloxacin or other CYP1A2 inhibitors: may affect rasagiline plasma concentrations. 
• 
Antitussive agent Dextromethorphan.: co-administration with rasagiline may lead to 
psychosis. 
• 
Analgesic agents such as tramadol, methadone, meperidine and propoxyphene due to risk of 
serotonin syndrome. 
• 
St. John's Wort or cyclobenzaprine (tricyclic muscle relaxant).  
• Marijuana or previous exposure to Marijuana during the last 30 days prior to the baseline 
visit. 
 
Incidence table including subject counts (no. of subjects) and percentages broken down by 
treatment group will be generated and data listing will be provided. 
15.6.6 Protocol Violations/Deviations 
Protocol deviations and violations will be recorded on an ongoing basis and will be included in a 
DV domain in the SDTM database.  
The number of subjects with at least 1 protocol violation/deviation in each category will be 
summarized using descriptive statistics. Detailed individual subject listing will also be provided. 
15.6.7 Efficacy Endpoints and Analyses 
All efficacy endpoints will be tested for the ITT analysis set controlling for multiplicity as detailed 
in Section 15.5. 
An effort to obtain the efficacy outcome measures data regardless if study treatment was 
discontinued will be made. 
Week 12/Treatment Termination is defined for all statistical analyses involving significance 
testing as the last visit in which a subject was treated with the study drug. 
15.6.8 Primary Efficacy Endpoint and Principal Statistical Analysis 
The primary efficacy endpoint for this study is the change from baseline to Week 12/Treatment 
Termination in total UPDRS score (defined as sum of parts II and III, scores (0-160). The statistical 

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model will be a Mixed Model for Repeated Measures (MMRM) (SAS® MIXED procedure with 
REPEATED sub-command). The model will include the following fixed effects: categorical week 
in trial by treatment interaction, country or geographical region (CGR), and baseline UPDRS 
score. The model will use the unstructured covariance structure and the REML estimation method 
and degrees of freedom will be adjusted using the Kenward-Roger method. Data from all three 
changes form baseline to post-baseline visits (weeks 4, 8 and 12) collected from all subjects 
randomized into the study will be used as response in the model. The differences between the 
P2B001 0.6/0.75mg arm as compared to its 2 individual components at Week 12/Treatment 
Termination will be estimated and tested using 2 contrasts: P2B001 0.6/0.75mg vs. pramipexole 
0.6mg and P2B001 0.6/0.75mg vs. rasagiline 0.75mg. The study primary endpoint will be 
considered as met only if both contrasts will favor P2B001 0.6/0.75mg at a two-tailed alpha level 
of 5% each. 
15.6.9 Sensitivity Analyses for the Primary Endpoint 
The robustness of the results of the principal analysis of the primary endpoint will be explored 
employing the following: 
15.6.9.1 Sensitivity Analysis Using Difference Analyses Sets 
The primary analysis described above will be used for the ITT, mITT, CO and PP Analysis Sets 
with or without efficacy measurements taken after study treatment termination. 
15.6.9.2 Sensitivity Analysis Using Change from Baseline to Last Observed Value (LOV) 
The Total UPDRS score change from baseline to last observed value (LOV), with or without 
UPDRS measurements taken after study treatment termination, will be calculated and analyzed for 
the ITT Analysis Set.  
The statistical model to be used for the analysis of the change from baseline to LOV in the Total 
UPDRS score will be an analysis of covariance (SAS® MIXED procedure) and the model will 
include treatment group, CGR and baseline Total UPDRS score. The change from baseline to LOV 
will be used as response variable in the model and differences between P2B001 0.6/0.75mg to its 
2 individual components at LOV will be tested using 2 contrasts: P2B001 0.6/0.75mg vs. 
pramipexole 0.6mg and P2B001 0.6/0.75mg vs. rasagiline 0.75mg. 
15.6.9.3 Sensitivity Analysis Using the Total UPDRS Responders Analysis 
The ITT analysis set will further be used to compare the LOV responders’ rate, with or without 
UPDRS measurements taken after study treatment termination, between the P2B001 0.6/0.75mg 
and its 2 individual components in the primary endpoint. 

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A subject with an improvement of 4 point or more at LOVas compared to baseline will be classified 
as a “Responder” while other randomized subjects not falling into this definition will be classified 
as a “Non-Responders”. 
The analysis of this binary end-point will be based on estimating 2 contrasts (2 contrasts: P2B001 
0.6/0.75mg vs. pramipexole 0.6mg and P2B001 0.6/0.75mg vs. rasagiline 0.75mg) derived from a 
baseline-adjusted, Logistic Regression model [SAS® PROC GENMOD with DIST=BIN and 
LINK=LOGIT] to this binary outcome measure. In addition to the treatment group the model will 
include the following covariates: CGR and baseline Total UPDRS score. The treatment effect 
(odds-ratios) of P2B001 0.6/0.75mg vs its 2 individual components at LOV on the proportion of 
responders at week 12/Treatment Termination and the corresponding adjusted proportions will be 
displayed. In addition, the number and proportion of responders at Week 12/Treatment 
Termination will be displayed by treatment group. 
15.6.9.4 Sensitivity Analysis Accounting for Missing Values 
The ITT analysis set will be used for the below sensitivity analysis. 
To evaluate the possible impact of missing values on the principal analysis of the primary endpoint 
results assuming all missing data are Missing Not At Random (MNAR), a sensitivity analysis 
using the Tipping Point Method and multiple imputations will be performed according to the 
following steps: 
1. Multiple Imputations Assuming Missing At Random Missingness Mechanism: The Multiple 
Imputations procedure, using the Markov-Chain-Monte-Carlo (MCMC) method (SAS® MI 
procedure) will be used on the total UPDRS at baseline and at LOV, with or without UPDRS 
measurements taken after study treatment termination, to impute Missing At Random (MAR) 
missing values. Treatment and country will be included in the imputation model. 
The number of imputations that will be used will be 100. Minimum and maximum imputation 
values will be 0 and 160 in line with the total UPDRS score range. The seed that will be used 
for the MI procedure random numbers generator will be 12345678. 
2. The change from baseline based on step 1 will then be calculated. 
3. For the P2B001 0.6/0.75mg -treated subjects only with imputed missing values, the value of 
S, the tipping parameter, where S>0 (reduction over time is an improvement), will be added to 
the calculated change from baseline artificially worsening the change for these imputed values. 
4. Each of the 100 imputed data sets for a given S will be analyzed using an ANCOVA model 
(SAS® MIXED procedure) to derive the treatment effect of the P2B001 0.6/0.75mg vs its 2 
individual components and standard errors. The model will include treatment, country and 
baseline Total UPDRS score. 
5. Treatment effects, 95% CIs and p-values will be calculated for a given S using the 
SAS® MIANALYZE procedure on the treatment effects and SE estimates for each of the 100 
imputed datasets.  

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6. Imputations and analyses will be repeated while increasing S by 1% each time until one of the 
two p-values (for the two between groups contrasts) in the primary model will be greater than 
0.05. The first S causing significance on both contrasts to be lost is the tipping point.  
15.6.10 Key Secondary Efficacy Endpoints and Analyses 
All efficacy endpoints will be tested for the ITT analysis. Secondary endpoints will be tested once 
both primary endpoint contrasts (P2B001 0.6/0.75mg as compared to its individual components) 
will favor P2B001 0.6/0.75mg at a two-tailed alpha level of 5% each.  
Multiplicity adjustment for multiple endpoints testing for the secondary endpoints will utilize the 
gate keeping hierarchical method according to the following order and plan: 
15.6.10.1 
Change from Baseline to Week 12/Treatment Termination in the ESS 
For the 1st secondary endpoint, namely, the P2B001 0.6/0.75mg vs. Pramipexole ER contrast in 
the change from baseline to Week 12/Treatment Termination in the ESS, will be considered as 
met only if both primary endpoint contrasts as above defined and the P2B001 0.6/0.75mg vs. 
pramipexole ER contrast in the change from baseline to Week 12/Treatment Termination in the 
ESS will all be met (total of 3 contrasts) at a two-tailed alpha level of 5% each. 
The statistical model to be used for the analysis of the change from baseline to Week 12/Treatment 
Termination in the ESS will be a Mixed Model for Repeated Measures (MMRM) (SAS® MIXED 
procedure with REPEATED sub-command). The model will include the following fixed effects: 
categorical week in trial by treatment interaction, CGR, and baseline ESS score. The model will 
use the unstructured covariance structure and the REML estimation method and degrees of 
freedom will be adjusted using the Kenward-Roger method. Data from all three changes form 
baseline to post-baseline visits (weeks 5, 8 and 12) collected from all subjects randomized into the 
study will be used as response in the model. The difference between the P2B001 0.6/0.75mg as 
compared to Pramipexole ER at Week 12/Treatment Termination will be estimated and tested 
using a contrast. 
15.6.10.2 
Change from Baseline to Week 12/Treatment Termination in the Total PDQ39 
The 2nd secondary endpoint, namely, the change from baseline to Week 12/Treatment Termination 
visit in the Total PDQ39 will be considered as met if all of the 3 previous tested contrasts (primary 
endpoint and 1st secondary endpoint) as well the two contrasts: P2B001 0.6/0.75mg vs. 
pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg once daily in the 
2nd secondary endpoint will all be met (total of 5 contrasts) at a two-tailed alpha level of 5% each. 
The statistical model to be used for the analysis of the change from baseline to Week 12/Treatment 
Termination visit in the Total PDQ39 will be an analysis of covariance (SAS® MIXED procedure) 
and the model will include treatment group, CGR and baseline PDQ39 score. The change from 
baseline to Week 12/Treatment Termination will be used as response variable in the model and 
differences between P2B001 0.6/0.75mg to its 2 individual components at Week 12/Treatment 

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Termination will be tested using 2 contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg and 
P2B001 0.6/0.75mg vs. rasagiline 0.75mg. 
15.6.10.3 
Change from Baseline to Week 12/Treatment Termination in the ADL UPDRS 
(part II) 
The 3rd secondary endpoint, namely, the change from baseline to Week 12/Treatment Termination 
in the ADL UPDRS (part II) score will be considered as met if all of the 5 previous tested contrasts 
(primary endpoint, 1st and 2nd secondary endpoints) as well the two contrasts: P2B001 0.6/0.75mg 
vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg once daily in the 
3rd secondary endpoint will all be met (total of 7 contrasts) at a two-tailed alpha level of 5% each. 
The statistical model to be used for the analysis of the change from baseline to Week 12/Treatment 
Termination in the ADL UPDRS (part II) will be a Mixed Model for Repeated Measures (MMRM) 
(SAS® MIXED procedure with REPEATED sub-command). The model will include the following 
fixed effects: categorical week in trial by treatment interaction, CGR, and baseline ADL UPDRS 
(part II). The model will use the unstructured covariance structure and the REML estimation 
method and degrees of freedom will be adjusted using the Kenward-Roger method. Data from all 
three changes form baseline to post-baseline visits (weeks 5, 8 and 12) collected from all subjects 
randomized into the study will be used as response in the model.  
The difference between P2B001 0.6/0.75mg to its 2 individual components at Week 12/Treatment 
Termination will be tested using 2 contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg and 
P2B001 0.6/0.75mg vs. rasagiline 0.75mg. 
15.6.10.4 
Change from Baseline to Week 12/Treatment Termination in the Motor 
UPDRS (part III) Score 
The 4th secondary endpoint, namely, the change from baseline to Week 12/Treatment Termination 
in the motor UPDRS (part III) score will be considered as met if all of the 7 previous tested 
contrasts (primary endpoint, 1st, 2nd and 3rd secondary endpoints) as well the two contrasts: P2B001 
0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. rasagiline 0.75mg once 
daily in the 4th secondary endpoint will all be met (total of 9 contrasts) at a two-tailed alpha level 
of 5% each. 
The statistical model to be used for the analysis of the change from baseline to Week 12/Treatment 
Termination in the Motor UPDRS (part III) will be a Mixed Model for Repeated Measures 
(MMRM) (SAS® MIXED procedure with REPEATED sub-command). The model will include 
the following fixed effects: categorical week in trial by treatment interaction, CGR, and baseline 
Motor UPDRS (part III). The model will use the unstructured covariance structure and the REML 
estimation method and degrees of freedom will be adjusted using the Kenward-Roger method. 
Data from all three changes form baseline to post-baseline visits (weeks 5, 8 and 12) collected 
from all subjects randomized into the study will be used as response in the model.  

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The difference between P2B001 0.6/0.75mg to its 2 individual components at Week 12/Treatment 
Termination will be tested using 2 contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg and 
P2B001 0.6/0.75mg vs. rasagiline 0.75mg. 
15.6.10.5 
CGI-S Responder’s Analysis at Week 12/Treatment Termination (change from 
baseline ≥1 CGI-S points) 
The 5th secondary endpoint, namely, the CGI-S responder’s analysis at Week 12/Treatment 
Termination (change from baseline ≥1 CGI-S points) will be considered as met if all of the 9 
previous tested contrasts (primary endpoint, 1st, 2nd, 3rd and 4th secondary endpoints) as well the 
two contrasts: P2B001 0.6/0.75mg vs. pramipexole 0.6mg once daily and, P2B001 0.6/0.75mg vs. 
rasagiline 0.75mg once daily in the 4th secondary endpoint will all be met (total of 11 contrasts) at 
a two-tailed alpha level of 5% each. 
A subject with an improvement of 1 point or more at Week12/Treatment Termination as compared 
to baseline will be classified as a “Responder” while other randomized subjects not falling into 
this definition will be classified as a “Non-Responders”. 
 
The analysis of this binary end-point will be based on estimating 2 contrasts (2 contrasts: 
P2B001 0.6/0.75mg vs. pramipexole 0.6mg and P2B001 0.6/0.75mg vs. rasagiline 0.75mg) 
derived from a baseline-adjusted, Logistic Regression model [SAS® PROC GENMOD with 
DIST=BIN and LINK=LOGIT] to this binary outcome measure. In addition to the treatment 
group the model will include the following covariates: CGR and baseline CGI-S. The treatment 
effect (odds-ratios) of P2B001 0.6/0.75mg vs its 2 individual components at Week 12/Treatment 
Termination on the proportion of responders at Week 12/Treatment Termination and the 
corresponding adjusted proportions will be displayed. In addition, the number and proportion of 
responders at Week 12/Treatment Termination will be displayed by treatment group. Exploratory 
Efficacy Endpoints 
Analyses of the exploratory endpoints will provide additional insight into the therapeutic effect 
of P2B001 0.6/0.75. These endpoints will be tested for the ITT analysis set using the nominal 
alpha level of 5% without controlling for multiplicity. Detailed statistical methodology to be 
used for the analyses of these exploratory endpoints will be provided in a more detailed SAP to 
be developed while the study is ongoing and prior to locking the database and unblinding. 
15.6.11 
The exploratory endpoints to be analyzed are: 
• To evaluate the efficacy of P2B001 0.6/0.75 mg compared to its individual components in 
the following endpoints: 
- 
Change from baseline to Week 12/Treatment Termination visit in each of the 8 PDQ39 
subscales scores. 
- 
Change from baseline to Week 12/Treatment Termination visit in Health-Related Quality 
of Life (HRQOL) SF-12v2 questionnaire.  

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- 
Clinical Global Impression of Improvement (CGI-I) at Week 12/Treatment Termination 
visit.  
• To evaluate the superiority of P2B001 0.6/0.75 mg over Pramipexole ER with respect to the 
following outcome measures: 
- 
Proportion (%) of patients with ESS score >10 at Week 12/Treatment Termination. 
- 
Proportion (%) of patients with ESS Score <10 at baseline and ESS score >10 at Week 
12/Treatment Termination. 
- 
3-Months rate of total number of adverse events. 
- 
Change from baseline to Week 12/Treatment Termination in the differences in systolic and 
diastolic blood pressure measured during supine and standing positions.   
- 
Proportion (%) of patients with both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
3-Months rate of total number of both symptomatic/non-symptomatic Orthostatic 
Hypotension. 
- 
Proportion (%) of patients with symptomatic Orthostatic Hypotension. 
- 
3-Months rate of total number of symptomatic Orthostatic Hypotension. 
- 
Proportion (%) of patients with daytime sleepiness/drowsiness related AE’s.  
- 
Proportion (%) of patients with gastrointestinal (GI) adverse events  
- 
Proportion (%) of patients presenting neurological adverse events  
- 
Change from baseline to Week 12/Treatment Termination visit in the Orthostatic 
Hypotension Symptoms Assessment (OHSA) question 1. 
 
• To descriptively evaluate the comparability of P2B001 0.6/0.75 mg with reference to the 
calibration arm (Pramipexole ER) in total UPDRS score (defined as sum of parts II and III, 
scores (0-160). 
15.7 Safety Assessments 
All safety assessments will use the Safety Analysis Set (ST) which includes all randomized 
subjects who were administered at least one study dose, according to the treatment actually 
received. The ST analysis set will serve as the principal analysis set for safety assessment. Safety 
analyses will exclude measurements taken 30 days after study treatment discontinuation as well as 
adverse events initiated 30 days after study treatment discontinuation. 
15.7.1 Adverse Events 
Adverse events will be recorded from the time a subject has signed the Informed Consent Form 
until the end of subject’s study participation, including up to Week 14 Follow-Up visit, regardless 
of study IP administration. 
The MedDRA dictionary will be used to standardize the terms used by the Investigator to describe 
the Adverse Events (AEs).  

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The following will be incorporated into the analysis of adverse events: 
• As analysis of AEs can incorporate only coded AEs, it is mandatory that at the time of database 
lock all AEs will be coded. 
• Adverse events analyses will include only the Treatment Emergent Adverse Events (TEAEs), 
namely, those events which started at the time of first study IP administration or afterwards. 
AEs lacking start day or AEs recorded on day of first study IP lacking start time will be 
considered as TEAE. 
The following analyses are pre-planned for adverse events: 
• The incidence (no. of patients) and frequency (no. of events) of most frequent TEAEs (>5% 
of subjects in at least one study arm) by Preferred Term (PT). 
• The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by 
System Organ Class (SOC) and PT. 
• The incidence (no. of patients) and frequency (no. of events) of TEAEs by SOC and PT in 
Subjects Early Discontinued from Study/Treatment. 
• The incidence (no. of patients) and frequency (no. of events) of serious TEAEs by SOC and 
PT 
• The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken down by 
severity. 
• The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by 
relationship to study IP.  
• The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken down by 
action taken with study IP.  
• The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken down by 
event outcome. 
• Adverse Events dictionary used to code Investigator’s verbatim terms will be provided. 
• Individual subject listings of all SAEs, treatment emergent SAEs, TEAEs and non-TEAEs. 
15.7.2 Laboratory Tests 
Analyses of safety central laboratory data will be performed in the following manner: 
• The more detailed SAP to be developed while the study is ongoing and prior to locking the 
database and unblinding will provide quantitative criteria used to define the potentially 
clinically significant (PCS) abnormal laboratory values. Measurements to be used in the 
analysis are those taken only after the initiation of the 1st study IP administration. The 
incidence tables of PCS lab values as well as the individual subject listing will be provided. 
Please note that the denominator to be used for calculating percentages is the number of 
subjects with at least one measurement post initiation of the 1st study IP administration. 

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• Quantitative laboratory measurements will be categorized with reference to the normal ranges 
as Low, Normal or High. The incidence (no. of subjects) of abnormal values at any time post 
initiation of the 1st study IP administration, calculated for subjects with normal values at 
baseline will be provided. Analysis will include, per tested parameter, those subjects with 
normal baseline and at least one post-treatment measurement. Summary table will display the 
number and relative percentage of subjects with at least one abnormal value (above upper or 
below the lower normal range) at any time post initiation of the 1st study IP administration. 
• Quantitative laboratory measurements will be categorized with reference to the normal ranges 
as Low, Normal or High. Shift analysis of the categorical change from baseline to each 
scheduled visit and to the last observed value will be provided. In case of sporadic repeated 
measurement within a visit, the last measurement per visit will be used to represent subject’s 
value in the analysis. 
Box-Plots of measurements done and figures of mean values ± SEs as well as descriptive statistics 
for all laboratory quantitative parameters and changes from baseline will be provided by scheduled 
visits and treatment groups.  In case of sporadic repeated measurement within a visit, the last 
measurement per visit will be used to represent subject’s value in the analysis.  
15.7.3 Vital Signs 
Analyses of vital signs will be performed in the following manner: 
• The more detailed SAP to be developed while the study is ongoing and prior to locking the 
database and unblinding will provide quantitative criteria used to define the potentially 
clinically significant (PCS) abnormal values. Measurements to be used in the analysis are those 
taken immediately following the first administration of the study IP and onwards. The 
incidence tables of PCS values as well as the individual subject listing will be provided. The 
denominator to be used for calculating percentages is the number of subjects with at least one 
observation post 1st study IP administration. 
• Box-Plots of measurements done, figures of mean values ±SEs as well as descriptive statistics 
for all parameters and changes from baseline (derived) will be provided by scheduled visits 
and treatment groups. Please note that the last measurement per visit will be used to represent 
subject’s value in the analysis in case of sporadic repeated measurement within a visit. 
15.8  ECG 
The incidence of abnormal ECG findings will be presented by treatment group. Shift analysis from 
baseline will be provided as well. 
15.9 Columbia Suicide Severity Rating Scale (CSSRS) 
The Columbia Suicide Severity Rating Scale Screening/Baseline Version (CSSRS-BL) will be 
taken at screening. The Columbia Suicide Severity Rating Scale Since Last Visit (CSSRS-SLV) 
was to be taken at baseline and in all subsequent study visits.  

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Any positive answer to its behavior subcomponents at screening or baseline will identify a subject 
as with “Suicidal Behavior at Baseline”. Similarly, any positive answer to it’s the ideation 
subcomponents at any of these two visits will identify a subject as with “Suicidal Ideation at 
Baseline”. A subject identified with either “Suicidal Behavior at Baseline” or with “Suicidal 
Ideation at Baseline” was also classified as with “Suicidal Behavior or Ideation at Baseline”. 
Similarly, any positive answer to its behavior subcomponents in any of the post-dosing visits will 
identify a subject as with “Suicidal Behavior Post Dosing”. Similarly, any positive answer to it’s 
the ideation subcomponents in any of the post-randomization visits will identify a subject as with 
“Suicidal Ideation Post Dosing”. A subject identified with either “Suicidal Behavior Post Dosing” 
or with “Suicidal Ideation Post Dosing” was also classified as with “Suicidal Behavior or Ideation 
Post Dosing”. 
The distribution of the number of subjects by these classifications post-dosing as well as shift 
analysis from baseline will be displayed. In addition, for the CSSRS-SLV, listing of Post First 
Study Dose CSSRS (Ideation) Grade 4 and 5 / Suicidal Behavior will be provided. 
15.10 
Tolerability Assessments 
Tolerability analysis will be based on the number (%) of subjects who discontinued the study 
treatment early and  the number (%) of subjects who discontinued study treatment early due to 
adverse events. Time to withdrawal will be presented by Kaplan-Meier curves. 
15.11 
Exploratory Safety Endpoint 
Exploratory comparison between P2B001 0.6/0.75 mg and Pramipexole ER at Week 
12/Treatment Termination will be performed in the following safety endpoints: 
• 
Change from baseline to Week 12/Treatment Termination in the ESS score > 10.  
• 
Adverse event frequency 
• 
Change from baseline to Week 12/Treatment Termination in the differences in systolic and 
diastolic blood pressure measured during supine and standing positions.   
• 
Comparison of percentage of patients presenting with sleepiness/drowsiness related AE’s. 
• 
Comparison of percentage of patients presenting with gastrointestinal (GI) adverse events. 
• 
Comparison of percentage of patients presenting with neurological adverse events. 
• 
Change from baseline to Week 12/Treatment Termination visit in the Orthostatic 
Hypotension Symptoms Assessment (OHSA) question 1. 
15.12 
Safety assessment scales 
Results of scale assessments of daytime sleepiness, suicidality, and impulse control behaviors 
will be presented by study group 
15.13 
Statistical Analysis Plan (SAP) 

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A more detailed SAP will be developed while the study is ongoing and prior to locking the 
database and unblinding. 
 
If ever there is a discrepancy between the Protocol and the Statistical Analysis Plan, the methods 
defined in the SAP will have precedence. 
16 STUDY PERSONNEL 
16.1 Study Site 
At each study center the staff will consist of a minimum of one Principal Investigator and a 
clinical coordinator. If the Principal Investigator at a study center is not a neurologist, then the 
study center will need at least one sub-Investigator who is a neurologist. The neurologist will: 
Verify subject eligibility (including diagnosis of early PD and UPDRS part III) at Visits 1 and 2 
Perform complete physical and neurological examinations at Visit 1 and symptom-directed 
physical and neurological examination at visit 7 and unscheduled visits.  
The neurologist will also decide on the dose of Pramipexole ER (or matching placebo) during the 
titration phase based on subject reporting of efficacy and tolerability. This will be done by a 
study visit at the end of week 3, and a phone call or an unscheduled visit at the end of week 4.  
The Pramipexole ER (or matching placebo) dose will be evaluated again at the end of week 5 as 
part of the activities done in study visit 4.  
Assess Clinical Global Impression- Severity at Visits 2 and 6. 
Assess Clinical Global Impression- Improvement at Visits 4, 5 and 6. 
Perform UPDRS part III at Visits 1, 2, 4, 5 and 6 or the Site PI may delegate this responsibility 
to other senior trained research staff with at least 10 years’ experience in conducting the UPDRS 
All other study procedures can be conducted by the Principal Investigator, Clinical Coordinator 
or other member of the clinical staff with the relevant experience and who the PI has delegated to 
perform those procedures.   
16.1.1 The Principal Investigator 
The Principal Investigator (PI) will have overall responsibility to lead the site study team and all 
aspects of the study. The PI will oversee the accrual of appropriate subjects, the conduct of the 
study according to the trial protocol, communication with the IRB/EC, and the collection of 
required data.  
16.1.2 The Clinical Coordinator or designee 
The clinical coordinator or designee, as delineated on the Personnel Delegation Log, will be 
responsible for subject scheduling; completing and reviewing all subjects’ case report forms and 
other documents and recording of adverse events as well as drug accountability.  He/she will 
instruct the subject on proper study drug administration and completion of study scales 

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(including follow-up phone calls to the subject to obtain missing data from subject efficacy or 
safety scales completed at the previous visit).  He/she will instruct the subject on proper study 
drug dosing.  During the titration phase at the end of Weeks 1, 2 and 6 he/she will make a phone 
call to the subject to assure proper study dosing in the past week and remind of the dosing 
regimen for the next week.  
He/she will collect and forward blood samples and requests to the appropriate laboratories, will 
obtain and forward laboratory results and will assist the Investigator. 
16.2 The Sponsor 
Pharma Two B 
3 Pekeris st. Weizmann science park  
Rehovot 7670203 Israel 
Tel: 972 8 9462672 
Fax: 972 8 9366832 
Email: David@pharma2b.com  
 
The sponsor will provide the following: 
- 
Final protocol  
- 
Study medication  
- 
Drug Distribution 
- 
Insurance for product liability 
16.3 CRO 
Name: PRA Health Science 
Address: 4130 ParkLake Avenue - Suite 400 Raleigh,  
North Carolina 27612 
Tel: +1 (919) 786-8200    
Fax: +1 913.890.5969  
 
The CRO commissioned by Pharma Two B will assist in the conduct and analysis of the trial. 
The CRO will be responsible for the following: 
- 
Project management 
- 
Clinical operation 
- 
Drug safety plan and reporting 
- 
Study specific training 
- 
Data management 
- 
Monitoring 
- 
Quality Assurance 
- 
Final clinical report 

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- 
Central laboratories 
 
 
16.3.1 CRO Clinical Trials Manager 
The CRO Clinical Trials Manager is responsible for all aspects of the study including the proper 
design and conduct, and day-to-day activities of the study and to ensure that the sponsor supplies 
adequate resources to provide high quality study management, monitoring and data management.  
The Corporate Clinical Trials Manager will represent the sponsor on the study various 
Committees: 
Name: Lysander Stemmerik or designee 
Address: PRA Health Science, WTC Papendorp, Papendorpseweg 100, 3528 BJ Utrecht ,  The 
Netherlands . 
Tel: +31 50.850.5749 
Email;  StemmerikLysander@prahs.com 
 
The CRO will be responsible for review of all Serious Adverse Events (SAEs) to ensure that 
each SAE is adequately described to allow determination of deportability to the Regulatory 
Authorities. 
 
16.3.2 Statistics and Data Management Centers (S&DM) 
The CRO’s lead data manger is responsible for data management of electronic CRF's. Statistical 
analyses will be performed by StatExcellence Ltd., Israel.  
16.3.3 Medical Monitor 
The Medical Monitor is responsible to periodically review the safety data in a blinded fashion to 
include AEs, vital signs, ECG and laboratory values. A consistency check of safety and efficacy 
variables will be performed. 
16.3.4 Local Clinical Trial Manager (LCTM) 
The LCTM based at CRO subsidiaries, is responsible for the local day-to-day activities of the 
study and to ensure that the sponsor supplies adequate resources to provide high quality study 
management, monitoring and data management.  The LCTM is responsible for submitting all 
safety reports to local regulatory authorities and to Investigators, as required. The LCTM 
supervises the monitoring activities. 
16.3.5 Clinical Research Associate 
Clinical Research Associate (CRA, monitor) is responsible for monitoring visits. These visits 
will be arranged in advance, at a mutually acceptable time, with site personnel. Sufficient time 

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must be allowed by the site personnel for the Monitor to review the relevant source documents. 
The coordinator and/or Investigator(s) should be available to answer questions or resolve data 
clarifications. Adequate time and space for these visits should be made available by the 
Investigator. The monitor will review, on a regular basis, the progress of the study with the 
Investigator and other site personnel and check completeness and blind maintenance. The 
monitor will verify the data entered into the eCRF for accuracy and completeness. At the end of 
the study, a close-out monitoring visit will be performed.  
16.4 Study Committees 
 
16.4.1 Data & Safety Monitoring Board (DSMB) 
The DSMB is intended to assist and consult on any safety aspects to ensure the safety of study 
subjects. Pharma Two B with the study CRO (PRA Health Science) will be responsible to select 
DSMB members among different experts in the field. The committee will review, periodically, 
in unblinded fashion, all safety data accumulated in the study. The committee will document all 
their recommendations which will be provided to the sponsor and the CRO.    
16.4.2 Subject Central Eligibility Monitoring Committee (EMC) 
After the Investigator has determined a subject has met all of the inclusion criteria and none of 
the exclusion criteria but before randomizing the subject via RTSM, the Investigator will need to 
complete a randomization authorization form (RAF) for that subject and e-mail it to the EMC, 
which consists of expert Parkinson’s disease neurologists. Upon receipt of the RAF, the EMC 
will review the provided information to confirm the subject's eligibility for the study. Only after 
receiving confirmation from the EMC that the subject meets eligibility criteria via a signed RAF, 
may the Investigator randomize the subject using the RTSM system.    
The EMC may also reject the inclusion of a subject due to that subject not meeting eligibility 
criteria. Any rejection will be explained to the Investigator via email.  
17 REGULATORY AND ETHICAL ISSUES 
17.1 Compliance with Regulations Applicable to Clinical Trials 
The study will be conducted according to the protocol, the laws, regulations and administrative 
provisions relating to the implementation of GCP in the conduct of clinical trials on medicinal 
products for human use, as applicable by national legislation and directives, including Directive 
2001/20/EC of the European Parliament and the Council of the European Union and US 21 CFR 
Part 11, 50, 54, 56 and 312. 
17.2 Informed Consent 

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The principles of informed consent, according to Declaration of Helsinki 1964 and all its 
updates, the International Conference on Harmonization (ICH) step 5 guidelines on Good 
Clinical Practice (GCP), 21 CFR part 50 of the FDA Regulations and/or EU Directives, will be 
followed. A subject should not enter a clinical study or perform any study-related procedures 
until subject has been properly informed, has been given time to contemplate participation, and 
has freely given his/her consent by signing and dating the EC/IRB approved informed consent 
form. 
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB together with the protocol and must be approved prior to study start. 
A signed copy of the consent form will be given to the subject and the original will be 
maintained at the site following the signing and dating by the person administering the consent 
and witness (where appropriate). 
17.3 Ethics Committee (EC) / Institutional Review Board (IRB) 
The study must have unconditional approval in writing, by an appropriate Ethics 
Committee/Institutional Review Board (EC/IRB). A copy of the Letter of Approval from the 
EC/IRB, which contains specific identification of the documents approved, must be received by 
the sponsor prior to site initiation. 
Any substantial amendments to the protocol or subsequent changes to the informed consent form 
as a result of changes to the protocol and/or Investigator's Brochure that is approved by the 
sponsor, must also be sent to the EC/IRB and written opinion has to be provided to the sponsor. 
Records of the EC/IRB review and opinion of all documents pertaining to this study must be 
kept on file by the Investigator and are subject to regulatory authority and/or sponsor inspection 
during or after completion of the study.  
Serious Adverse Events (SAEs) must also be reported to the EC/IRB by the Investigator or the 
sponsor. 
Periodic status reports must be submitted to the EC/IRB as required, as well as notification of 
completion of the study and a final report where applicable. A copy of all reports submitted to 
the EC/IRB must be sent to the sponsor. 
17.4 Protocol Amendments 
Changes to the protocol should only be made by an approved protocol amendment. Protocol 
amendments must be approved by the sponsor and each respective site’s EC/IRB prior to 
implementation.  
For clinical trial sites located in EU member states, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable. Elsewhere, the country regulations apply. 
17.5 Subject Confidentiality 

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All subject data will be identified only by a subject identification number, subject initials and 
date of birth. The subject’s personal data (e.g. name and address) will be blinded 
correspondingly in all data analyses. However, after receiving the subject’s approval (by signing 
the Informed Consent), it is required that the Investigator permit the study monitor, independent 
auditor or regulatory agency personnel (with or without the Investigator) to review that portion 
of the subject’s medical record that is directly related to the study. 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 (where 
available). 
The subject's authorization allows the sponsor to receive and review the subject’s protected 
health information which may be re-disclosed to any authorized representative of the sponsor or 
central laboratory facility for review of subject medical records in the context of the study. 
17.6 Liability and Insurance 
A Certificate of Clinical Trials Insurance will be provided to the study centers by the sponsor 
upon request. 
18 DOCUMENTATION 
18.1 Study File and Site Documents 
Prior to the initiation of the study, the following documents must be received by the sponsor 
from the study site: 
• Confidential Disclosure Agreement 
• Signed protocol, amendments and notifications (if applicable) pages by the Principal 
Investigator. 
• The Principal Investigator curriculum vitae and where required current medical license. 
• Signed Clinical Study Agreement. 
• EC/IRB membership list or an official statement that the EC/IRB is in compliance the 
local regulations.  
• EC/IRB written opinion for the protocol, amendments, informed consent, subject 
information sheet (if applicable), advertisements (if applicable). 
18.2 Site Documents/Equipment Supplied by the Sponsor 
Prior to the initiation visit of the study, the sponsor will supply the site Investigator with the 
following items, in addition to the protocol: 
• Current version of the Investigator’s Brochure or equivalent as agreed with the regulatory 
authority. 

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• Regulatory Binder including all study related forms 
• Informed Consent Template 
• Insurance Certificate 
18.3 Maintenance and Retention of Records 
The Investigator will get from the sponsor an essential documents binder EDB or set up a Site 
Master File (SMF) at the beginning of the study. It will be the responsibility of the Investigator 
and study staff to maintain a comprehensive and centralized filing system of all documents 
relevant to the study.  
These documents include:  
• Subject Files (Source documents) – substantiating the data entered in the eCRF with 
regards to laboratory data, subject histories, treatment regimens, etc. 
• Subject Exclusion records – reflecting the reasons any subject was screened for the study 
and found to be ineligible. 
• Drug Dispensing Log – reflecting the total amount of medication received and returned to 
the sponsor, and the amounts administrated to the subject. This information should agree 
with the information entered in the eCRF. 
• Informed Consent Forms (ICF) – will be available for each subject and will be verified 
for proper documentation. 
• Study Notes – this section of the eCRF is used to explain any aspect of the study that is 
not easily entered on the routine eCRF, and could include items such as: 
• Deviations from the protocol; nature, reasons and approval by the Investigator. 
• Comments or explanations of unusual findings. 
• Any data or clarification of data not explicitly requested on the eCRF. 
The EDB or SMF will be stored in a secure but accessible manner. The essential documents will 
be legible and accurate. The participating centers will keep copies of relevant documents, 
including essential center-specific documents. Essential documents should be retained until at 
least 2 years after the approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the Investigational product. These 
documents should be retained for a longer period, however if required by the regulatory 
requirements or by informing the Investigator/institution as to when these documents no longer 
need to be retained. 
The EDB orSMF will be archived by the Sponsor for a minimum of 15 years following the 
signing of the clinical report. 
▪ Site Investigators will be instructed to retain all study records required 
by the sponsor and regulatory authorities in a secure and safe facility 

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with limited access for at least 15 years or longer if required by local 
regulations. 
The site Investigator will be instructed to consult with the sponsor before disposal of any study 
records and to notify the sponsor of any change in the location, disposition or custody of the 
study files. 
18.4 Data Handling 
An Electronic Data Capture (EDC) system to collect subject electronic Case Report Form 
(eCRF) information will be used. All the information collected during the study will be recorded 
in the eCRF identified by subject initials and subject ID number, for each subject enrolled, 
including those removed for any reason after administering the first dose. It is the responsibility 
of the Investigator and sub-Investigator to ensure that the eCRFs are properly and completely 
filled in. 
Central data management will be performed by PRA.  Internet-based remote data capture will be 
used for entering, managing, and validating data from centers. The following regulation will be 
followed: 
• 
FDA 21CRF part 11 rule 
• 
ICH, Good Clinical Practice, Consolidated guideline 
• 
FDA Guidance for Industry “Computerized system used in clinical trials. 
• 
EU Directives 
 
Data will be entered at the site by the site Investigator, study coordinator or the site coordinator, 
onto the eCRF.  
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 and enrolled 
according to the subject’s source data on a per-visit basis. For screen failures, only date of 
screening, date of screen failure, subject demographics and inclusion/exclusion criteria not met 
will be recorded within EDC. Any adverse events for screen failures that occur after signing the 
ICF will be captured only in the source documents and not in the eCRF.  
Subjects should not be identified by name. Appropriately coded identification and subject initials 
must be used. The site Investigator must keep a separate log of subject names and addresses (i.e. 
Subject Identification Record). 
All data collected in the eCRF must be approved by the site Investigator or designee and can be 
verified against the subject’s source documents by the monitor, according to the monitoring plan.  
18.4.1 Source Documents 
Prescription forms, label logs, laboratory test results, ECG strips and all other source documents 
should be maintained and kept at the study site in the subject's study binder. If the hospital file is 

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an electronic system (computerized database), all data should be printed out, signed and dated by 
the Investigator. 
19 STUDY MONITORING 
19.1 Monitors and Monitoring Visits 
The Study monitor/CRA will be responsible for ensuring adherence to local regulations, EU 
Directives (where applicable), ICH guidelines and the sponsor’s SOPs. Study monitors for this 
trial will be provided by the sponsor or sponsor’s designee. The monitors will operate according 
to the EU Directives and in compliance with ICH guidelines, as well as local regulations. 
Monitors will be trained to monitor the study. They will be trained on ICH GCP guidelines, 
study protocol. 
Regular monitoring of study data at the site will be performed in accordance with applicable 
regulations and according to a study specific monitoring plan. The site will be monitored to 
ascertain that enrollment rate, data recording and protocol adherence are satisfactory. The 
frequency of monitoring the site may fluctuate depending upon enrollment rate and the quantity 
of data collected. 
The monitor will review the maintenance of regulatory documentation and Study Drug 
accountability. The monitor will review the progress of the study with the site Investigator and 
other site personnel on a regular basis. At the end of the study, a close-out monitoring visit will 
be performed. Monitoring visits will be arranged in advance with site personnel at a mutually 
acceptable time. Sufficient time must be allowed by the site personnel for the monitor to review 
eCRFs and relevant source documents or resolve data clarifications. Adequate time and space for 
these visits will be made available by the site Investigator. 
19.2 Primary Source Documents 
The site Investigator must maintain primary source documents supporting eCRF data entries. 
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 eligibility to participate 
in the study 
▪ Medical history, physical and neurological findings 
▪ Hospitalization or Emergency Room records (if applicable) 
▪ Each study visit by date, including any relevant findings/notes by the 
site Investigator(s); occurrence (or lack) of AEs; and changes in 

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medication usage, including the date the IMP was commenced and 
completed 
▪ Drug dispensing 
▪ Vital signs 
▪ Subject evaluation scales 
▪ Any additional visits during the study 
▪ Any relevant telephone conversations with the subject regarding the 
study, subject’s satisfaction and tolerability of the treatment during 
titration phase or possible AEs 
▪ Original, signed informed consent forms for study participation 
The site Investigator must also retain all subject-specific printouts, reports of tests and 
procedures performed as a requirement of the study. During monitoring visits, the monitor will 
need to verify data in the eCRFs against these source data.  
20 USE  OF INFORMATION AND PUBLICATION 
20.1 Confidential Information 
All information supplied by the sponsor in association with this study and not previously 
published, is considered confidential information. This information includes, but is not limited 
to, the Investigator's Brochure, clinical protocol, eCRFs and other scientific data. Any data 
collected during the study are also considered confidential. This confidential information shall 
remain the sole property of the sponsor, shall not be disclosed to others without the written 
consent of the sponsor and shall not be used except in the performance of this study. 
The information developed during the conduct of this clinical study is also considered 
confidential, and will be used by the sponsor in connection with the development of P2B001. 
The information may be disclosed as deemed necessary by the sponsor. To allow the use of the 
information derived from this clinical study, the site Investigator is obliged to provide the 
sponsor with complete test results and all data developed in this study. Should the Investigator 
wish to publish the results of this study, the Investigator agrees to provide the sponsor with a 
manuscript for review 60 days prior to submission for publication. The sponsor retains the right 
to delete from the manuscript confidential information and to object to suggested publication 
and/or its timing (at the sole discretion of the sponsor). 

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21 INVESTIGATOR AGREEMENT 
I have carefully read the foregoing protocol including all appendices 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 GCP 
regulations and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information relating to pre-clinical and prior 
clinical experience submitted by the sponsor to all personnel responsible to me who participate 
in the study. I will discuss this information with them to assure that they are adequately informed 
regarding the drug and conduct of the study. 
I agree to keep records on all subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) in accordance with the current GCP 
and local regulations. 
 
 
 
 
Principal Investigator’s name 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
 
 
 
Institution 
 
 
 
 
 

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22 APPENDICES 
22.1 Appendix I: Schedule of Activities: 
 
Visit Number 
1 
2 
3 
**** 
4 
5 
6 
7 
Visit Type 
Screening 
 
Baseline   
 
End of 
Week   
3  
 
End of 
Week   
4  
 
End 
of 
Wee
k 5 
 
End of 
Week 8 
 
End 
of 
Wee
k 12  
 
End of 
Week 
14  
 
Time 
-28 days to 
day 0** 
Day 1 
21 ±2 
days 
28±2 
days 
35 ±2 
days 
56 ±2 
days 
84 ±2 
days 
98 ±2 
days 
ACTIVITIES 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
UK Parkinson's Disease 
Society Brain Bank Clinical 
Diagnostic Criteria 
 
X 
 
 
 
 
 
 
 
Modified H&Y Stage 
X 
 
 
 
 
 
 
 
Mini Mental State Exam 
(MMSE) 
X 
 
 
 
 
 
 
 
Medical History & 
Demographics 
X 
 
 
 
 
 
 
 
Complete Physical and 
Neurological Examination  
X 
 
 
 
 
 
 
 
Symptom-directed physical 
and neurological Examination 
 
 
 
 
 
 
 
X 
Laboratory tests (serum 
biochemistry, hematology, 
urinalysis, serum pregnancy  
test)* 
X*** 
 
 
 
 
 
 
X 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
ECG 
X 
X 
 
 
 
 
 
X 
Randomization to Study 
Medication/Enrollment ID 
Assignment 
X as soon 
as subject 
approved 
by PI and 
EMC  
 
 
 
 
 
 
 
Distribute Dosing Instruction 
Cards and emergency contact 
cards 
 
X 
 
 
 
 
 
 

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Visit Number 
1 
2 
3 
**** 
4 
5 
6 
7 
Visit Type 
Screening 
 
Baseline   
 
End of 
Week   
3  
 
End of 
Week   
4  
 
End 
of 
Wee
k 5 
 
End of 
Week 8 
 
End 
of 
Wee
k 12  
 
End of 
Week 
14  
 
Time 
-28 days to 
day 0** 
Day 1 
21 ±2 
days 
28±2 
days 
35 ±2 
days 
56 ±2 
days 
84 ±2 
days 
98 ±2 
days 
Dispense Study Drug 
 
X 
 
 
 
 
 
 
Phone call for evaluation of 
Pramipexole ER (or placebo) 
dose 
 
 
 
X**** 
 
 
 
 
Vital 
Signs/Height/Weight***** 
X 
X 
 
 
X 
X 
X 
X 
On-site evaluation of 
Pramipexole ER (or placebo) 
dose 
 
 
X 
 
X 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
X 
X 
X 
X 
X 
X 
X 
X 
UPDRS Part III 
X 
X 
 
 
X 
X 
X 
 
UPDRS Part II 
 
X 
 
 
X 
X 
X 
 
Columbia Suicide Severity 
Rating Scale (CSSRS) 
X 
X 
X 
 
X 
X 
X 
X 
QUIP-RS 
 
X 
X 
 
X 
X 
X 
X 
PDQ-39 
 
X 
 
 
 
 
X 
 
Epworth Sleepiness Scale 
(ESS) 
 
X 
 
 
X 
X 
X 
 
Clinical Global Impression- 
severity  (CGI-S) 
 
X 
 
 
 
 
X 
 
Clinical Global Impression- 
improvement  (CGI-I) 
 
 
 
 
X 
X 
X 
 
 HRQOL SF-12v2 
 
X 
 
 
 
 
X 
 
 OHSA question 1 ****** 
 
X 
 
 
X 
X 
X 
 
Drug Accountability/ 
Compliance 
 
 
 
 
X 
X 
X 
X 
Collect study drug kit from 
previous month 
 
 
 
 
X 
X 
X 
X 
Trial Completion 
 
 
 
 
 
 
 
X 
 
* Lab tests for renal/hepatic functions for subjects with mild renal and or mild hepatic impairment will be 
performed at visits 4 and 5. 

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** The maximal interval between the screening and baseline visits can be extended to 35 days, however, 
additional Sponsor approval will be required. 35 – 90 days may be approved but a new collection of screening 
laboratory samples will be required to verify eligibility prior to baseline. 
*** Coagulation will also be performed at screening to determine eligibility and at visits 4 and 5 for subjects 
with mild hepatic impairment. 
**** An unscheduled on-site visit may be conducted per PI’s or sub-Investigator’s decision to evaluate the new 
dose and consider the need for further dose increase. 
*****height will be measured only at screening 
****** OHSA question 1 will be completed only by subjects experiencing orthostatic hypotension  

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22.2 Appendix II: Laboratory Tests 
- 
Hematology (will be performed on screening visit, and visit 7 safety follow up visit):  
White Cell and Differential Count, Red Cell Count, Hemoglobin, Hematocrit, Mean Cell 
Volume, Mean Cell Hemoglobin, Mean Cell Hemoglobin Concentration and Platelet 
Count. 
- 
Clinical Chemistry (will be performed on screening and visit 7 safety follow up visit): 
Sodium 
Potassium 
Chloride 
Glucose 
BUN 
Creatinine 
Calcium 
Phosphate 
Bilirubin 
Alkaline Phosphatase 
Gamma glutamyl transpeptidase (Gamma GT) 
Aspartate transaminase (SGOT; AST) 
Alanine transaminase (SGPT; ALT) 
Total protein 
Albumin 
Cholesterol  
- 
Urinalysis (will be performed on screening, and safety follow up visit): pH, Protein, 
Glucose, Ketones, Urine microscopic: White Blood Cell Count, Red Blood Cell Count, 
Casts. 
- 
Coagulation (will be performed at screening to determine eligibility and at visits 4 and 5 
for subjects with mild hepatic impairment to determine compliance with exclusion 
criteria): PT/INR – prothrombin time and ratio as well as aPTT. 
 
Additional renal / hepatic functions tests will be performed at visits 4 and 5 for subjects with 
mild renal and or mild hepatic impairment, respectively. 
  
Serum pregnancy test at screening and  safety visit . Urine pregnancy test at baseline visit.   
(Minimum sensitivity 25 IU/L or equivalent units of β-HCG). 
 
 

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22.3 Appendix III: The Epworth Sleepiness Scale (ESS) 
 
How likely are you to doze off or fall asleep in the situations described below, in contrast to 
feeling just tired? 
This refers to your usual way of life in recent times. 
Even if you haven't done some of these things recently try to work out how they would have 
affected you. 
Use the following scale to choose the most appropriate number for each situation:- 
 
0 = would never doze 
1 = Slight chance of dozing 
2 = Moderate chance of dozing 
3 = High chance of dozing 
 
Situation Chance of dozing 
Sitting and reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
Watching TV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
Sitting, inactive in a public place (e.g. a theatre or a meeting) . . . . . . . 
As a passenger in a car for an hour without a break . . . . . . . . . . . . . . . 
Lying down to rest in the afternoon when circumstances permit . . . . . 
Sitting and talking to someone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
Sitting quietly after a lunch without alcohol . . . . . . . . . . . . . . . . . . . . . . 
In a car, while stopped for a few minutes in the traffic . . . . . . . . . . . . . 
 
 
 
 
 
 
 
 
 

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22.4 Appendix IV: Clinical Global Impression - Severity 
The Clinical Global Impression – Severity scale (CGI-S) is a 7-point scale that requires the 
clinician to rate the severity of the patient’s illness (Parkinson’s Disease) at the time of 
assessment relative to the clinician’s past experience with patients who have the same diagnosis 
as one of the following:  
 
0 = not assessed 
1 = normal; 
2 = borderline ill 
3 = mildly ill 
4 = moderately ill 
5 = markedly ill 
6 = severely ill 
7 = among the most extremely ill patients 
 
 

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22.5 Appendix V: OHAS question 1 (Kaufmann H, 2012) 
 
Question 1:  “Dizziness, lightheadedness, feeling faint or feeling as though you might pass out"” 
 
Please circle the number on the scale (where 0 = None and 10 = Worst Possible) that best rates 
how severe your symptoms from low blood pressure have been on average over the past week. 
If you have not experienced the symptom, circle zero (0). PLEASE RATE THE SYMPTOMS 
THAT ARE DUE ONLY TO YOUR LOW BLOOD PRESSURE PROBLEM. 
 
 
 
 

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22.6 Appendix VI: Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s disease rating Scale (QUIP-RS) 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP-RS version).  
The questionnaire should be completed according to the past 4 weeks. 
 
 1. How much do you think about the following behaviors (such as having trouble keeping thoughts out of 
your mind or feeling guilty)?  
Gambling? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Sex? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Buying? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Eating? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Performing tasks or hobbies? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Repeating simple activities? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Taking your PD medications? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very 
often(4)  
2. Do you have urges or desires for the following behaviors that you feel are excessive or cause you 
distress (including becoming restless or irritable when unable to participate in them)?  
Gambling? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Sex? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Buying? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Eating? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Performing tasks or hobbies? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Repeating simple activities? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Taking your PD medications? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very 
often(4)  
3. Do you have difficulty controlling the following behaviors (such as increasing them over time, or 
having trouble cutting down or stopping them)?  
Gambling? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Sex? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Buying? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Eating? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Performing tasks or hobbies? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Repeating simple activities? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Taking your PD medications? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very 
often(4)  
4. Do you engage in activities specifically to continue the following behaviors (such as hiding what you 
are doing, lying, hoarding things, borrowing from others, accumulating debt, stealing, or being involved 
in illegal acts)?  
Gambling? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Sex? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Buying? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  

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Eating? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Performing tasks or hobbies? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Repeating simple activities? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very often(4)  
Taking your PD medications? ___Never(0) ___Rarely(1) ___Sometimes(2) ___Often(3) ___Very 
often(4) 
 
 
 

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22.7 Appendix VII: Health-Related Quality of Life (HRQOL) SF-12v2 
 
 
 
 

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22.8 Appendix VIII: Columbia Suicide Severity Rating Scale (CSSRS) 
 
 

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22.9 Appendix IX: UPDRS  (Fahn S, 1987) 
The Unified Parkinson's Disease Rating Scale (UPDRS) is divided into five parts. In this study 
only parts II and III will be performed and their scores will be summarize (maximum sum of 
160) .  Part II, Activities of Daily Living (ADL) (for both "on" and "off") (questions 5-17) is also 
historical information.  Part III (questions 18-31) is done as a motor examination at the time of a 
visit as defined in this protocol.   
The various items to be rated are scored using a 5-point system (i.e., 0 is normal and 4 indicates 
a severe abnormality). 
      
 
 
Part II: Activities of Daily Living (Score 0-4) 
 5)   Speech 
     0 - Normal 
     1 - Mildly affected.  No difficulty being understood. 
     2 - Moderately affected.  Sometimes asked to repeat statements. 
     3 - Severely affected.  Frequently asked to repeat statements. 
     4 - Unintelligible most of the time 
 
6)   Salivation 
     0 - Normal 
     1 - Slight but definite excess of saliva in mouth; may have nighttime  
drooling 
     2 - Moderately excessive of saliva; may have minimal drooling 
     3 - Marked excess of saliva with some drooling 
     4 - Marked drooling, requires constant tissue or handkerchief 
 
7)   Swallowing 
     0 - Normal 
     1 - Rare choking 
     2 - Occasional choking 
     3 - Requires soft food 
     4 - Requires nasogastric tube or gastrotomy feeding 
 
8)   Handwriting 
     0 - Normal 
     1 - Slightly slow or small 
     2 - Moderately slow or small; all words are legible 
     3 - Severely affected; not all words are legible 

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     4 - The majority of words are not legible 
 
9)   Cutting Food, Handling Utensils 
     0 - Normal 
     1 - Somewhat slow, but no help needed 
     2 - Can cut most foods, although clumsy and slow; some help needed 
     3 - Food must be cut by someone, but can still feed slowly 
     4 - Needs to be fed 
 
10)  Dressing 
0 - Normal 
1 - Somewhat slow, but no help needed 
2 - Occasional assistance with buttoning, getting arms in sleeves 
3 - Considerable help required, but can do some things alone 
4 – Helpless 
 
11)  Hygiene 
0 - Normal 
1 - Somewhat slow, but no help needed 
2 - Needs help to shower or bathe, or very slow in hygienic care 
3 - Requires assistance for washing, brushing teeth, combing hair, going  to bathroom 
4 - Foley catheter or other mechanical aids 
 
12)  Turning In Bed And Adjusting Bed Clothes 
 0 - Normal 
 1 - Somewhat slow and clumsy, but no help needed 
 2 - Can turn alone or adjust sheets, but with great difficulty 
 3 - Can initiate, but not turn or adjust sheets alone 
 4 – Helpless 
 
13) Falling (Unrelated To Freezing) 
0 - None 
1 - Rare falling 
2 - Occasionally falls, less than once per day 
3 - Falls an average of once daily 
4 - Falls more than once daily 
 
14) Freezing When Walking 
0 - None 

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1 - Rare freezing when walking; may have start-hesitation        
2 - Occasional freezing when walking  
3 - Frequent freezing.  Occasionally falls from freezing 
4 - Frequent falls from freezing 
 
15)  Walking 
  0 - Normal 
  1 -Mild difficulty.  May not swing arms or may tend to drag leg 
  2 - Moderate difficulty, but requires little or no assistance 
  3 - Severe disturbance of walking, requiring assistance 
  4 - Cannot walk at all, even with assistance 
 
16)  Tremor 
   0 - Absent 
   1 - Slight and infrequently present 
   2 - Moderate; bothersome to patient 
   3 - Severe; interferes with many activities 
   4 - Marked; interferes with most activities. 
 
17)  Sensory Complaints Related To Parkinsonism 
  0 - None 
  1 - Occasionally has numbness, tingling or mild aching 
  2 - Frequently has numbness, tingling or aching; not distressing 
  3 - Frequent painful sensations 
  4 - Excruciating pain 
 
PART III: Motor Examination (score 0-4) 
18)  Speech 
   0 - Normal 
   1 - Slight loss of expression, diction and/or volume 
   2 - Monotone, slurred but understandable; moderately impaired 
   3 - Marked impairment, difficult to understand -  
   4 – Unintelligible 
 
19)  Facial Expression 
     0 - Normal 
     1 - Minimal hypomania, could be normal “Poker Face” 
     2 - Slight but definitely abnormal diminution of facial expression 
     3 - Moderate hypomania; lips parted some of the time 

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     4 - Masked or fixed faces with severe or complete loss of facial expression ; lips parted 1/4     
inch or more 
 
20)  Tremor at Rest 
Face, lips and chin 
     0 - Absent 
     1 - Slight and infrequently present 
     2 - Mild in amplitude and persistent; or moderate in amplitude, but only intermittently  
present 
     3 - Moderate in amplitude and present most of the time 
     4 - Marked in amplitude and present most of the time 
 
Right hand 
     0 - Absent 
     1 - Slight and infrequently present 
     2 - Mild in amplitude and persistent; or moderate in amplitude, but only intermittently  
present 
     3 - Moderate in amplitude and present most of the time 
     4 - Marked in amplitude and present most of the time 
 
Left hand 
     0 - Absent 
     1 - Slight and infrequently present 
     2 - Mild in amplitude and persistent; or moderate in amplitude, but only intermittently  
present 
     3 - Moderate in amplitude and present most of the time 
     4 - Marked in amplitude and present most of the time 
 
Right foot 
     0 - Absent 
     1 - Slight and infrequently present 
     2 - Mild in amplitude and persistent; or moderate in amplitude, but only intermittently  
present 
     3 - Moderate in amplitude and present most of the time 
     4 - Marked in amplitude and present most of the time 
 
Left foot 
     0 - Absent 
     1 - Slight and infrequently present 

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     2 - Mild in amplitude and persistent; or moderate in amplitude, but only intermittently  
present 
     3 - Moderate in amplitude and present most of the time 
     4 - Marked in amplitude and present most of the time 
 
21)  Action or Postural Tremor Of Hands 
Right 
     0 - Absent 
     1 - Slight; present with action 
     2 - Moderate in amplitude, present with action 
     3 - Moderate in amplitude with posture holding as well as action 
     4 - Marked in amplitude; interfere with feeding 
Left 
     0 - Absent 
     1 - Slight; present with action 
     2 - Moderate in amplitude, present with action 
     3 - Moderate in amplitude with posture holding as well as action 
     4 - Marked in amplitude; interfere with feeding 
 
22) RIGIDITY (Judged on Passive Movement of Major Joints with Subject Relaxed In  
 
 
 
sitting position. Cogwheeling to be ignored) 
    Neck   
      0 - Absent 
      1 - Slight or detectable only when activated by mirror or other movements 
      2 - Mild or moderate 
      3 - Marked, but full range of motion easily achieved 
      4 - Severe, range of motion achieved with difficulty    
     Right Upper Extremities 
      0 - Absent 
      1 - Slight or detectable only when activated by mirror or other movements 
      2 - Mild or moderate 
      3 - Marked, but full range of motion easily achieved 
      4 - Severe, range of motion achieved with difficulty    
 
      Left Upper Extremities 
      0 - Absent 
      1 - Slight or detectable only when activated by mirror or other movements 
      2 - Mild or moderate 
      3 - Marked, but full range of motion easily achieved 

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      4 - Severe, range of motion achieved with difficulty    
 
    Right Lower Extremities 
      0 - Absent 
      1 - Slight or detectable only when activated by mirror or other movements 
      2 - Mild or moderate 
      3 - Marked, but full range of motion easily achieved 
      4 - Severe, range of motion achieved with difficulty    
 
    Left Lower Extremities 
      0 - Absent 
      1 - Slight or detectable only when activated by mirror or other movements 
      2 - Mild or moderate 
      3 - Marked, but full range of motion easily achieved 
      4 - Severe, range of motion achieved with difficulty    
 
23) Finger Taps (Subject taps thumb with index finger in rapid succession  
with widest amplitude possible, each hand separately) 
Right hand 
0 - Normal  15/5 sec) 
1 - Mild slowing and/or reduction in amplitude (11-14.5 sec) 
2 - Moderately impaired.  Definite and early fatiguing. May have occasional arrests in movement 
(7-10/5 sec) 
3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement (3-6/5 sec) 
4 - Can barely perform the task (0-2/5 sec) 
 
Left hand 
0 - Normal  15/5 sec) 
1 - Mild slowing and/or reduction in amplitude (11-14.5 sec) 
2 - Moderately impaired.  Definite and early fatiguing. May have occasional arrests in movement 
(7-10/5 sec) 
3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement (3-6/5 sec) 
4 - Can barely perform the task (0-2/5 sec) 
 
24)  Hand Movement (Subject opens and closes hands in rapid succession with widest amplitude   
possible, each hand separately) 

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Right 
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2 - Moderately impaired. Definite and early fatiguing.  May have occasional arrests in 
movements 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
 
Left 
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2 - Moderately impaired. Definite and early fatiguing.  May have occasional arrests in 
movements 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
 
25)  Rapid Alternating Movements Of Hands (Pronation, supination  
movements of hands, 
vertically or horizontally with as large an amplitude as possible, both hands simultaneously) 
 Right 
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2 - Moderately impaired.  Definite and early fatiguing. May have occasional arrests in 
movement 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
Left 
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2 - Moderately impaired.  Definite and early fatiguing. May have occasional arrests in 
movement 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
 
26)  Leg Agility (Subject taps heel on ground in rapid succession, picking up entire  
 
 
leg. Amplitude should be about 3 inches) 

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Right      
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2  - Moderately   impaired. Definite and early fatiguing. May have occasional arrest in 
movement 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
Left 
     0 - Normal 
     1 - Mild slowing and/or reduction in amplitude 
     2  - Moderately   impaired. Definite and early fatiguing. May have occasional arrest in 
movement 
     3 - Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing 
movement 
     4 - Can barely perform the task 
 
27)  Arising From Chair (Subject attempts to arise from a straight-back wood or metal chair with 
arms folded across chest) 
     0 - Normal 
     1 - Slow, or may need more than one attempt 
     2 - Pushes self up from arms of seat 
     3 - Tends to fall back and may have to try more than one time, but can get up without help 
     4 - Unable to arise without help 
 
28)  Posture 
     0 - Normal erect 
     1 - Not quite erect, slightly stooped posture; could be normal for older person 
     2 - Moderately stooped posture, definitely abnormal, can be slightly leaning  
 
 
    to one side 
     3 - Severely stooped posture with kyphosis; can be moderately leaning to one side 
     4 - Marked flexion with extreme abnormality of posture 
 
29)  Gait 
     0 - Normal 
     1 - Walks slowly, may shuffle with short steps, but no festination or propulsion 
     2 - Walks with difficulty, but requires little or no assistance; may have some festination, short 
steps, or propulsion 
     3 - Severe disturbance, of gait requiring assistance 

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     4 - Cannot walk at all, even with assistance 
 
30)  Postural Stability (Response to sudden posterior displacement 
     0 - Normal 
     1 - Retropulsion, but recovers unaided 
     2 - Absence of postural response; would fall if not caught by examiner  
     3 - Very unstable, tends to lose balance spontaneously 
     4 - Unable to stand without assistance 
 
31)  Body Bradykinesia And HypokinesIA (Combining slowness, hesitancy, decreased arm 
swing, small amplitudes and poverty of movement in general) 
     0 - None 
     1 - Minimal slowness, giving movement a deliberate character; could be normal for some 
person. Possibly reduced amplitude. 
     2 - Mild degree of slowness and poverty of movement which is definitely abnormal.  
Alternatively, some reduced amplitude. 
     3 - Moderate slowness, poverty or small amplitude of movement 
     4 - Marked slowness, poverty or small amplitude of movement 
 
 
 
 

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22.10 
Appendix X: Quality of Life - PDQ39 
Please tick one box for each question.  
Due to having Parkinson’s disease, how often (never, occasionally, sometimes, often, always) 
during the last month have you:  
1. Had difficulty doing the leisure activities which you would like to do? 
2. Had difficulty looking after your home, e.g. DIY, house work, cooking? 
3. Had difficulty carrying bags of shopping? 
4. Had problems walking half a mile? 
5. Had problems walking 100yards? 
6. Had problems getting around the house as easily as you would like? 
7. Had difficulty getting around in public? 
8. Needed someone else to accompany you when you went out? 
9. Felt frightened or worried about falling over in public? 
10. Been confined to the house more than you would like? 
11. Had difficulty washing yourself? 
12. Had difficulty dressing yourself? 
13. Had problems doing up your shoe laces? 
14. Had problems writing clearly? 
15. Had difficulty cutting up your food? 
16. Had difficulty holding a drink without spilling it? 
17. Felt depressed? 
18. Felt isolated and lonely? 
19. Felt weepy or tearful? 
20. Felt angry or bitter? 
21. Felt anxious? 
22. Felt worried about your future? 
23. Felt you had to conceal your Parkinson's from people? 
24. Avoided situations which involve eating or drinking in public? 
25. Felt embarrassed in public due to having Parkinson's disease? 
26. Felt worried by other people's reaction to you? 
27. Had problems with your close personal relationships? 
28. Lacked support in the ways you need from your spouse or partner? (If you do not have a 
spouse or partner please mention) 
29. Lacked support in the ways you need from your family or close friends? 
30. Unexpectedly fallen asleep during the day? 
31. Had problems with your concentration, e.g. when reading or watching TV? 
32. Felt your memory was bad? 
33. Had distressing dreams or hallucinations? 

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34. Had difficulty with your speech? 
35. Felt unable to communicate with people properly? 
36. Felt ignored by people? 
37. Had painful muscle cramps or spasms? 
38. Had aches and pains in your joints or body? 
39. Felt unpleasantly hot or cold? 
 
 
 

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22.11 
Appendix XI : UK Parkinson's Disease Society Brain Bank Clinical 
Diagnostic Criteria (Hughes AJ, 1992) 
Step 1: Diagnosis of Parkinsonian Syndrome  
•  Bradykinesia  
•  At least one of the following  
Muscular rigidity  
4-6 Hz rest tremor  
postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction  
Step 2: Exclude other cause of Parkinson's 
•  history of repeated strokes with stepwise progression of parkinsonian features  
•  history of repeated head injury  
•  history of definite encephalitis  
•  oculogyric crises  
•  neuroleptic treatment at onset of symptoms  
•  more than one affected relative  
•  sustained remission  
•  strictly unilateral features after 3 years  
•  supranuclear gaze palsy  
•  cerebellar signs  
•  early severe autonomic involvement  
•  early severe dementia with disturbances of memory, language, and praxis  
•  Babinski sign  
•  presence of cerebral tumor or communication hydrocephalus on imaging study  
•  negative response to large doses of levodopa in absence of malabsorption  
•  MPTP exposure  
Step 3:  Supportive prospective positive criteria for Parkinson’s disease  
Three or more required for diagnosis of definite Parkinson’s disease in combination with step one  
•  Unilateral onset  
•  Rest tremor present  
•  Progressive disorder  
•  Persistent asymmetry affecting side of onset most  
•  Excellent response (70-100%) to levodopa  
•  Severe levodopa-induced chorea  
•  Levodopa response for 5 years or more  
•  Clinical course of ten years or more 
*From: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic  
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55:181-184. 
22.12 
Appendix XII: Modified Hoehn & Yahr scale 

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The H&Y scale is a commonly used system for describing how the symptoms of Parkinson's 
disease progress. It was originally published in 1967 in the journal Neurology by Melvin Yahr 
and Margaret Hoehn. The original scale included stages 1 through 5. Since then, stage 0 has been 
added, and stages 1.5 and 2.5 have been proposed. This modified scale allocates stages from 0 to 
5 to indicate the relative level of disability. 
Stage 0: No signs of disease. 
Stage 1: Unilateral symptoms only. 
Stage 1.5: Unilateral and axial involvement. 
Stage 2: Bilateral symptoms. No impairment of balance. 
Stage 2.5: Mild bilateral disease with recovery on pull test. 
Stage 3: Balance impairment. Mild to moderate disease. Physically independent. 
Stage 4: Severe disability, but still able to walk or stand unassisted. 
Stage 5: Needing a wheelchair or bedridden unless assisted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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22.13 
Appendix XIII: Mini-Mental State Examination (MMSE) 
Instructions: Score one point for each correct response within each question or activity.  
Questions 
Orientation to Time 
1. “What is the year?  Season?  Date?  Day?  Month?” 5 points 
Orientation to Place 
2.  “Where are we now?  State?  County?  Town/city?  Hospital?  Floor?” 5 points 
Registration 
3. Name 3 common objects (APPLE, TABLE and PENNY): Take 1 second to say each. Then 
ask the patient to repeat them after you have said them. Give 1 point for each correct answer. 
Then repeat them until he/she learns all three. 3 points 
Attention and Calculation 
4. “Spell WORLD backwards.” (D-L-R-O-W) 5 points. 
Recall 
5.“Earlier I told you the names of three things.  Can you tell me what those were?” 3 points 
Naming 
6. Show the patient two simple objects, such as a wrist watch and a pencil, and ask the patient to 
name them. 2 point. 
Repetition 
7. “Repeat the phrase: ‘No ifs, ands, or buts.’” 1 point 
Comprehension 
8. “Take the paper in your right hand, fold it in half, and put it on the floor.” (The examiner gives 
the patient a piece of blank paper) 3 points 
Reading 
9. “Please read this and do what it says.” (Written instruction is “Close your eyes.”) 1 point. 
Writing 
10. “Make up and write a sentence about anything.” (This sentence must contain a noun and a 
verb.) 1 point. 
Copying 
11. “Please copy this picture.”  (The examiner gives the patient a blank piece of paper and asks 
him/her to draw the symbol below.  All 10 angles must be present and two must intersect.) 1 
point. 
30 points  total. 
Sources:   
• Folstein MF, Folstein SE, McHugh PR. "Mini-mental state": a practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.  
 
 

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22.14 
Appendix XIV: Clinical Global Impression - Improvement 
 
The Clinical Global Impression =improvement (CGI-I) is a 7-point scale that requires the 
clinician to compares the patient's overall clinical condition after medication has been initiated to 
the one week period just prior to the initiation of medication use (baseline visit) as one of the 
following: 
  
1=very much improved since the initiation of treatment 
2=much improved  
3=minimally improved 
4=no change from baseline (the initiation of treatment)  
5=minimally worse  
6= much worse  
7=very much worse since the initiation of treatment 
 
 

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