Clinical trial NCT03329508
Conditions: Parkinson Disease Early Parkinson's Disease
Keywords: Parkinson disease early Parkinson's Disease Parkinson's diagnosis Parkinson's tretment Parkinson's medications
Sponsor: Pharma Two B Ltd.
Start date: 2018-01-19; Completion date: 2021-10-31
Enrollment: 544 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
P2B001 is an investigational drug that comprised of low doses of two drugs, pramipexole and rasagiline, which are both approved drugs and routinely used in standard therapy for Parkinson's disease. The two drugs work in two different mechanisms that help each other, so there is a reason to believe that their combined activity will be better than each individual drug, and that lower doses can be used without losing the therapeutic effect. Thus, the development of P2B001 is intended to provide a combination of low doses of these two drugs, in an improved formulation, that is hoped to be more effective in controlling Parkinson's disease symptoms and with less side effects than each of the drugs taken alone or the current available commercial drugs taken together. In a previously completed clinical trial a significant improvement in Parkinson's disease symptoms was seen in patients treated with P2B001 compared to patients that were treated with placebo.

In this phase 3 study , the safety and efficacy of P2B001 will be assessed by comparing P2B001 to its individual components pramipexole and rasagiline. This will be done by monitoring the motor and non-motor symptoms, evaluating responses participants provide on questionnaires relating to Parkinson's disease and quality of life that will be completed on every visit. In addition, this study will also compare P2B001 to a marketed drug of pramipexole ER. Approximately 525 patients will participate in this research study and the participation in this study will last between 14 to 18 weeks.

Detailed description:
A total of 525 eligible subjects with early untreated Parkinson's disease (PD), will be randomized to 4 treatment groups. Each subject will participate in the study for approximately 18 weeks including a 30 day screening period, 12 week treatment period, and 2 weeks follow-up period. Subjects will be requested to take one capsule and 1-3 tablets of study drug by mouth with a glass of water every day for 13 weeks. The study requires seven visits to the clinic one every 2-4 weeks.

Arms: arm 1: Fixed dose combination once daily capsule of pramipexole 0.6mg and rasagiline 0.75mg, + matching placebo tablet arm 2: Rasagiline 0.75mg Once daily capsule, component of P2B001, + matching placebo tablet arm 3: Pramipexole 0.6mg once daily capsule, component of P2B001 + matching placebo tablet arm 4: Marketed pramipexole ER tablet titrated to optimal dose of 1.5, 3.0 or 4.5mg + matching placebo capsule
Interventions: intervention 1: P2B001 0.6/0.75 mg intervention 2: Rasagiline 0.75 mg intervention 3: Pramipexole 0.6 mg intervention 4: Marketed Pramipexole ER
Intervention descriptions: intervention 1: Fixed low dose extended release combination capsule of pramipexole and rasagiline intervention 2: Rasagiline 0.75 mg oral extended release capsule, component intervention 3: Pramipexole 0.6 mg oral extended release capsule, component intervention 4: Marketed Pramipexole ER titrated to optimal dose of 1.5, 3 or 4.5 mg tablet

Protocol documents:
SAP_002.pdf: 
Addendum to Statistical Analysis Plan Dated 21October2021               
 
           
NCT03329508
P2B001/003 
Protocol 
2
of 
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ADDENDUM TO STATISTICAL ANALYSIS 
PLAN (SAP) 
 
Protocol 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 Date: 
October 7, 2020, Version 3.0 
 
 
SAP Date: 
October 21, 2021, Version 2.0 
 
 
Addendum Date: 
November 11, 2021 
 
   
 


Addendum to Statistical Analysis Plan Dated 21October2021               
 
           
NCT03329508
P2B001/003 
Protocol 
2
of 
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Page 
 
 
 
This addendum to Statistical Analysis Plan (SAP Version 2.0) dated October 21, 2021 was written and 
approved prior to study unblinding. Furthermore, all personnel approving this SAP are currently fully 
blinded to the randomization scheme. 
The SAP currently defines the modified Intent-to-Treat (mITT) Analysis Set in section 8.2 as follows: 
“The mITT Analysis Set is a subset of the ITT Analysis Set and includes subjects who were randomized, 
have taken at least one dose of study drug, and have at least one post-Baseline UPDRS (UPDRS II+III) 
measurement score at the planned scheduled visits. The mITT Analysis Set will use treatment 
according to the group to which subjects were originally randomized to. The mITT Analysis Set will 
serve as the principal analysis set for efficacy assessments.”  
Addendum topics: 
1. Based on review of blinded data, the above definition of the mITT Analysis Set would exclude a 
total of 13 randomized subjects that took at least one dose of study drug but early terminated the 
treatment/study (ETT/EST) prior to the first planned scheduled post baseline visit (End of Week 
5 visit) and therefore have no scheduled post baseline UPDRS (UPDRS II+III) measurements at 
all. However, in line with protocol guidelines, a post-treatment UPDRS (UPDRS II+III) was 
collected at the unscheduled ETT/EST visit.  
2. Consistent with the intent-to-treat principle, these 13 subjects should be included in the mITT 
population, since they were randomized, took at least one dose of study drug, and completed at 
least one post-treatment efficacy assessment, even though it occurred at an unscheduled, rather 
than a scheduled visit. Therefore, in order to be as thorough and complete as possible, we will 
interpret the early termination visit for these specific subjects as a scheduled visit in order to 
include these patients in the primary MMRM analysis. 
3. The data collected from these 13 subjects at the earlier of ETT/EST visit will be mapped to End 
of week 5 visit. 
4. In order to explore the impact of this modification, an additional sensitivity analysis will be 
conducted, repeating the principal analysis of the primary endpoint while excluding these 13 
patients. 
5. One subject with no baseline UPDRS (UPDRS II+III) measurement will be excluded from the 
mITT Analysis Set as the endpoint, change of total UPDRS score (defined as sum of parts II and 
III, scores (0-160) cannot be calculated. 
 
 
 
 

ICF_003.pdf: 
 
 
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INFORMED CONSENT  
 
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 NO.:  
P2B001/003 
 
SPONSOR:  
 
Pharma Two B 
 
INVESTIGATOR: 
 
SITE ADDRESS: 
 
 
 
24 HR. TELEPHONE #: 
 
 
 
INTRODUCTION 
Before agreeing to participate in this research study, it is important that you read and 
understand the following explanation of the proposed research study.  This consent 
document describes the purpose, procedures, benefits, risks, discomforts and 
precautions of the study.  It also describes the alternative procedures that are available 
to you and your right to withdraw from the study at any time.  No guarantees or 
assurances can be made as to the results of the study. It is up to you to decide if you 
wish to participate. Your study doctor or member of the study staff will go through this 
Information Sheet with you and answer any questions you might have. Ask the study 
doctor or member of the study staff if there is anything you do not understand. Talk to 
others about the study if you wish. Once you understand the study, and if you agree to 
take part, you will be asked to sign the Consent Form.  You will be given a copy to keep. 
You are free to withdraw at any time, without giving a reason. This would not affect the 
standard of care you receive. 
 
If you are not completely truthful with your Investigator regarding your health history, 
you may harm yourself by participating in this study. 
 
This study is being organized by a pharmaceutical company, Pharma Two B, located at 
3 Pekeris St., Weizmann Science Park Rehovot 7670203 Israel. 
 
BACKGROUND AND PURPOSE  
 
You are being asked to participate in this research study because you have early 
Parkinson’s disease (PD). This is a research study to test a new investigational drug 


 
 
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(P2B001).  An investigational drug is one that is not approved by the United States 
Food and Drug Administration (FDA).    
 
The purpose of this research study is to:  
• test the safety and effectiveness of the study drug, P2B001, in treating patients 
with early Parkinson’s disease 
 
P2B001 is comprised of low doses of two drugs, pramipexole and rasagiline, which are 
both approved drugs in the United States and routinely used in standard therapy for 
Parkinson’s disease. The two drugs work in two different mechanisms that help each 
other, so there is a reason to believe that their combined activity will be better than each 
individual drug, and that lower doses can be used without losing the therapeutic effect. 
Thus, the development of P2B001 is intended to provide a combination of low doses of 
these two drugs, in an improved formulation, that is hoped to be more effective in 
controlling Parkinson's disease symptoms and with less side effects than each of the 
drugs taken alone or the current available commercial drugs taken together.  
 
The safety and efficacy of P2B001 will be assessed by comparing P2B001 to its 
individual components; pramipexole and rasagiline. This will be done by evaluating the 
responses participants provide on questionnaires relating to Parkinson’s disease and 
quality of life that will be completed on every visit. In addition, this study will also 
compare P2B001 to another FDA approved extended-release version of pramipexole.  
 
Because this is a research study, the study product will be given to you only during this 
study and not after the study is over.  
 
NUMBER OF SUBJECTS / LENGTH OF PARTICIPATION  
 
About 525 subjects will participate in this study.  Your participation in this study will last 
approximately 14 to 18 weeks and include 7 study visits to the study center.   
 
PROCEDURES  
 
Before any study-related tests and procedures are performed, you will be asked to read 
and sign this consent document.  The following tests and procedures will be performed 
to determine if you qualify to take part in this study:   
Visit 1 Screening – performed up to 28 days before Visit 2 (Baseline) 
• Interview regarding your Medical History and Personal Information (name, date of 
birth, gender, race/ethnicity, etc.) 
• Complete Physical and Neurological Examination 
• Laboratory blood and urine tests (including a pregnancy test if you are a woman 
of child-bearing potential). The study doctor or study staff will tell you if the 
pregnancy test results are positive.  The results of the pregnancy testing must be 
negative in order for you to be in the study. 


 
 
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• Electrocardiogram (ECG) to evaluate heart function 
• Completion of questionnaires relating to your disease and symptoms and your 
mental health (including thoughts of suicide) 
• Vital Signs (blood pressure, pulse, respiration, body temperature, height and 
weight) 
• Review of symptoms and medications taken 
After completion of all the testing for the assessment of eligibility, it will be decided by the 
study doctor whether you are eligible for the study. 
If your study doctor decides you are eligible for the study, you will be randomly assigned 
by chance (like the flip of a coin) to receive either P2B001, Rasagiline, Pramipexole or 
extended-release Pramipexole.  You will have a 2 in 7 chance of being assigned to one 
of the three first groups and 1 in 7 chance of being assigned to the fourth group: 
• Group 1 : P2B001 (Pramipexole dihydrochloride 0.6 mg/Rasagiline 0.75 mg) once 
daily + Placebo of extended-release Pramipexole 
• Group 2 : Pramipexole dihydrochloride 0.6 mg once daily + Placebo of extended-
release Pramipexole 
• Group 3: Rasagiline 0.75 mg once daily + Placebo of extended-release 
Pramipexole 
• Group 4: extended-release Pramipexole individually titrated to optimal dose (1.5 - 
4.5 mg / day) + Placebo of P2B001 
This is a double-blind study, which means neither you nor the Investigator will know to 
which of these study drug groups you are assigned.  In case of an emergency, however, 
the Investigator can get this information. In order to ensure that no one knows which of 
the 4 groups you have been assigned to you will be asked to take one capsule and one 
to three tablets once daily. The capsule will contain either P2B001 0.6/0.75 mg, 
pramipexole 0.6 mg, rasagiline 0.75 mg or matching placebo. The tablet(s) will contain 
either extended release Pramipexole or matching placebo. If you are assigned to groups 
1, 2 or 3, you will take the assigned capsule together with placebo tablets of extended-
release Pramipexole. If you are assigned to group 4, you will take extended-release 
Pramipexole tablet(s) with one placebo capsule. 
Visit 2 – Baseline – performed within the 4 weeks after Visit 1 (Screening) 
• Randomization to study drug dosing group (as described above) 
• Electrocardiogram (ECG)  
• Receive study drug as well as dosing instructions and emergency contact cards 
• Completion of questionnaires relating to your disease, symptoms and mental 
health 
• Vital Signs (Heart rate, blood pressure and respiration and weight) 
• Review of symptoms and medications taken 
• Urine pregnancy test (for women of child-bearing potential) 
Visit 3 – Week 3 (± 2 days) 


 
 
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At the end of week 3 ± 2 days, you will be required to visit the clinic so that the study 
doctor can evaluate how you tolerate the study drugs, at this time you will be taking the 
1.5 mg dose of pramipexole ER (or matching placebo tablets). After this evaluation, the 
study doctor may decide to keep your dose of this medication at 1.5 mg or increase it to 
3.0 mg depending on how you tolerate the study drugs and how they are affecting your 
Parkinson’s symptoms. If you are unable to tolerate a dose of least 1.5 mg of Pramipexole 
ER (or placebo) per day you will be asked to stop taking all study medications. 
The following activities will be performed: 
• Evaluation of Pramipexole ER (or matching placebo tablets ) dose 
• Review of symptoms and medications taken 
• Completion of questionnaires relating to your disease, symptoms and mental 
health 
Phone Call - Week 4 (± 2 days)     
At the end of week 4, you will receive a phone call from the study doctor so that the study 
doctor can again evaluate how you tolerate the study drugs and how they are affecting 
your Parkinson’s symptoms. At this time you may be taking 1.5 mg or 3.0 mg of 
pramipexole ER (or matching placebo tablets). After this evaluation, the study doctor may 
decide to keep your dose of this medication unchanged or the study doctor may decide 
to increase or decrease your dose of this medication if you need it.  During this phone call 
a review of symptoms and medications taken will also be done. If the study doctor deems 
it necessary, you may be asked to visit the clinic so that the study doctor can perform 
these evaluations in person.  
Visit 4 – Week 5 (± 2 days) 
At the end of week 5 (± 2 days) you will be required to visit the clinic so that the study 
doctor can evaluate how you tolerate the study drugs. At this time you may be taking 1.5 
mg or 3.0 mg or 4.5 mg of Pramipexole ER (or matching placebo tablets). Again, the study 
doctor may adjust your dosage of this medication based on how you tolerate the study 
drugs and how they are affecting your Parkinson’s symptoms. The study doctor can 
continue to evaluate your dosage of Pramipexole ER (or matching placebo tablets) up to 
the end of the following week (Week 6). At that point, you will stay at the same dose of 
this medication through to Week 12. 
The following activities will be performed: 
• Return bottles of study medication of the titration box (opened and unopened 
bottles)  
• Completion of questionnaires relating to your disease, symptoms and mental 
health 
• Vital Signs (Heart rate, blood pressure and respiration and weight) 
• Review of symptoms and medications taken 
• Laboratory test (only in specific cases when required by the study doctor; the study 
doctor will tell you if you need these blood tests) 


 
 
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Visit 5 – Week 8 (± 2 days) 
The following activities will be performed: 
• 
Return bottles of study medication of the first maintenance box (opened and 
unopened bottles) 
• 
Completion of questionnaires relating to your disease, symptoms and mental 
health 
• 
Vital Signs (Heart rate, blood pressure and respiration and weight) 
• 
Review of symptoms and medications taken 
• 
Laboratory test (only in specific cases when required by the study doctor; the 
study doctor will tell you if you need these blood tests) 
Visit 6 – Week 12 (± 2 days) Treatment termination 
The following activities will be performed: 
• 
Return bottles of study medication of the second maintenance box (opened and 
unopened bottles)  
• 
Completion of questionnaires relating to your disease, symptoms and mental 
health 
• 
Vital Signs (Heart rate, blood pressure and respiration and weight) 
• 
Review of symptoms and medications taken 
Visit 7 – Dosing Follow-up – performed 2 weeks after termination visit 
The following activities will be performed: 
• 
Physical and Neurological Examination  
• 
Completion of questionnaires relating to your disease, symptoms and mental 
health 
• 
Vital Signs (Heart rate, blood pressure and respiration and weight) 
• 
Return bottles of study medication of the down titration box (opened and 
unopened bottles)  
• 
Electrocardiogram (ECG) 
• 
Review of symptoms and medications taken 
• 
Laboratory blood and urine tests (including a pregnancy test if you are a woman 
of child-bearing potential). The study doctor or study staff will tell you if the 
pregnancy test results are positive 
Unscheduled Visits 
If needed, your study doctor may request unscheduled visits: 
• Unscheduled visit for titration follow-up: 
During the titration phase (first 6 weeks) an unscheduled visit may be conducted to assess 
the need to raise or lower the dose of extended-release pramipexole or placebo. In 
addition to the dose evaluation, a review of symptoms and medications will also be 
conducted. No other study activities will be performed at this visit unless safety 
considerations arise (see next section).  


 
 
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• Unscheduled visit for other reasons: 
An unscheduled visit may take place at any time during the study (for example new 
Parkinson’s Disease symptoms or any symptom that warrant personal evaluation). The 
following activities will be performed: 
• Vital signs (Heart rate, blood pressure and respiration and weight) 
• Review of symptoms and medications taken  
• Physical and Neurological Examination 
• Completion of any uncompleted questionnaires, as needed 
A summary of the visits and activities that will be performed are in the table below: 
 
 


 
 
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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 
Week 5 
End of 
Week 8 
End of 
Week 12 
End of 
Week 14 
ACTIVITIES 
 
 
 
 
 
 
 
 
Obtain your written informed consent 
X 
 
 
 
 
 
 
 
Determine if you meet the study entry criteria 
X 
X 
 
 
 
 
 
 
Test your  thinking abilities 
X 
 
 
 
 
 
 
 
Obtain your medical history & demographic information 
X 
 
 
 
 
 
 
 
Complete Physical and Neurological examination performed 
X 
 
 
 
 
 
 
 
Physical and Neurological examination performed (only if you have 
symptoms) 
 
 
 
 
 
 
 
X 
Take blood and urine samples for safety laboratory tests (including 
pregnancy test if you are a woman of child bearing potential) 
X 
 
 
 
 
 
 
X 
Urine pregnancy test (if you are a woman of child bearing potential) 
 
X 
 
 
 
 
 
 
Heart Function Test (ECG)  
X 
X 
 
 
 
 
 
X 
Randomization to study drug 
 
X 
 
 
 
 
 
 
Receive study drug and review dosing instructions 
 
X 
 
 
 
 
 
 
Receive dosing instruction cards and emergency contact cards 
 
X 
 
 
 
 
 
 
Obtain  your vital signs/weight 
X 
X 
 
 
X 
X 
X 
X 
Review  medications you are taking 
X 
X 
X 
X 
X 
X 
X 
X 
Review  any  symptoms you may be having 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of your Parkinson’s disease and symptoms 
X 
X 
 
 
X 
X 
X 
 
Complete questionnaires regarding your thoughts and feelings 
including thoughts of suicide 
X 
X 
X 
 
X 
X 
X 
X 
Complete questionnaire regarding any changes in obsessive 
behaviors 
 
X 
X 
 
X 
X 
X 
X 
Complete questionnaires regarding your blood pressure and your 
sleep 
 
 
X 
 
 
X 
X 
X 
 
Complete questionnaires regarding your health, mood and 
Parkinson’s disease symptoms 
 
X 
 
 
 
 
X 
 
Evaluation of how well you are tolerating study drugs 
 
 
X 
X 
X 
 
 
 
Return study drug and review your compliance 
 
 
 
 
X 
X 
X 
X 
Trial Completion 
 
 
 
 
 
 
 
X 


 
 
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STUDY RESTRICTIONS 
 
There are certain medications you cannot take while you are in the study, including 
most medications to treat Parkinson’s disease. The study doctor will review those 
medications with you, and you should let the study team know when any of your 
medications change. 
 
You may not take the following medications during the study: 
• Other investigational drugs (within 30 days before starting study drug) 
• Anti-Parkinson’s Disease drugs such  as:  
o  MAO-B inhibitors (selegiline (Emsam, Eldepryl, Zelapar) or rasagiline 
(Azilect)) (within 3 months before starting study drug); 
o Levodopa or other dopamine agonists (pramipexole (Mirapex), ropinerole 
(Requip), pergolide (Permax), apomorphine (Apokyn), piribedil (Trivastal), 
cabergoline (Dostinex), lisuride (Dopergin), bromocriptine (Cycloset)) 
(within 2 months before starting study drug). 
o Anticholinergic drugs such as benztropine (Cogentin), biperiden 
(Akineton), ethopropazine (Parsitan), orphenadrine hydrochloride, 
(Disipal), procyclidine (Kemadrin) and trihexyphenidyl (Artane) and 
amantadine (within 1 month before starting study drug). 
 
Taking certain other drugs together with P2B001 may increase the chance of serious 
unwanted effects; therefore you may not take the following medications during the 
study: 
• Ciprofloxacin (Cipro) or other CYP1A2 inhibitors 
• Dextromethorphan (Delsym)  cough suppressant 
• Opioid based pain medications such as tramadol (Ultram), methadone, 
meperidine (Demerol) and propoxyphene (Darvon) 
• St. John's Wort or cyclobenzaprine (Flexeril - muscle relaxant) 
• Non selective MAO inhibitors, such as  phenelzine (Nardil), tranylcypromine 
(Parnate) 
• Dopamine antagonists, such as the neuroleptics (phenothiazines (eg. 
prochlorperazine (Compro, Procomp) or promethazine (Promethegan), 
butyrophenones (eg. haloperidol or droperidol), thioxanthenes (eg. thiothixene 
(Navane)) or metoclopramide (Reglan). 
• Marijuana (within 30 days before starting study drug)  
 
You can take peripheral anticholinergic drugs (such as oxybutynin (Ditropan), 
orphenadrine citrate (Norflex), tiotropium bromide (Spiriva) if you are stable on low dose 
for at least 4 weeks prior to study entry, and without (or with minor) effects on your 
thinking abilities; however, once enrolled into the study use of new peripheral 
anticholinergic drugs is not allowed. If you are taking one of these drugs, you will be 
followed very closely for possible side effects related to your thinking abilities. 
 


 
 
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Care should be taken to avoid or minimize use of sympathomimetic medications, 
including nasal, oral and ophthalmic decongestants and cold remedies and sedating 
medication (such as ephedrine, and tetrahydrozoline-ophthalmic (Clarif-Eye, Murine Plus, 
Opti-Clear, Visine)) due to possible hypertensive reactions. 
Care should also be taken when taking sedating medications (e.g. Diphenhydramine, 
(Benadryl, Sominex) Doxylamine Succinate (Unisom) and other first generation 
antihistamines such as clemastine (Tavist), chlorpheniramine (Chlor-Trimeton), and 
brompheniramine (Dimetane)) as these may make you sleepy when combined with the 
study drugs. You should exercise special caution when driving or using machinery since 
the study drugs may cause drowsiness, lack of coordination or decreased reaction time. 
Finally, if you take antidepressant medication such as a selective-serotonin reuptake 
inhibitor (SSRI) like Prozac, Zoloft or Paxil, you will need to pay special attention for signs 
and 
symptoms 
of 
serotonin 
syndrome 
(for 
example, 
headache, 
agitation, hypomania, mental 
confusion, 
sweating,  
hyperthermia 
(high 
body 
temperature),  
hypertension, tachycardia 
(rapid 
heartbeat), nausea, diarrhea, 
myoclonus (muscle  twitching), overactive reflexes (involuntary twitching), tremor, as the 
risk of experiencing this rare syndrome are increased when taking study drug with 
antidepressants.  
Because of possible drug reactions, you cannot enter this study if you are allergic or 
sensitive to pramipexole or rasagiline. Notify your study doctor if you have had allergic 
reactions to components of other drugs. 
Taking certain other drugs (described above) together with study drugs may increase 
the chance of unwanted effects.  The risk will depend on how much of each drug you 
take every day, and on how long you take the drugs together.  If your medical doctor 
directs you to take these drugs together on a regular basis, follow his or her directions 
carefully. 
Alcohol may increase drowsiness or sleepiness that can be caused by taking the study 
drug. You 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 drug.  
You will be requested to take one capsule and 1-3 tablets of study drug by mouth with a 
glass of water.  Study drugs can be taken with or without food. You should try to take 
study drug at about the same time each day. 
You will need to limit yourself from eating certain aged cheeses, like stilton cheese, that 
contain very high amounts of a chemical called tyramine, which can potentially cause a 
hypertensive reaction (a sudden increase in blood pressure) in subjects taking study 
drug. 
 
EXPECTATIONS  
 
If you participate in this study, you will be expected to:  
• Complete all required visits and procedures 
• Bring your study drug with you for accountability 


 
 
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• Take the study drug as prescribed 
• Follow the medication restrictions 
• Report all side effects, changes in your health or the way you feel, and medical 
problems to the study personnel 
• Complete all questionnaires 
• If you miss or forget to answer questions on these questionnaires, study personnel 
may phone you to obtain answers to these questions 
• Inform the study doctor or study staff if you decide to discontinue your participation.  
You will be asked to complete a treatment termination visit and continue with all 
study visits and activities as planned, for follow up, without taking any study 
medication.  
 
RISKS, SIDE EFFECTS AND/OR DISCOMFORTS  
 
Based on previous studies with P2B001 as well as past experience with the doses of 
rasagiline, pramipexole and extended-release pramipexole used in this study, possible 
side effects of the drugs used in this study include the following:   
Common (more than 10% of people) 
• 
Drowsiness 
• 
Nausea 
Uncommon (between 2 to 10% of people) 
• 
Headache  
• 
Constipation  
• 
Fall  
• 
Hallucinations 
• 
Accidental injury  
• 
Vomiting  
• 
Indigestion 
• 
Dry mouth, loss of appetite 
• 
Diarrhea 
• 
Involuntary movements  
• 
Dizziness, spinning 
sensation  
• 
Joint Pain 
• 
Loss of appetite 
• 
Swelling of the limbs 
• 
Depression  
• 
Fatigue 
• 
Weight loss  
• 
Abdominal discomfort / pain 
• 
Flu symptoms  
• 
Loss of balance, 
• 
Loss of coordination 
• 
Skin rash 
• 
Shortness of breath 
• 
Insomnia 
• 
Muscle spasms 
• 
Problems with Impulse Control  
• 
Excessive daytime 
sleepiness 
• 
Compulsive Behaviors 
• 
Decrease in blood 
pressure when standing 
• 
Erectile Dysfunction 
• 
Behavioral/mental status changes 
• 
Stooped Posture 
Rare (between 1 to 2% of people) 


 
 
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• 
Pink Eye 
• 
Cough  
• 
Fever  
• 
Stomach Flu 
• 
Runny Nose 
• 
Tremor  
• 
Skin discolorations 
• 
“Pins and Needles” 
• 
Abnormal dreams  
• 
Back pain  
• 
Involuntary muscle 
contractions 
• 
Increased appetite  
• 
Infection  
• 
Sleep disorder  
• 
Sweating  
• 
Arthritis  
• 
Weakness 
• 
Fatigue 
• 
Muscle Weakness 
• 
Neck Pain  
• 
Tendon inflammation 
 
 
Other less common side effects have been reported.  The Investigator or staff can 
discuss these with you. 
 
Please tell the study doctor or study staff right away if you have any side effects.  
Please tell them if you have any other problems with your health or the way you feel 
during the study, whether or not you think these problems are related to the study drug. 
 
RISKS OF STUDY PROCEDURES 
 
• Blood samples:  possible side effects from blood drawing include faintness, 
inflammation of the vein, pain, bruising, or bleeding at the site of puncture.  There is 
also a slight possibility of infection. 
• ECG:   skin irritation is rare but could occur during an ECG from the electrodes or 
gel that is used. 
• Questionnaires: filling out the questionnaires or answering the study doctor or study 
staff’s questions could lead you to feel uncomfortable or upset.  Please tell the study 
doctor or study staff if you feel uncomfortable or upset while filling out a questionnaire 
or answering questions.  You have the right to refuse to answer any questions. 
 
UNFORESEEN RISKS  
 
Since the study drug is investigational when taken alone or in combination with other 
medications, there may be other risks that are unknown.  You will be informed in a 
timely manner if new information about the study becomes available that may be 
relevant to continued participation in the trial. All drugs have a potential risk of an 
allergic reaction, which if not treated promptly, could become life-threatening. Some 
things that happen during an allergic reaction that could be a sign or symptom of a life-
threatening allergic reaction (anaphylaxis) are: 
• a rash 
• a fast pulse 
• sweating 


 
 
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• a feeling of dread 
• swelling around the eyes and mouth 
• swelling of the throat 
• wheezing 
• having a hard time breathing 
• a sudden drop in blood pressure (making you feel dizzy or lightheaded) 
• inability to breathe without assistance 
 
You should get medical help and contact the study doctor or study staff if you have any 
of these or any other side effects during the study. 
 
PREGNANCY / BIRTH CONTROL  
Taking the study drug may involve unknown risks to a pregnant woman, an embryo, 
fetus (unborn baby) or nursing infant.  Therefore, if you are pregnant, planning to 
become pregnant or are breastfeeding a child, you cannot participate in this study. 
 
Females of child bearing potential must have a negative pregnancy test before the 
study starts and again just before receiving study drug. In order to reduce the risk of 
pregnancy, if you are a female of child bearing potential you must use an effective 
method of birth control while you are participating in this study.  Acceptable methods of 
birth control include 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 or abstinence.  Oral, 
implantable, or injectable contraceptives are only considered effective if used properly 
and started at least 30 days prior to the screening visit.  Some drugs (e.g., antibiotics) 
may interact with hormonal contraceptives, making them not work properly.  Please 
inform your study doctor of all other drugs you are taking.   
 
If you suspect that you may have become pregnant during the study, you must contact 
the study doctor immediately and have a urine pregnancy test 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 you will be permanently discontinued from study drug and be 
asked to return to the site for a study termination visit. Your study doctor will ask to 
follow you and the progress of your pregnancy until the baby is born.  Information about 
your pregnancy and its outcome will be collected and used to learn more about the 
effects of the study drug on pregnancy. 
 
ALTERNATIVE TREATMENT 
You do not have to be in this study to get help for your Parkinson’s Disease. 
If you do not wish to participate in this study, you will continue to be treated by your regular 
doctor and your care will not be jeopardized in any way.  Your regular doctor may continue 
with your current treatment regimen with modifications that you and your regular doctor 
agree are appropriate.   


 
 
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Other treatments available for Parkinson’s Disease include:  levodopa/carbidopa, 
pramipexole or other dopamine agonists, rasagiline, selegiline, amantadine or several 
anticholinergic drugs.  There are benefits and risks associated with these medications 
that should be discussed with your study doctor. In addition, you may discuss your options 
with your regular health-care provider. 
 
NEW FINDINGS  
 
Any new important information that is discovered during the study and which may 
influence your willingness to continue participation in the study will be made available to 
you. 
 
BENEFITS 
 
The study drug may result in an improvement in the mental and movement symptoms 
associated with early Parkinson’s disease as well as your performance of daily 
activities. There is, however, no guarantee that you will benefit from your participation in 
this study.  Results from this study may benefit others with Parkinson’s disease in the 
future.  
 
COMPENSATION FOR PARTICIPATION  
 
You will not receive any monetary compensation for your participation in this study.   
 
CONFIDENTIALITY    
 
Records of your participation in this study will be held confidential except when sharing 
the information is required by law or as described in this informed consent.  The 
Investigator, the sponsor or persons working on behalf of the sponsor, and under 
certain circumstances, the United States Food and Drug Administration (FDA) and the 
Institutional Review Board (IRB) will be able to inspect and copy confidential study-
related records which identify you by name.  This means that absolute confidentiality 
cannot be guaranteed.  If the results of this study are published or presented at 
meetings, you will not be identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
COMPENSATION FOR INJURY   
 
If you are injured as a result of taking the study drug(s) or from procedures done for the 
purpose of this study, the sponsor will pay for those medical expenses necessary to 
treat your injury that are not covered by your medical insurance or any other third party 


 
 
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coverage.  There are no plans to provide other compensation beyond that which is 
listed in this informed consent document.  You will not lose any of your legal rights or 
release the Sponsor, the Investigator, the study staff, or study site from liability for 
mistakes or intentional misconduct by signing this consent document. 
 
If you are injured during this study, your Investigator will discuss with you the available 
medical treatment options. 
 
COSTS  
 
There will be no charge to you for your participation in this study.  The study drug, 
study-related procedures, and study visits will be provided at no charge to you or your 
insurance company. 
 
EMERGENCY CONTACT / IRB CONTACT  
 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
Investigator at the telephone number listed on page 1 of this consent document.  If you 
seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in a research study being conducted by the Investigator listed on page 
1 of this document.   
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research subjects.  If you have any questions about your rights as a 
research subject, and/or concerns or complaints regarding this research study, you 
should write to Schulman IRB, 4445 Lake Forest Drive – Suite 300, Cincinnati, Ohio 
45242, or call toll-free 1-888-557-2472 during business hours Monday - Friday 8:00 
a.m. to 6:00 p.m. EST.   
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
 
Your decision to participate in this study is voluntary.  You may choose to not participate 
or you may withdraw from the study for any reason without penalty or loss of benefits to 
which you are otherwise entitled and without any effect on your future medical care.   
 
The Investigator or the sponsor can stop your participation at any time without your 
consent for the following reasons: 
 
• If it appears to be medically harmful to you; 
• If you fail to follow directions for participating in the study; 
• If it is discovered that you do not meet the study requirements; 
• If the study is canceled; or  
• For administrative reasons, including competitive enrollment - the target number of 
subjects has entered the study. 


 
 
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If you leave the study for any reason, the Investigator may ask you to have some end-
of-study tests for your safety.   
If for any reason you or your doctor decide you need to completely stop taking the study 
drug during the course of the study (prior to visit 6), you will need to undergo an early 
treatment termination visit.  
This visit can be conducted as part of the next scheduled study visit if it is within 5 days 
of the day you stopped taking study medication. If the next scheduled visits is more than 
5 days away your doctor may ask you to return to the clinic as soon as possible for an 
“unscheduled” visit. All efforts should be made to schedule the early treatment termination 
visit as close to the day when you stopped taking study medication 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 opened and 
unopened bottles should be returned at this time. 
After the early treatment termination visit is performed, you will be asked to continue 
with all study visits and activities as planned, for follow up, without taking any study 
medication. During this time, you will be allowed to take medications for your 
Parkinson’s disease if needed. 
 
Finally, if you decide to stop study participation for any reason before the end of week 
12, including study treatment and study scheduled visits and activities, you will need to 
undergo an early study termination visit. Again, all efforts should be made to schedule 
the early study termination visit as close to the day when you decided to stop your 
participation in all study visits and activities. Again, all activities listed in the treatment 
termination (visit 6) and safety visits (visit 7) will be performed at this visit. If not already 
returned, the entire study medication kit with all boxes and opened and unopened 
bottles should be returned at this time. 
 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION 
 
Please indicate below whether you want us to notify your primary care physician or your 
specialist of your participation in this study. 
 
________ 
Yes, I want the Investigator to inform my primary care physician/specialist 
of my participation in this study. 
 
________ 
No, I do not want the Investigator to inform my primary care 
physician/specialist of my participation in this study. 
 
________ 
I do not have a primary care physician/specialist. 
 
________ 
The Investigator is my primary care physician/specialist. 
 
 
 


 
 
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CONSENT   
 
I have read and understand the information in this informed consent document.  I have 
had an opportunity to ask questions and all of my questions have been answered to my 
satisfaction. I voluntarily agree to participate in this study until I decide otherwise.  I do 
not give up any of my legal rights by signing this consent document.  I will receive a 
copy of this signed consent document. 
 
 
____________________________________  
 
 
Subject’s Printed Name  
 
 
____________________________________  
 
_________  
Subject’s Signature  
 
 
 
 
 
Date 
 
 
____________________________________  
 
 
Printed Name of the Person Conducting the  
 
 
 
Consent Discussion  
 
 
_____________________________________  
 
___________ 
Signature of the Person Conducting the   
 
 
Date  
Consent Discussion  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
During your participation in this research study, the Investigator and study 
staff will collect or create personal health information about you (for 
example, medical histories and results of any tests, examinations or 
procedures you undergo while in the study) and record it on study 
documents.  The Investigator will keep this personal health information in 
your study-related records (that we will refer to as "your study records").  In 
addition, the Investigator may obtain, and include in your records, 
information regarding your past, present and/or future physical or mental 
health and/or condition.  Your Investigator may ask you to sign a separate 
authorization to obtain some or all of your medical records from your 
doctor.  Your study records may include other personal information (such 
as social security number, medical record numbers, date of birth, etc.), 
which could be used to identify you.  Health information that could identify 
you is called "Protected Health Information" (or "PHI").  
 
Under federal law (the "Privacy Rule"), your PHI that is created or obtained 
during this research study cannot be "used" to conduct the research or 
"disclosed" (given to anyone) for research purposes without your 
permission.  This permission is called an "Authorization".  Therefore, you 
may not participate in this study unless you give your permission to use 
and disclose your PHI by signing this Authorization.  By signing, you are 
agreeing to allow the Investigator and staff to use your PHI to conduct this 
study. 
 
By signing this Authorization, you also are agreeing to allow the 
Investigator to disclose PHI as described below: 
 
• The sponsor of this study and anyone working on behalf of the sponsor 
to conduct this study (referred to as "the sponsor").  The sponsor will 
analyze and evaluate the PHI and may use it to develop new tests, 
procedures and commercial products.  The study staff will assign a code 
number and/or letters to your records, which means that you will not 
ordinarily be identified in the records sent to the sponsor.  The sponsor 
may, however, look at your complete study records that identify you.  In 
addition, the sponsor may visit the study site to oversee the way the 
study is being conducted and may review your PHI during these visits to 


 
 
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make sure the information is correct.   
• The Institutional Review Board ("IRB") may have access to your PHI in 
relation to its responsibilities as an Institutional Review Board. 
• Central Laboratory: Your blood and urine laboratory samples collected 
for this study will be temporarily stored and analyzed by a central 
laboratory. Your privacy is kept as only your study patient number will be 
written by the study personnel on the sample label beside the barcode 
number. All testing samples will be destroyed at the end of the testing 
process, which is estimated to take approximately 3 years. 
• Data & Safety Monitoring Board (DSMB): will periodically review all data 
collected for this study in order to monitor safety for study patients. 
Again, the study staff will assign a code number and/or letters to your 
records, which means that you will not ordinarily be identified in the 
records reviewed by the DSMB.  
 
The Investigator or sponsor may disclose your PHI to the United States 
Food and Drug Administration ("FDA") or similar regulatory agencies in the 
United States and/or foreign countries. 
 
These disclosures also help ensure that the information related to the 
research is available to all parties who may need it for research purposes. 
 
Except for the disclosures described above, your PHI will not be shared 
with others unless required by law.  If your PHI is given to the parties listed 
above and/or to others who are not required to comply with the federal law, 
your PHI will no longer be protected by this law and could possibly be used 
or disclosed in ways other than those listed here.  
 
You have a right to see and make copies of your PHI.  You are agreeing, 
however, by signing this document, not to see or copy some or all of your 
PHI until the sponsor has completed all work related to this study.  At that 
time, you may ask to see your records. 
 
This Authorization will expire 50 years from the date you sign it unless you 
revoke (cancel or withdraw) it sooner.   
 
You have a right to revoke your Authorization at any time.  If you revoke it, 
your PHI will no longer be used for this study, except to the extent the 
parties to the research have already taken action based upon your 


 
 
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Authorization or need the information to complete analysis and reports for 
this research.  To revoke your Authorization, you must write to the 
Investigator, stating that you are revoking your Authorization to Use and 
Disclose Protected Health Information.  If you revoke this Authorization, 
you will not be allowed to continue to be in this study.   
 
You will receive a copy of this Authorization after you have signed it. 
 
 
____________________________________ 
Printed Name of Subject 
 
____________________________________  
__________ 
Signature of Subject 
 
 
 
 
 
Date 
 
 
____________________________________ 
Printed Name of the Person Obtaining the  
Authorization 
 
____________________________________  
__________ 
Signature of the Person Obtaining the 
 
 
Date 
Authorization 
 
 

Prot_000.pdf: 
Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 1 of 131 
 
 
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 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 2 of 131 
 
 
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 
 
 
 
 
 
 
 
 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 3 of 131 
 
 
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 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 4 of 131 
 
 
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 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 5 of 131 
 
 
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 
 
 
 
 
 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
Version 3.0  
 
18, November, 2020 
 
 
NCT Number: NCT03329508 
Page 6 of 131 
 
 
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. 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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: 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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: 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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: 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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. 
 
 
 
 
 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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.  
 


Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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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Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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22.8 Appendix VIII: Columbia Suicide Severity Rating Scale (CSSRS) 
 
 


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Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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Protocol P2B001/003                                                                                                                     CONFIDENTIAL 
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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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23 REFERENCES 
 
Aronow WS, . (2011). Hypertension in the Elderly. JACC , 57, 2037–2114. 
Du F, L. R. (2005). Dopamine D3 receptor-preferring agonists induce neurotrophic effects on 
mesencephalic dopamine neurons. . Eur J Neurosci , 22 (10), 2422-2430. 
Fahn S, E. R. (1987). Uniﬁed Parkinson’s Disease Rating Scale. (M. C. Fahn S, Ed.) Recent 
Developments in Parkinson’s Disease,: Macmillan Healthcare Information; , 2, 153-163, 293-
304. 
Hauser RA, S. A. (2010). Randomized, Double-Blind, Multicenter Evaluation of Pramipexole 
Extended Release Once Daily in Early Parkinson’s Disease. Movement Disorders  , 25 (15), 
2542–2549. 
Hubble JP, K. W. (1995). Pramipexole in patients with early parkinson’s disease. Clin 
Neuropharmacol. , 18, 338-347. 
Hughes AJ, D. S. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A 
clinico-pathological study of 100 cases. JNNP , 55, 181-184. 
Imamura K, T. T. (2008). Pramipexole has astrocyte-mediated neuroprotective effects against 
lactacystin toxicity. Neurosci Lett. , 440 (2), 97-102. 
Kaufmann H, M. R.-K. (2012). The Orthostatic Hypotension Questionnaire (OHQ): validation of 
a novel symptom assessment scale. Clin Auton Res. , 22 (2), 79-90. 
Label, A. (2010).  Azilect Label.  Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021641s002s003s004s005s007s008s
010lbl.pdf . 
Lecht S, H. S. (2007). Rasagiline – anovel MAO B inhibitor in parkinson’s disease therapy. . 
Therapeutics and clinical risk management , 3 (3), 467-474. 
 Lucey MR, B. K. (1997). Minimal criteria for placement of adults on the liver transplant waiting 
list: a report of a national conference organized by the American Society of Transplant 
Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. , 3 
(6), 628-637. 
Li C, G. Y. (2010). Neuroprotection of pramipexole in UPS impairment induced animal model 
of Parkinson's disease. Neurochem Res. , 35 (10), 1546-1556. 
Mirapex ER Label. (2010). Mirapex ER Label,. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022421lbl.pdf.  
Olanow CW, Kieburtz K, Leinonen M, Elmer L, Giladi N, Hauser RA, Klepiskaya OS, 
Kreitzman DL, Lew MF, Russell DS, Kadosh S, Litman P, Friedman H, Linvah N, (2017). A 
randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early 
Parkinson's disease. Mov Disord. , 32 (5), 783-789. 
Olanow CW, M. F. (2013). Factors Predictive of the Development of Levodopa-Induced. 
Movement Disorders , 28, 1064-1071. 


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Olanow W, S. a. (2009). The scientific and clinical basis for the treatment of Parkinson disease. 
Neurology , 26;72(21 Suppl 4):S1-136. 
Perez-Lloret S, R. O. (2010). Dopamine receptor agonists for the treatment of early or advanced 
Parkinson's disease. CNS Drugs , 24 (11), 941-968. 
PSG, P. S. (1997). Safety and efficacy of pramipexole in early Parkinson disease. J Am Med 
Assoc. , 278, 125-130. 
Rascol PB, R. A. (2010). Efficacy, Safety, and Tolerability of Overnight Switching from 
Immediate- to Once Daily Extended-Release Pramipexole in Early Parkinson’s Disease for the 
Pramipexole Switch. Movement Disorder Society , 25 (14), 2326–2332. 
Shannon KM, B. J. (1997). Efficacy of pramipexole, a novel dpoamine agonist, as monotherapy 
in mild to moderate parkinson's disease. In Neurology (pp. 724-728). 
summary, M. (1997). Summary Basis of Approval NDA 20667. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020667.cfm . 
Thebalut JJ, G. M. (2004). Tolerability, safety, pharmacodynamics, and pharmacokinetics of 
rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor. 
Pharmacotherapy , 24 (10), 1295-1305. 
Wright CE, S. T. (1997). Steady-state pharmacokinetic properties of pramipexole in healthy 
volunteers. J Clin Pharmacol. , 37 (6), 520-525. 
Wu Y, K. K. (2015). Rasagiline and selegiline suppress calcium efflux from mitochondria by 
PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic 
function for neuroprotection. J Neural Transm (Vienna). , 122 (10), 1339-1407. 
Youdim MB, G. A. (2001). Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent 
inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol. , 132 (2), 500-506. 
 

SAP_001.pdf: 
Protocol P2B001/003 – Statistical Analysis Plan                                   21October2021                  Page 1 of 96 
NCT03329508 
 
 
 
 
 
  
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
Protocol 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 Date: 
October 7, 2020, Version 3.0 
 
 
SAP Date: 
October 21, 2021, Version 2.0 
 
 
SAP Author: 
Shaul E. Kadosh, StatExcellence Ltd. 
 
 
 
 
 
 
 
 


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NCT03329508 
 
SIGNATURE PAGE 
 
Approved by: 
 
 
 
 
 
 


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NCT03329508 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ADL 
Activities of Daily Living 
AR 
Autoregressive 
ARH 
Heterogeneous Autoregressive 
ATC 
Anatomical Therapeutic Chemical Classification 
ATC2 
Therapeutic Subgroup (ATC2)  
ATC4 
Chemical Subgroup (ATC4) 
BP 
Blood Pressure 
CDMS 
Clinical Data Management System 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CGR 
Country/Geographical Region 
CGR1  
Pooled Country Geographical Region 
CHS 
Heterogeneous Compound Symmetry 
CO 
Completers Analysis Set 
CR 
Controlled Release 
CRO 
Contract Research Organization 
CS 
Compound Symmetry 
CSH 
Heterogeneous Compound Symmetry 
CSSRS-BL 
Columbia Suicide Severity Rating Scale - baseline 
CSSRS-SLV 
Columbia Suicide Severity Rating Scale – since last visit 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EM 
Expectation-Maximization 
EMC 
Eligibility Monitoring Committee 
ER 
Extended Release 
ESS 
Epworth Sleepiness Scale 
EST 
Early Study Termination 
ETT 
Early Treatment Termination 
FCS 
Fully conditional specification 
H&Y 
Hoehn and Yahr 
HR 
Heart Rate 
HRQOL 
Health-related quality of life 
IP 
Investigational Product  
IMP 
Investigational Medicinal Product  
IR 
Immediate Release 


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NCT03329508 
 
Abbreviation 
Description 
IRB 
Institutional Review Board 
ICD 
Impulse control disorders 
ITT 
Intent to Treat 
GI 
Gastrointestinal 
LDM 
Lead Data Manger 
LOV 
Last Observed Value 
LSM 
Least Square Means 
MAO 
Mono Amine Oxidase 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Milligram 
mITT 
Modified Intent to Treat 
ML 
Maximum-Likelihood 
MMSE 
Mini Mental State Exam 
OH 
Orthostatic Hypotension 
PCS 
Potentially Clinically Significant 
PD 
Parkinson’s Disease 
PDQ39 
Parkinson’s Disease Questionnaire 39 
PI 
Principal Investigator 
PT 
Preferred Term 
QA 
Quality Assurance 
QUIP 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease 
REML 
Restricted Maximum-Likelihood 
RR 
Respiratory Rate 
RTSM 
Randomization and Trial Supply Management  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SDV 
Source Data Verification 
SOC 
System Organ Class 
ST 
Safety Analysis Set 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Table Figure Listing 
UK 
United Kingdom 
UPDRS 
Unified Parkinson's Disease Rating Scale 
 
 
 


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NCT03329508 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE .................................................................................................................................... 2 
LIST OF ABBREVIATIONS ........................................................................................................................ 3 
TABLE OF CONTENTS .............................................................................................................................. 5 
1 
INTRODUCTION .............................................................................................................. 10 
2 
STUDY OBJECTIVES ...................................................................................................... 12 
2.1 
PER-PROTOCOL PRIMARY OBJECTIVE ............................................................................. 12 
2.2 
PER-PROTOCOL SECONDARY OBJECTIVES ...................................................................... 12 
2.3 
PER-PROTOCOL EXPLORATORY OBJECTIVES .................................................................. 12 
2.4 
PER-PROTOCOL SAFETY & TOLERABILITY OBJECTIVES ................................................ 13 
2.5 
PER-PROTOCOL SAMPLE SIZE AND POWER CONSIDERATIONS ...................................... 13 
2.6 
BLINDED SAMPLE SIZE RE-ASSESSMENT .......................................................................... 15 
2.6.1 
Protocol Pre-Defined Plan ................................................................................................. 15 
2.6.2 
Notes on the Gould and Shih Algorithm .......................................................................... 15 
2.6.3 
Results and Conclusions .................................................................................................... 16 
3 
STUDY METHODS ........................................................................................................... 17 
3.1 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION ......................................................... 17 
3.2 
DOSING REGIMEN ............................................................................................................... 17 
3.3 
STUDY STRUCTURE ............................................................................................................. 18 
3.3.1 
Up-Titration Phase ............................................................................................................. 18 
3.3.2 
Maintenance Phase ............................................................................................................. 18 
3.3.3 
Down-Titration Phase ........................................................................................................ 18 
3.3.4 
Safety Follow-Up Phase ..................................................................................................... 18 
3.3.5 
Study Design Scheme and Schedule of Activities ............................................................ 19 
4 
STUDY CONDUCT AND PROCEDURES ..................................................................... 22 
4.1 
STUDY PERIOD .................................................................................................................... 22 
4.2 
STUDY PROCEDURES ........................................................................................................... 22 
4.2.1 
Detailed Study Plan ............................................................................................................ 22 
4.2.2 
Visit 1 - Screening Visit ...................................................................................................... 22 
4.2.3 
Visit 2 - Baseline ................................................................................................................. 23 
4.2.4 
Visit 3 (Week 3) .................................................................................................................. 24 
4.2.5 
Visit 3.5 (Week 4 Phone Call) ............................................................................................ 24 
4.2.6 
Visit 4 (Week 5) .................................................................................................................. 24 
4.2.7 
Visit 5 (Week 8) .................................................................................................................. 25 
4.2.8 
Visit 6 – Treatment Termination (Week 12) .................................................................... 25 
4.2.9 
Visit 7 – Safety Follow Up .................................................................................................. 26 
4.2.10 
Unscheduled Visits ............................................................................................................. 26 
4.2.11 
Early Treatment/Study Termination Visit ....................................................................... 27 
4.2.12 
Follow-up of Early Treatment Terminated (ETT) Subjects .......................................... 27 
4.3 
STUDY POPULATION ........................................................................................................... 27 


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 4.3.1 
Inclusion Criteria ............................................................................................................... 27 
4.3.2 
Exclusion Criteria .............................................................................................................. 28 
5 
TREATMENT ASSIGNMENT, RANDOMIZATION AND BLINDING .................... 30 
5.1 
RANDOMIZATION PROCEDURE .......................................................................................... 30 
5.2 
RANDOMIZED SUBJECTS EARLY STUDY TERMINATED DURING SCREENING/BASELINE 
VISITS ................................................................................................................................... 31 
5.3 
MISSING OBSERVATIONS DUE TO COVID-19 ................................................................... 31 
5.4 
BLINDING ............................................................................................................................. 31 
6 
PROCEDURES PRIOR TO REVEALING OF THE BLIND ....................................... 32 
6.1 
“CLEAN” STUDY DATABASE .............................................................................................. 32 
6.2 
DETERMINATION OF DISALLOWED MEDICATIONS .......................................................... 33 
6.3 
RESCUE THERAPY POST 1ST STUDY DRUG DOSE .............................................................. 34 
6.4 
DATABASE LOCKING PROCEDURES ................................................................................... 34 
6.4.1 
Freezing Activities to be performed by PRA ................................................................... 34 
6.4.2 
Locking Activities to be Performed by PRA .................................................................... 34 
6.5 
DATABASE UNBLINDING ACTIVITIES BY PRA .................................................................. 35 
6.6 
SPONSOR QA REVIEW OF RANDOMIZATION SCHEME ..................................................... 35 
7 
COMPARATIVE INTERIM ANALYSES ...................................................................... 35 
8 
DATA ANALYSES SETS ................................................................................................. 35 
8.1 
INTENTION-TO-TREAT ANALYSIS SET (ITT) .................................................................... 35 
8.2 
MODIFIED INTENTION-TO-TREAT ANALYSIS SET (MITT) ............................................... 35 
8.3 
COMPLETERS ANALYSIS SET (CO) .................................................................................... 36 
8.4 
PER PROTOCOL ANALYSIS SET (PP) ................................................................................. 36 
8.5 
SAFETY ANALYSIS SET (ST) ............................................................................................... 36 
9 
GENERAL ISSUES AND DEFINITIONS ...................................................................... 37 
9.1 
DEFINITION OF POOLED COUNTRY/GEOGRAPHICAL REGION (CGR1) .......................... 37 
9.2 
DEFINITION OF STUDY DRUG START/END DATES ............................................................ 37 
9.2.1 
Definition of Date of First Study Drug Treatment .......................................................... 37 
9.2.3 
Definition of Date of Last Dose of P2B001/Placebo ......................................................... 37 
9.2.4 
Definition of Date of Last Dose of Pramipexole ER/Placebo .......................................... 38 
9.3 
CALCULATION OF STUDY PERIODS ................................................................................... 38 
9.3.1 
Calculation of Study Duration .......................................................................................... 38 
9.3.2 
Calculation of Treatment Duration .................................................................................. 38 
9.3.3 
Calculation of P2B001/Placebo Treatment Duration ...................................................... 38 
9.3.4 
Calculation of Pramipexole ER/Placebo Treatment Duration ....................................... 38 
9.4 
DEFINITION OF BASELINE (DERIVED) VALUES ................................................................. 39 
9.6 
DERIVATION OF PERCENT STUDY DRUG COMPLIANCE ................................................... 39 
9.7 
INCOMPLETE DATE IMPUTATION ...................................................................................... 40 
9.8 
BY SUBJECT DATA LISTINGS .............................................................................................. 40 
9.9 
CONVERGENCE ISSUES AND PRE-PLANNED STRATEGY ................................................... 40 


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STUDY POPULATION SUMMARY .............................................................................. 41 
10.1 
SUBJECT DISPOSITION ........................................................................................................ 41 
10.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................... 41 
10.3 
MEDICAL HISTORY ............................................................................................................. 41 
10.4 
PRIOR, CONCOMITANT AND DISALLOWED MEDICATIONS .............................................. 41 
10.5 
PROTOCOL DEVIATIONS/CLARIFICATIONS ...................................................................... 42 
11 
STUDY QUESTIONNAIRES AND SCORES DERIVATION ...................................... 43 
11.1 
UK PARKINSON'S DISEASE SOCIETY BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA 
(UPDSBB) ........................................................................................................................... 43 
11.2 
UNIFIED PARKINSON'S DISEASE RATING SCALE (UPDRS) ............................................. 43 
11.3 
MODIFIED HOEHN & YAHR STAGING ............................................................................... 45 
11.4 
CLINICAL GLOBAL IMPRESSION – SEVERITY SCALE (CGI-S)......................................... 46 
11.5 
CLINICAL GLOBAL IMPRESSION – IMPROVEMENT SCALE (CGI-I) ................................ 46 
11.6 
MINI-MENTAL STATE EXAMINATION (MMSE) ............................................................... 47 
11.7 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) .............................................. 48 
11.8 
PARKINSON’S DISEASE QUALITY OF LIFE QUESTIONNAIRE (PDQ39)............................ 51 
11.9 
EPWORTH SLEEPINESS SCALE (ESS) ................................................................................. 53 
11.10 
ORTHOSTATIC HYPOTENSION SYMPTOMS ASSESSMENT (OHSA) QUESTION 1 ............. 54 
11.11 
IMPULSIVE-COMPULSIVE DISORDERS IN PARKINSON'S DISEASE                                          
(QUIP-RATING SCALE) ...................................................................................................... 54 
11.12 
HEALTH-RELATED QUALITY OF LIFE (HRQOL) SF-12V2 ............................................. 56 
12 
PLANNED SUBGROUPS ANALYSES ........................................................................... 58 
13 
EFFICACY ENDPOINTS ................................................................................................. 59 
13.1 
PRIMARY EFFICACY ENDPOINT ......................................................................................... 59 
13.2 
SECONDARY EFFICACY ENDPOINTS .................................................................................. 59 
13.3 
EXPLORATORY ENDPOINTS ................................................................................................ 59 
13.4 
ADDITIONAL EXPLORATORY ENDPOINTS ......................................................................... 59 
14 
SIGNIFICANCE LEVEL AND MULTIPLICITY ADJUSTMENT ............................. 60 
15 
ESTIMANDS AND MULTIPLE IMPUTATIONS ......................................................... 62 
15.1 
PRIMARY ESTIMAND (MAIN SUPPORTIVE ESTIMAND) .................................................... 62 
15.2 
SECONDARY ESTIMAND (ADDITIONAL SUPPORTIVE ESTIMAND).................................... 63 
15.3 
TERTIARY ESTIMAND (SENSITIVITY ESTIMAND) ............................................................. 64 
15.4 
MULTIPLE IMPUTATIONS ................................................................................................... 64 
16 
PRIMARY EFFICACY ENDPOINT AND ANALYSES ............................................... 69 
16.1 
PRINCIPAL ANALYSIS OF THE PRIMARY ENDPOINT ......................................................... 69 
16.2 
MAIN SUPPORTIVE ANALYSIS FOR THE PRIMARY ENDPOINT ......................................... 69 
16.3 
ADDITIONAL SUPPORTIVE ANALYSIS FOR THE PRIMARY ENDPOINT ............................. 70 
16.4 
SENSITIVITY ANALYSES FOR THE PRINCIPAL ANALYSIS OF THE PRIMARY ENDPOINT 71 
16.4.1 
Sensitivity Analysis to the Main Supportive Analysis using the Tertiary Estimand .... 71 


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 16.4.2 
Additional Sensitivity Analysis to the Main Supportive Analysis using the                   
CO Analysis Set .................................................................................................................. 71 
16.4.3 
Additional Sensitivity Analysis to the Main Supportive Analysis using the                    
PP Analysis Set ................................................................................................................... 71 
16.4.4 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint using the        
CO Analysis Set .................................................................................................................. 71 
16.4.5 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint using the         
PP Analysis Set ................................................................................................................... 72 
16.4.6 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint Accounting      
for the Potential Unblinding Incident ............................................................................... 72 
16.4.7 
Tipping Point Analysis ....................................................................................................... 72 
16.4.8 
Descriptive Subgroups Analysis ........................................................................................ 73 
17 
SECONDARY EFFICACY ENDPOINT AND ANALYSES ......................................... 74 
17.1 
1ST SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF              
WEEK 12 IN TOTAL ESS SCORE ......................................................................................... 74 
17.2 
2ND SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE (DERIVED) TO           
END OF WEEK 12 IN MOTOR UPDRS (PART III) SCORE .................................................. 74 
17.3 
3RD SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF              
WEEK 12 IN ADL UPDRS SCORE ...................................................................................... 75 
17.4 
4TH SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF               
WEEK 12 IN ADL SUBSCALE SCORE OF PDQ39 ............................................................... 75 
17.5 
5TH SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF                
WEEK 12 IN TOTAL PDQ39 SCORE ................................................................................... 76 
18 
EXPLORATORY ENDPOINTS AND ANALYSES (P2B001 VS.               
COMPONENTS) ................................................................................................................ 77 
18.1 
END OF WEEK 12 CGI-S RESPONDERS ANALYSIS ............................................................ 77 
18.1.1 
Primary CGI-S Responders Analysis ............................................................................... 77 
18.1.2 
Supportive CGI-S Responders Analysis ........................................................................... 77 
18.2 
END OF WEEK 12 TOTAL UPDRS RESPONDERS ANALYSIS ............................................. 80 
18.3 
CHANGE FROM BASELINE TO END OF WEEK 12 IN TOTAL ESS SCORE ......................... 81 
18.4 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE PDQ39               
SUBSCALES SCORES ............................................................................................................ 81 
18.5 
CHANGE FROM BASELINE (DERIVED) IN THE IMPULSIVE-COMPULSIVE DISORDERS         
IN PD (QUIP-RS) TOTAL SCORE AND SUBSCALES SCORES ............................................. 82 
18.6 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE SUMMARY                
SCORES OF HEALTH-RELATED QUALITY OF LIFE (HRQOL) SF-12V2 .......................... 82 
18.7 
END OF WEEK 12 CGI-I  RESPONDERS ANALYSIS ........................................................... 83 
19 
ADDITIONAL EXPLORATORY ENDPOINTS AND ANALYSES (P2B001 VS. 
PRAMI-ER) ........................................................................................................................ 85 
19.1 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN TOTAL UPDRS            
(PART II AND III) SCORE..................................................................................................... 85 
19.2 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN MOTOR UPDRS            
(PART III) SCORE ................................................................................................................ 85 
19.3 
CHANGE FROM BASELINE TO END OF WEEK 12 IN ADL UPDRS SCORE ....................... 86 


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END OF WEEK 12 CGI-S RESPONDERS ANALYSIS ............................................................ 86 
19.5 
END OF WEEK 12 TOTAL UPDRS RESPONDERS ANALYSIS ............................................. 86 
19.6 
END OF WEEK 12 CGI-I  RESPONDERS ANALYSIS ........................................................... 86 
19.7 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE PDQ39                
SUBSCALES SCORES ............................................................................................................ 87 
19.8 
PROPORTION (%) OF PATIENTS WITH POST-BASELINE ESS SCORE >10 ........................ 87 
19.9 
PROPORTION (%) OF PATIENTS WITH ESS SCORE ≤10 AT BASELINE AND ESS            
SCORE >10 POST-BASELINE ............................................................................................... 88 
20 
SAFETY ANALYSES ........................................................................................................ 89 
20.1 
ANALYSES OF ADVERSE EVENTS ....................................................................................... 89 
20.1.1 
Treatment Emergent AEs .................................................................................................. 89 
20.1.2 
TEAEs of Special Interest .................................................................................................. 89 
20.1.3 
Time to Event Onset (Temporal Pattern of AEs) ............................................................ 90 
20.2 
ANALYSES OF LABORATORY DATA ................................................................................... 90 
20.3 
ANALYSES OF VITAL SIGNS ................................................................................................ 92 
20.4 
ANALYSES OF ELECTROCARDIOGRAMS (ECG) ................................................................ 93 
20.5 
ANALYSES OF PHYSICAL EXAMINATION ........................................................................... 94 
20.6 
ANALYSES OF SUICIDALITY (COLUMBIA-SUICIDE SEVERITY RATING SCALE) .............. 95 
20.7 
ANALYSES OF ORTHOSTATIC HYPERTENSION SYMPTOMS ASSESSMENT                            
(OHSA) Q1 .......................................................................................................................... 95 
20.8 
TOLERABILITY AND DROP-OUT ASSESSMENTS ................................................................ 95 
21 
DEVIATION FROM STATISICAL ANALYSIS PLAN (SAP) .................................... 96 
 


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 1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
Protocol P2B001/003, (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). When differences exist in descriptions or explanations provided in 
the Study Protocol and this SAP, the SAP prevails. 
The purpose of this SAP is to outline the planned analyses to support the completion 
of the Clinical Study Report (CSR). The planned analyses identified in this SAP will 
be included in regulatory submissions and/or future manuscripts. Also, exploratory 
analyses not necessarily identified in this SAP may be performed to support further 
clinical development program. Any post-hoc, or unplanned, analyses not identified in 
this SAP will be identified in the CSR. 
This SAP was written and approved prior to study unblinding. Furthermore, the Author 
of this SAP as well as all personal approving this SAP are currently fully blinded to 
the randomization scheme. 
Pharma Two Be would like to emphasize three topics of relevance to this study: 
• Randomized Subjects Early Study Terminated During Screening/Baseline Visits: 
Due to a “just-in-time” shipping strategy, randomization was done at the end of 
screening period to allow shipping of the kit to the site. Study monitoring identified 
that approximately 4% to 5% of randomized subjects early terminated the study 
following randomization but prior to first dose which was planned to be consumed 
during the day after baseline visit. For more detailed please see Section 5.2. 
• COVID-19 Pandemic: Due to COVID-19 pandemic, a total of approximately 8 
subjects have had their study visits remotely and therefore Motor UPDRS 
evaluations could not be performed (See Section 5.3). 
• Potential Unblinding Incident: An incident occurred during the conduct of this 
study wherein a total of 41 kits, from study medication kit Batches 353007 and 
353007-3, were shipped to multiple clinical sites with potentially unblinding 
packing lists between March 2020 and December 2020.  
Following a full audit conducted by two expert auditing companies, ProPharma 
Group and Lachman Consultants, during the period of May 24, 2021, to June 30, 
2021, Pharma Two B has concluded that the study blind remains intact, and that 
there were no compromises which would affect the integrity of the study data or 
bias interpretability of the study results and conclusions.  


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In the Type C response letter dated 29Sep2021, the Division requested that “In 
addition to the planned analysis of the primary efficacy outcome, Pharma Two B 
provides a sensitivity analysis for the possible impact of the potentially unblinded 
clinical supplies”. Pharma Two B accepts the Division’s request and provides this 
sensitivity analysis plan in Section 16.4.6.   
 
 
 


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 2 
STUDY OBJECTIVES 
Pharma Two B intends to show that: 
1. P2B001 has superior efficacy as compared to each of its components. 
2. P2B001 is safe and tolerable. 
3. P2B001 has descriptively comparable efficacy as well as safety benefits as 
compared to marketed pramipexole ER (here and after pramipexole ER, 
PramiER).  
2.1 
PER-PROTOCOL 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)).  
2.2 
PER-PROTOCOL SECONDARY OBJECTIVES  
1. 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.  
2. To determine the efficacy of P2B001 0.6/0.75 mg as compared to its individual 
components in the change of Total PDQ39 score. 
3. 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. 
4. 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. 
5. 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).  
2.3 
PER-PROTOCOL EXPLORATORY OBJECTIVES 
1. 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). 
2. 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. 


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✓ 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. 
3. 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.   
 
2.4 
PER-PROTOCOL 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. 
2.5 
PER-PROTOCOL SAMPLE SIZE AND POWER CONSIDERATIONS 
The study was powered to allow achieving two goals: 
1. 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 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.   
2. 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. 


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✓ 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, 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%. 
2.6 
BLINDED SAMPLE SIZE RE-ASSESSMENT 
2.6.1 
Protocol Pre-Defined Plan 
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 a protocol amendment. 
2.6.2 
Notes on the Gould and Shih Algorithm 
The blinded variance estimate was performed according to the Expectation-
Maximization (EM) algorithm described in Gould (1992), to estimate the variance of 
the primary endpoint, without breaking the blind.  
Posch et al [Statistical Methods in Medical Research 2018, Vol. 27(6) 1830–1846)] 
concluded that although this interim estimate is not consistent [(Govindarajulu Z. 
Robustness of sample size re-estimation procedure in clinical trials (arbitrary 
populations). Stat Med 2003; 22: 1819–1828)] and has a positive bias if the alternative 
hypothesis holds, the bias is negligible for effect sizes typically observed in clinical 
trials [Friede T and Kieser M. Blinded sample size re-estimation in superiority and 
noninferiority trials: bias versus variance in variance estimation. Pharmaceut Stat 
2013; 12: 141–146]. Furthermore, sample size reassessment based on the total variance 
has no relevant impact on the type I error rate in parallel group superiority trials [Kieser 
M and Friede T. Simple procedures for blinded sample size adjustment that do not 
affect the type I error rate. Stat Med 2003; 22: 3571–3581] and achieves the target 
power well. 


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Pritchett et al [Statistics in Biopharmaceutical Research: November 2015, Vol. 7, No. 
4] also concluded that data from a clinical trial with a sample size adaptation following 
a blinded sample size reassessment procedure can be used as whole without adjustment 
and the nominal level can be used as it is for final data analysis.  
FDA’s (2019) adaptive designs guidance encouraged the use of blinded sample size 
reassessment based on non-comparative data and concluded that “In general, 
adequately prespecified adaptations based on non-comparative data have no effect or 
a limited effect on the Type I error probability. This makes them an attractive choice 
in many settings, particularly when uncertainty about event probabilities or endpoint 
variability is high.” 
2.6.3 
Results and Conclusions 
Sample size reassessment was performed at the time dictated by the protocol. The EM 
algorithms used in this analysis suggested an SD estimate of 5.354 as compared to 6.0 
UPDRS units used in the protocol for study power assessment.  
However, given the under-estimation factor of the algorithm, estimated under the 
expected study conditions -0.855, it is not unreasonable to assume the STD value of 
6.209, somewhat higher from that assumed in the protocol (6.0).    
In conclusion, the analyses summarized in the report dated July 21, 2019, provided no 
clear evidence that advocated sample size modification for Study P2B001/003.  
 
 
 


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 3 
STUDY METHODS 
3.1 
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. 
 
A total of approximately 525 eligible subjects with early PD 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 principal investigator (PI) and the central Eligibility Monitoring Committee 
(EMC). Subjects will be recruited from approximately 70 sites in North America and 
Europe.  
3.2 
DOSING REGIMEN 
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.  
• 
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. 
• 
Rasagiline 0.75 mg Once Daily (RAS 0.75) + Placebo of Pramipexole ER. 
• 
Pramipexole ER individually titrated to optimal dose + Placebo of P2B001. 
 
 


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 3.3 
STUDY STRUCTURE 
3.3.1 
Up-Titration 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. 
3.3.2 
Maintenance Phase 
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.  
3.3.3 
Down-Titration Phase 
Down-titration phase (while blinding is maintained): 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.  
3.3.4 
Safety Follow-Up Phase  
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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 3.3.5 
Study Design Scheme and Schedule of Activities 
 
*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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Visit Number 
1 
2 
3 
3.5**** 
4 
5 
6 
7 
Visit Type 
Screening 
 
Baseline   
 
End of 
Week   
3  
End of 
Week   
4  
End of 
Week 
5 
End of 
Week  
8 
End of 
Week 
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 
 
 
 
 
 
 
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 


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NCT03329508 
 
Visit Number 
1 
2 
3 
3.5**** 
4 
5 
6 
7 
Visit Type 
Screening 
 
Baseline   
 
End of 
Week   
3  
End of 
Week   
4  
End of 
Week 
5 
End of 
Week  
8 
End of 
Week 
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 
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. 
** 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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NCT03329508 
 4 
STUDY CONDUCT AND PROCEDURES 
4.1 
STUDY PERIOD 
The study duration per subject is 14 weeks in addition to up to 28 days for screening. 
4.2 
STUDY PROCEDURES 
4.2.1 
Detailed Study Plan 
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).  
4.2.2 
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) 
• 
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 


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• 
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. 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.   
4.2.3 
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  
• 
UPDRS II and III questionnaire 
• 
CSSRS- SLV questionnaire 
• 
CGI-S questionnaire 


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• 
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. 
4.2.4 
Visit 3 (Week 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 
4.2.5 
Visit 3.5 (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.  
4.2.6 
Visit 4 (Week 5) 
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 
• 
Study drug accountability 
• 
Collection of the titration kit, (Weeks 1-4) 
• 
UPDRS II, III 
• 
CSSRS-SLV questionnaire 


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NCT03329508 
 
• 
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. 
4.2.7 
Visit 5 (Week 8) 
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. 
4.2.8 
Visit 6 – Treatment Termination (Week 12) 
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 
• 
CGI-S questionnaire 
• 
CGI-I questionnaire 
• 
PDQ39 questionnaire 
• 
ESS questionnaire 
• 
QUIP-RS questionnaire 


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NCT03329508 
 
• 
HRQOL SF-12v2  
• 
Orthostatic hypotension scale question 1 for subjects with OH 
4.2.9 
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 
4.2.10 
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 
✓ 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.  
 
 


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NCT03329508 
 4.2.11 
Early Treatment/Study Termination Visit  
There are two types of discontinuations in the study:  
• 
ETT: Early Treatment Termination 
• 
EST: Early Study Termination 
Subjects who ETT/EST 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 scheduled activities as planned. If a 
subject refuse 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.  
4.2.12 
Follow-up of Early Treatment Terminated (ETT) Subjects 
Subjects ETT 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. 
4.3 
STUDY POPULATION 
4.3.1 
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. 


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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. 
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. 
4.3.2 
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. 


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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. 
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. 
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). 
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. 


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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. 
 
5 
TREATMENT ASSIGNMENT, RANDOMIZATION AND BLINDING 
5.1 
RANDOMIZATION PROCEDURE 
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 site. 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 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. 
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. 


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 5.2 
RANDOMIZED SUBJECTS EARLY STUDY TERMINATED DURING 
SCREENING/BASELINE VISITS 
Due to a “just-in-time” shipping strategy, randomization was done at the end of 
screening period to allow shipping of the kit to the site. Study monitoring identified 
that approximately 4% to 5% of randomized subjects early terminated the study 
following randomization but prior to first dose which was planned to be consumed 
during the day after baseline visit. Reasons for early study termination included: 
• Some subjects were randomized just prior to the COVID-19 pandemic during 
March 2020 and could not continue in the study due to restrictions that didn't allow 
patients to come to the hospitals during that time.  
• Erroneous/premature randomization by PI due to mistaken use of RTSM system,  
• Lack of EMC approval to randomize a subject 
• Subject found ineligible during baseline visit.  
• Withdrawal of consent / lost to follow-up between day of randomization (Visit 1, 
at end of screening procedures) and drug dispensation to be performed at study 
Day 1 (Baseline, Visit 2).  
5.3 
MISSING OBSERVATIONS DUE TO COVID-19 
Due to COVID-19 pandemic a total of approximately 9 subjects have had their study 
visits remotely and therefore Motor UPDRS evaluations could not be performed. 
5.4 
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 
as well as the assigned Biostatistician (Shaul E. Kadosh, StatExcellence Ltd.) will all 
be blinded to the subject assignment. Specific, independent, unblinded study personnel 
from the CRO will be available to provide the DSMB with periodical safety reports 
and to release new IP supply in the RTSM system. 
 
 
 


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 6 
PROCEDURES PRIOR TO REVEALING OF THE BLIND 
The Author of this SAP as well as all personnel approving this SAP are currently fully 
blinded to the randomization scheme. 
Unblinding of the study database will be performed at end of study, when all subjects 
planned to be randomized into this study will undergo the Week 14 (Visit 7) Safety 
Follow-Up Visit and after all data base cleaning activities were completed. 
Guidelines for procedures to be performed prior to revealing of the blind and 
immediately after revealing of the blind are provided in this section in chronological 
order:  
6.1 
“CLEAN” STUDY DATABASE 
The study database will be considered to be “clean” when all of the below required 
tasks have been completed: 
• Required data entered into eCRF 
• Validations and manual review  
• Queries were resolved 
• SDV  
• Medical review activities  
• Data Management activities  
• SAEs reconciliation 
• Coding completed and approved by Sponsor 
• External central laboratory data reconciliation 
• External ECG data reconciliation 
• List of ETTs that were classified by Sponsor as treatment related or non-treatment. 
• List of disallowed medications use according to Determination of Disallowed 
Medications. 
• List of subjects consuming rescue therapy (ATC code: N04, ANTI-PARKINSON 
DRUGS) post first study drug dose (see Definition of Date of First Study Drug 
Treatment and Rescue Therapy Post 1st Study Drug Dose). 
• List of TEAEs of Special Interest will fully be identified prior to revealing of the 
blind. 


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• List of subjects flagged as with potential unblinding according to the potential 
unblinding incident described in Section 1 of this SAP. Note that this list will be 
provided to the assigned statistician after the receipt of the locked unblinded 
database. Since the entire kit of investigation product is dispensed to the subject 
prior to dosing, at the baseline visit, all study procedures were conducted after the 
potential unblinding document was sent to the site. Please note that since drug was 
dispensed at baseline visit, it implies that all post first dose assessments are 
subjected to the apparent potential unblinding and therefore exclusion of subjects 
will be performed on a by subject basis.    
6.2 
DETERMINATION OF DISALLOWED MEDICATIONS 
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 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. 


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A list with all concomitant medications, those initiated before or after study IP 
administration will be provided by the Sponsor to StatExcellence following the receipt 
of the blinded frozen database and prior to the receipt of the locked unblinded database. 
6.3 
RESCUE THERAPY POST 1ST STUDY DRUG DOSE 
Rescue therapies taken post 1st study drug will be identified by ATC code: N04, ANTI-
PARKINSON DRUGS. 
6.4 
DATABASE LOCKING PROCEDURES 
6.4.1 
Freezing Activities to be performed by PRA  
1. All checks are performed as agreed in the DMP and confirmed via the data delivery 
checklist (pre delivery) – Freezing of subjects, No new SAE’s etc. 
2. Data Delivery Approval Form signed  
3. LDM notifies Primary Programmer that checklist steps are completed and to 
proceed with extract  
4. QC checks completed on extracted data 
5. Primary programmer post extract 
6. LDM confirms to Sponsor of successful extract  
7. Sponsor to review data  
8. Any updates/ queries required are reviewed by the LDM and applicable team 
members  
9. Once all updates are made repeat steps 1-6.  
6.4.2 
Locking Activities to be Performed by PRA 
1. Confirm all the activities have been completed for lock per the DMP and Pre 
Delivery checklist.   
2. Data Delivery Approval Form signed by Sponsor (for Lock) 
3. LDM notifies Primary Programmer that checklist steps are completed and to 
proceed with extract  
4. QC checks completed on extracted data 
5. LDM or LCDC requests Customer Support to Lock the CDMS, including removal 
of update and delete permissions from all Oracle tables housing external data 
6. Systems Administrator will confirm that all System Users’ access is removed, the 
CDMS is locked, and permissions removed from Oracle tables.  
7. Sponsor and PRA team notified of successful lock.  
8. In the event where an unlock is absolutely necessary, an unlocking and relocking 
Checklist will be created along with a data delivery approval form to be signed by 
Sponsor, Project Manager, Director of Data Management  and Biostatistician.  
 
 


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 6.5 
DATABASE UNBLINDING ACTIVITIES BY PRA 
Upon all subject data records are hard-locked and upon a specific signed request from 
Sponsor, the following will be performed: 
1. The sponsor sends approval to UNBLIND the database. 
2. Notification is sent to the Sponsor of the UNBLINDED data transfer. 
3. PRA will incorporate the randomization information into the relevant SDTM 
domains. 
4. PRA will transfer the hard-locked UNBLINDED database to Sponsor. 
6.6 
SPONSOR QA REVIEW OF RANDOMIZATION SCHEME 
Following the receipt of the UNBLINDED SDTM but prior to initiation of any of the 
statistical analyses as per this SAP, Sponsor will verify the appropriateness of 
treatment assignment in the delivered SDTM database according to Sponsor’s 
guideline named “THE APPROPRIATENESS OF TREATMENT CODE 
ASSIGNMENT TO THE DATABASE OF P2B001/003 STUDY”. 
 
7 
COMPARATIVE INTERIM ANALYSES 
No comparative interim analysis was planned nor conducted for this clinical study. 
 
8 
DATA ANALYSES SETS 
The following data analysis sets are defined for this study: 
8.1 
INTENTION-TO-TREAT ANALYSIS SET (ITT) 
The ITT Analysis Set will include all randomized subjects, according to the treatment 
group to which they were originally randomized to.  
8.2 
MODIFIED INTENTION-TO-TREAT ANALYSIS SET (MITT) 
The mITT Analysis Set is a subset of the ITT Analysis Set and includes subjects who 
were randomized, have taken at least one dose of study drug, and have at least one 
post-Baseline UPDRS (UPDRS II+III) measurement score at the planned scheduled 
visits.  The mITT Analysis Set will use treatment according to the group to which 
subjects were originally randomized to.  The mITT Analysis Set will serve as the 
principal analysis set for efficacy assessments. 
 
 


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 8.3 
COMPLETERS ANALYSIS SET (CO) 
The Completers Analysis Set (CO) is a subset of the mITT Analysis Set excluding 
those subjects that failed to complete the 12 weeks of treatment according to the 
treatment group to which they were originally randomized. 
8.4 
PER PROTOCOL ANALYSIS SET (PP) 
The Per Protocol Analysis Set (PP) is a subset of the CO Analysis Set excluding those 
subjects with important protocol violations according to the treatment group to which 
they were originally randomized. Note that important violations will be determined 
prior to unblinding. 
8.5 
SAFETY ANALYSIS SET (ST) 
The Safety Analysis Set will include all randomized participants who took at least one 
dose of the study drug according to the treatment actually received. The ST analysis 
set will serve as the principal analysis set for safety assessments. 
 
 
 


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 9 
GENERAL ISSUES AND DEFINITIONS 
9.1 
DEFINITION OF POOLED COUNTRY/GEOGRAPHICAL REGION (CGR1)  
For the purpose of statistical modelling, Canadian subjects (due to very low number) 
will be included in the US_NE stratum.      
9.2 
DEFINITION OF STUDY DRUG START/END DATES 
9.2.1 
Definition of Date of First Study Drug Treatment 
Baseline visit (Visit 2) will be conducted no less than 24 hours and no more than 28 
days (or up to 90 days with sponsor approval) following the completion of the 
screening period which is ended by the randomization procedure (for eligible subjects). 
At Baseline visit (Visit 2), the study medication kit will be dispensed to the subject 
which will be instructed to initiate study medication consumption the day after the 
baseline visit. 
DM domain of SDTM database includes two first study date variables: RFXSTDTC 
and RFSTDTC which should make a reference to a sole date to be considered in all 
related analyses of this study as date of first study treatment.  
9.2.2 
Definition of Date of Last Treatment Day in Study 
Date of last treatment in study is defined as the latest treatment day among: 
• P2B001/Placebo, or, 
• Pramipexole ER/Placebo.  
DM domain of SDTM database includes two last study date variables: RFXENDTC 
and RFENDTC which should make a reference to a sole date to be considered in all 
related analyses of this study as date of last study treatment.  
9.2.3 
Definition of Date of Last Dose of P2B001/Placebo 
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 (Visit 6).  
The Date of Last Dose of P2B001/Placebo will be taken from SuppDS using 
QNAM='DSLDP2B' and QLABEL='Date of Last Dose of P2B001/Placebo'.  
 
 


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 9.2.4 
Definition of Date of Last Dose of Pramipexole ER/Placebo 
Following the cessation of treatment with Pramipexole ER/Placebo, a 7-day gradual 
down titration of pramipexole ER or matching placebo will be initiated. 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).  
The 'Date Last Dose of Pramipexole ER/Placebo' will be taken from SuppDS using 
QNAM=' DSLDPPX' and QLABEL='Date Last Dose of Pramipexole ER/Placebo'. 
9.3 
CALCULATION OF STUDY PERIODS 
9.3.1 
Calculation of Study Duration 
Study duration calculated for each subject, given in days, will be calculated as the 
number of days elapsed from study consent to the date of study termination + 1 day. 
9.3.2 
Calculation of Treatment Duration 
Treatment duration calculated for each subject, given in days, will be calculated as the 
number of days elapsed from first study drug treatment (See Definition of Date of First 
Study Drug Treatment) to the date of the latest study treatment date (See Definition of 
Date of Last Treatment Day in Study)  + 1 day. 
9.3.3 
Calculation of P2B001/Placebo Treatment Duration 
P2B001/Placebo treatment duration calculated for each subject, given in days, will be 
calculated as the number of days elapsed from first study drug treatment (See 
Definition of Date of First Study Drug Treatment) to the cessation date of treatment 
with P2B001/Placebo (See Definition of Date of Last Dose of P2B001/Placebo)  + 1 
day. 
9.3.4 
Calculation of Pramipexole ER/Placebo Treatment Duration 
Pramipexole ER/Placebo treatment duration calculated for each subject, given in days, 
will be calculated as the number of days elapsed from first study drug treatment (See 
Definition of Date of First Study Drug Treatment) to the cessation date of treatment 
with Pramipexole ER/Placebo (See Definition of Date of Last Dose of Pramipexole 
ER/Placebo) + 1 day. 
 
 


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 9.4 
DEFINITION OF BASELINE (DERIVED) VALUES 
At the end of the screening period, once a subject was found to be eligible for the study, 
he/she was randomized to receive one of the four study treatments. Later on, at baseline 
visit the study drug was dispensed and subject was instructed to start consuming the 
study medication on the next day.  
The programming rule to identify baseline (derived) measurements is the latest 
assessment reported in the database for measurements taken up to first study drug 
uptake, including the day of the first study drug uptake. For subjects randomized but 
not treated, the date of randomization will be used. 
Note that in TFLs reporting, “Baseline (Derived)” terminology will be used also for 
assessments planned to be taken only at screening (e.g. MMSE). 
9.5 
DEFINITION OF CHANGE FROM BASELINE (DERIVED) 
The change from the baseline (derived) value is calculated for an individual subject in 
a specific parameter as the difference between the post-baseline value and the baseline 
(derived) value. Negative changes are indicative of decreases over time while positive 
changes reflect increases in the measured parameter. 
9.6 
DERIVATION OF PERCENT STUDY DRUG COMPLIANCE 
• Study drug accountability (DA Domain) was based on the following: 
✓ No. Kits Dispensed each including: 
▪ 99  P2B/Placebo Capsules Dispensed (Blue) 
▪ 60 PPX ER 0.375/Placebo Tablets Dispensed (Yellow) 
▪ 240 PPX ER 1.5/Placebo Tablets Dispensed (Pink) 
✓ Returned PP2B/Placebo Capsules (Blue)              
✓ Returned PPX ER 0.375/Placebo Tablets (Yellow)       
✓ Returned PPX ER 1.5/Placebo Tablets Dispensed (Pink) 
✓ Lost PP2B/Placebo Capsules (Blue)                 
✓ Lost PPX ER 0.375/Placebo Tablets (Yellow)         
✓ Lost PPX ER 1.5/Placebo Tablets Dispensed (Pink)  
✓ For each capsule/tablet (Blue, Yellow or Pink), the amount consumed was 
calculated as the amount dispensed minus the amount returned / lost. 
• The amount of PPX ER tablets (Yellow and Pink) that a subject should have taken 
during the study was retrieved from PPX ER dose adjustment follow-up (Exposure 
as Collected - EC Domain) as follows: 
✓ For daily dose of 0.375: No. of days X 1 Yellow tablets. 
✓ For daily dose of 0.75  : No. of days X 2 Yellow tablets. 
✓ For daily dose of 1.5    : No. of days X 1 Pink tablets. 


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✓ For daily dose of  3      : No. of days X 2 Pink tablets. 
✓ For daily dose of  4.5   : No. of days X 3 Pink tablets. 
• The number of P2B/Placebo capsules (Blue) that a subject should have taken 
during the study (exposure as collected) was calculated as the number of days 
elapsed from first study dose date to the last one + 1 day. 
• Accordingly, for each individual subject, the % compliance for each Blue, Yellow 
or Pink were calculated as the % of capsules/tables consumed divided by the 
number of capsules/tables that were expected to be consumed (exposure as 
collected) by a subject. 
9.7 
INCOMPLETE DATE IMPUTATION  
In some cases, the database reported dates might be partial; the day of the month or 
the month might be missing. In such a case, full dates will be imputed; if the day will 
be missing it will be imputed as the 15 day of the month and if month was missing it 
was imputed as July of that year. 
This rule will be implemented with the following exceptions: 
• Full dates of randomization, date of first study dose and death dates, if occurred, 
are mandatory. 
• Partial dates imputation of end date: In some cases, an imputation, as above 
described may lead to a situation in which end date will be before start date. In 
these cases, end dates will be imputed as start date + 1 day. 
9.8 
BY SUBJECT DATA LISTINGS 
All data collected and accumulated in SDTM database of this study that are subjected 
to analyses according to this SAP will be displayed in by subject data listings. 
9.9 
CONVERGENCE ISSUES AND PRE-PLANNED STRATEGY 
The Mixed Model for Repeated Measures (MMRM) (SAS® MIXED procedure with 
REPEATED sub-command) will be used for the analysis of several efficacy and safety 
endpoints. Data analysis will use as a default the unstructured covariance structure and 
the REML estimation method and degrees of freedom will be adjusted using the 
Kenward-Roger method.  
In case that the model will not converge, the Maximum-Likelihood (ML) estimation 
method will be used instead of the default Restricted ML (REML). If the model still 
does not converge, then a simpler covariance structure with less parameters will be 
used, according to the following order: Heterogeneous Toeplitz, Heterogeneous 
Autoregressive(1) 
[ARH(1)], 
Heterogeneous 
Compound 
Symmetry 
(CSH), 
Autoregressive(1) [AR(1)], and Compound Symmetry (CS).  
 
 


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 10 
STUDY POPULATION SUMMARY 
The ITT and the mITT analysis sets will be used to describe the study population. 
Descriptive statistics of these data will be provided by treatment group and overall.  
10.1 
SUBJECT DISPOSITION 
Data 
from 
subjects 
who 
are 
screened/randomized, 
subjects 
who 
are 
screened/randomized and dosed, subjects in the pre-defined analysis sets, subjects who 
complete the study, subjects ETT, EST and subjects included in the ITT, mITT, CO 
and ST analysis sets will be summarized using descriptive statistics. Termination 
reasons will also be summarized by reason using descriptive statistics. The 
denominator for calculating the percentages will be the set of ITT. 
10.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline characteristics including demography, general medical history, baseline 
physical examination, underlying PD disease characteristics, prior medications and 
baseline efficacy endpoints will be provided in summary tables broken down by 
treatment groups and overall.  
For continuous variables, descriptive statistics (number [n], mean, standard deviation, 
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, if necessary. 
10.3 
MEDICAL HISTORY 
The incidence (no. of patients) will be provided when broken down by primary system 
organ class (SOC) and by SOC and dictionary derived preferred term (PT) according 
to MedDRA dictionary. Subjects with at least 1 abnormal finding for each category 
will be summarized using descriptive statistics. Subjects will be counted only once in 
each category. 
10.4 
PRIOR, CONCOMITANT AND DISALLOWED MEDICATIONS 
Prior, concomitant and disallowed medications use will be analyzed according to the 
ITT Analysis Set. 
All prior and concomitant medications will be coded using the WHODRUG 
dictionary. Coded medications that ATC coding does not have all 4 levels will be 
assigned “VARIOUS” for the missing value levels. 
The incidence of prior medications and separately those consumed concomitantly to 
study drug will be summarized using descriptive statistics by Therapeutic Subgroup 
(ATC2) and by ATC2 and Chemical Subgroup (ATC4).  


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Subjects will only be counted once in each Therapeutic Subgroup, and only once in 
each Chemical Subgroup.  
• Pre-Study Medications: Analyses will include all coded medications that were 
initiated prior to first study IP administration regardless if continued during dosing 
period. Coded medications with missing start date will be included in this category. 
• Concomitant Medications: Analyses will include coded medications that were 
consumed post start of study IP Administration regardless if drug initiation date 
was before or after first study dose. Uncertainty as to whether drug was consumed 
concomitantly due to missing medication start/end date will lead to consider 
medication as consumed concomitantly. 
• Disallowed Medications: Disallowed medications use will be identified according 
to the procedure outlined in Determination of Disallowed Medications. A summary 
table displaying the number and percent of subjects, by treatment group, with 
concomitant medications use prior to study or during it will be provided 
accompanied by a reference data listing. 
• Rescue Therapy: Rescue therapy consumption will be identified according to the 
procedure outlined in Rescue Therapy Post 1st Study Drug Dose. A summary table 
displaying the number and percent of subjects, by treatment group consuming 
rescue therapy post 1st study dose will be provided accompanied by a reference 
data listing. 
10.5 
PROTOCOL DEVIATIONS/CLARIFICATIONS 
Protocol deviations and violations will be recorded on an ongoing basis and will be 
included in a DV domain in the SDTM database. Each captured term will be classified 
according to the below: 
• EPOCH: Screening, Baseline, Blinded Treatment and follow-up. 
• Category: Clarification or Deviation. 
• Subcategory: Important (or not). 
• Coded Terms: 01-Inclusion Criteria, 02-Exclusion Criteria, 03-Study Drug, 04-
Assessment Safety, 05-Endpoint Data, 06-Visit Window, 07-Informed Consent, 
08-Prohibited Medication, 09-Other or 10-Compliance. 
An incidence table displaying the number and proportion (%) of subjects with at least 
one protocol deviation in each category and overall will be summarized using 
descriptive statistics. Individual subjects’ listings will also be provided. 
 
 


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 11 
STUDY QUESTIONNAIRES AND SCORES DERIVATION 
Listings provided to Sponsor in Excel and Word files were thoroughly reviewed by 
the Sponsor for derivation of scores used in the analysis prior to revealing of the study 
blind and all listed in this section were found to be accurately in line with the plan 
detailed in this section. 
11.1 
UK PARKINSON'S DISEASE SOCIETY BRAIN BANK CLINICAL DIAGNOSTIC 
CRITERIA (UPDSBB) 
Parkinson’s disease diagnosis will be confirmed for the purpose of the study as 
consistent with UK Parkinson's Disease Society Brain Bank Clinical Diagnostic 
Criteria. Expected answer to be obtained in database is “Yes”. Response provided will 
be collected from SDTM FA dataset. 
11.2 
UNIFIED PARKINSON'S DISEASE RATING SCALE (UPDRS) 
The Unified Parkinson's Disease Rating Scale (UPDRS) questionnaire is composed of 
several parts. In this study, only parts II and III will be performed. 
• UPDRS Part II: Activities of Daily Living 
Part II of the UPDRS disease rating scale is composed of 13 items as provided 
below. The total score (UPD901Derived) of this subscale can range from 0 to 52 
as each item can get the value of 0, 1, 2, 3 or 4.  
If there are missing items in this subscale, the subscale total score 
(UPD901Derived) will be adjusted by dividing the obtained value by the total 
number of items that had responses and then multiplying by 13. If more than 3 
items are missing, the Part-II score will be considered invalid and will be set to 
missing value. 
The below identify the UPDRS Part II metrics (ADQS for QSCAT=”UPDRS”): 
Subcategory for Question 
Question Short Name Question Name 
II.ACTIVITIES OF DAILY LIVING 
UPD105 
UPDRS II ADL: Speech 
II.ACTIVITIES OF DAILY LIVING 
UPD106 
UPDRS II ADL: Salivation 
II.ACTIVITIES OF DAILY LIVING 
UPD107 
UPDRS II ADL: Swallowing 
II.ACTIVITIES OF DAILY LIVING 
UPD108 
UPDRS II ADL: Handwriting 
II.ACTIVITIES OF DAILY LIVING 
UPD109 
UPDRS II ADL: Cut Food/Handle Utensil 
II.ACTIVITIES OF DAILY LIVING 
UPD110 
UPDRS II ADL: Dressing 
II.ACTIVITIES OF DAILY LIVING 
UPD111 
UPDRS II ADL: Hygiene 
II.ACTIVITIES OF DAILY LIVING 
UPD112 
UPDRS II ADL: Turn Bed/Adj Clothes 
II.ACTIVITIES OF DAILY LIVING 
UPD113 
UPDRS II ADL: Falling 
II.ACTIVITIES OF DAILY LIVING 
UPD114 
UPDRS II ADL: Freezing When Walking 
II.ACTIVITIES OF DAILY LIVING 
UPD115 
UPDRS II ADL: Walking 
II.ACTIVITIES OF DAILY LIVING 
UPD116 
UPDRS II ADL: Tremor 
II.ACTIVITIES OF DAILY LIVING 
UPD117 
UPDRS II ADL: Sensory Complaints 
II.ACTIVITIES OF DAILY LIVING 
UPD901Derived 
Total UPDRS II ADL 


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• UPDRS PART III: Motor Examination 
Part III of the UPDRS disease rating scale is composed of 27 items as provided 
below. The total score (UPD902Derived) of this subscale can range from 0 to 108 
as each item can get the value of 0, 1, 2, 3 or 4. 
If there are missing items in this subscale, the subscale total score 
(UPD902Derived) will be adjusted by dividing the obtained value by the total 
number of items that had responses and then multiplying by 27. If more than 5 
items are missing, the Part-III score will be considered invalid and will be set to 
missing value. 
The below identify the UPDRS Part III metrics (ADQS for QSCAT=”UPDRS”): 
Subcategory for Question 
Question Short Name Question Name 
III.MOTOR EXAMINATION 
UPD118 
UPDRS III Motor: Speech 
III.MOTOR EXAMINATION 
UPD119 
UPDRS III Motor: Facial Expression 
III.MOTOR EXAMINATION 
UPD120A 
UPDRS III Motor: Tremor at Rest:Face Lips Chin 
III.MOTOR EXAMINATION 
UPD120B 
UPDRS III Motor: Tremor at Rest:Hands: Right 
III.MOTOR EXAMINATION 
UPD120C 
UPDRS III Motor: Tremor at Rest:Hands: Left 
III.MOTOR EXAMINATION 
UPD120D 
UPDRS III Motor: Tremor at Rest:Feet: Right 
III.MOTOR EXAMINATION 
UPD120E 
UPDRS III Motor: Tremor at Rest:Feet: Left 
III.MOTOR EXAMINATION 
UPD121A 
UPDRS III Motor: Action Tremor:Hand: Right 
III.MOTOR EXAMINATION 
UPD121B 
UPDRS III Motor: Action Tremor:Hand: Left 
III.MOTOR EXAMINATION 
UPD122A 
UPDRS III Motor: Rigidity Neck 
III.MOTOR EXAMINATION 
UPD122B 
UPDRS III Motor: Rigidity Upper Extrem: Right 
III.MOTOR EXAMINATION 
UPD122C 
UPDRS III Motor: Rigidity Upper Extrem: Left 
III.MOTOR EXAMINATION 
UPD122D 
UPDRS III Motor: Rigidity Lower Extrem: Right 
III.MOTOR EXAMINATION 
UPD122E 
UPDRS III Motor: Rigidity Lower Extrem: Left 
III.MOTOR EXAMINATION 
UPD123A 
UPDRS III Motor: Finger Taps: Right 
III.MOTOR EXAMINATION 
UPD123B 
UPDRS III Motor: Finger Taps: Left 
III.MOTOR EXAMINATION 
UPD124A 
UPDRS III Motor: Hand Grips: Right 
III.MOTOR EXAMINATION 
UPD124B 
UPDRS III Motor: Hand Grips: Left 
III.MOTOR EXAMINATION 
UPD125A 
UPDRS III Motor: Hand Pronate/Supinate: Right 
III.MOTOR EXAMINATION 
UPD125B 
UPDRS III Motor: Hand Pronate/Supinate: Left 
III.MOTOR EXAMINATION 
UPD126A 
UPDRS III Motor: Leg Agility: Right 
III.MOTOR EXAMINATION 
UPD126B 
UPDRS III Motor: Leg Agility: Left 
III.MOTOR EXAMINATION 
UPD127 
UPDRS III Motor: Arising from Chair 
III.MOTOR EXAMINATION 
UPD128 
UPDRS III Motor: Posture 
III.MOTOR EXAMINATION 
UPD129 
UPDRS III Motor: Gait 
III.MOTOR EXAMINATION 
UPD130 
UPDRS III Motor: Postural Stability 
III.MOTOR EXAMINATION 
UPD131 
UPDRS III Motor: Bradykinesia and Hypokinesia 
III.MOTOR EXAMINATION 
UPD902Derived 
Total UPDRS III Motor 
 
 
 


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• Total UPDRS score (Sum of Part II and Part III)  
The Total UPDRS Score (ADQS for UPD903Derived) for this study is defined as 
the sum of scores of UPDRS Parts II (UPD901Derived) and III (UPD902Derived) 
as above defined. This score which ranges from 0 to 160 will be calculated only if 
both subscales scores are non-missing namely, Total UPDRS Score will be set to 
missing value if one or more of the below conditions is met: 
✓ For Part-II: If more than 3 items are missing. 
✓ For Part III: If more than 5 items are missing.  
The below identifies the Total UPDRS (ADQS for QSCAT=”UPDRS”): 
Subcategory for Question 
Parameter Code Parameter 
II ADL AND III MOTOR 
UPD903Derived Total UPDRS 
 
• Total UPDRS (Sum of Part II and Part III) End of Week 12 Responder 
A subject will be defined as a “Responder” in the case that the End of Week 12 
improvement from baseline will be of 4 Total UPDRS points or more. Otherwise 
(precluding missing values) the subject will be defined as a “Non-Responder”. 
11.3 
MODIFIED HOEHN & YAHR STAGING 
The H&Y scale is a commonly used system for describing how the symptoms of 
Parkinson's disease progress. 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 indicative of relative level of disability as described 
below: 
✓ 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. 
The below identifies the H&Y metric (ADQS for QSCAT=”UPDRS”): 
Subcategory for Question 
Parameter Code Parameter 
V.MODIFIED HOEHN AND YAHR STAGING UPD143 
Modified Hoehn and Yahr Staging 
 


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 11.4 
CLINICAL GLOBAL IMPRESSION – SEVERITY SCALE (CGI-S) 
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 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. Efforts must be made to ensure that the 
same neurologist performs the CGI-S at all visits. 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 
✓ 7=Extremely ill 
The below identifies the CGI-S metric (ADQS for QSCAT=”CGI”): 
Subcategory for Question 
Parameter Code Parameter 
PD 
CGI0201 
CGI-Severity 
 
• Definition of  End of Week 12 CGI-S Responder 
A subject experiencing an improvement of 1 point or more in change from Baseline 
(Derived) to End of Week 12 visit of the CGI-S will be classified as a “Responder” 
and a subject failing to meet this criterion will be classified as a “Non-Responder”.  
11.5 
CLINICAL GLOBAL IMPRESSION – IMPROVEMENT SCALE (CGI-I) 
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. Efforts 
must be made to ensure that the same neurologist performs the CGI-I at all visits  
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 


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✓ 5=Minimally worse  
✓ 6=Much worse 
✓ 7=Very much worse 
The below identifies the CGI-S metric (ADQS for QSCAT=”CGI”): 
Subcategory for Question 
Parameter Code Parameter 
PD 
CGI0203 
CGI-Improvement 
• Definition of  End of Week 12 CGI-I Responder 
A subject classified at the End of Week 12 visit with an improved scores of 1 or 2 
will be classified as a “Responder” and a subject failing to meet this criterion will 
be classified as a “Non-Responder”.  
11.6 
MINI-MENTAL STATE EXAMINATION (MMSE) 
Mini-Mental State Examination (MMSE), will be completed at screening to evaluate 
the subject for cognitive abilities necessary for study participation.  
The MMSE questionnaire, 30 items test, each scored 0 or 1, is a widely used test of 
cognitive function among the elderly.  
To ensure precision, the EDC system calculated scores (MMS104, MMS113) will not 
be used in any analyses, summary tables or listings. Instead, the SAS® algorithm 
calculated scores (MMS104Derived, MMS112Derived) will be used. Note that no total 
score adjustment will be made for any potentially missing items.  
The total MMSE can range from 0 to 30. The below identifies the MMSE items: 
 
Subcategory for Question 
Parameter Code 
Parameter 
Comment 
ORIENTATION TO TIME 
MMS101A 
MMSE: What Is the Year 
 
ORIENTATION TO TIME 
MMS101B 
MMSE: What Is the Season 
 
ORIENTATION TO TIME 
MMS101C 
MMSE: What Is the Month of Year 
 
ORIENTATION TO TIME 
MMS101D 
MMSE: What Is the Day of Week 
 
ORIENTATION TO TIME 
MMS101E 
MMSE: What Is the Date 
 
ORIENTATION TO PLACE 
MMS102A 
MMSE: What Is the State 
 
ORIENTATION TO PLACE 
MMS102B 
MMSE: What Is the County 
 
ORIENTATION TO PLACE 
MMS102C 
MMSE: What Is the City/Town 
 
ORIENTATION TO PLACE 
MMS102D 
MMSE: What Is the Building 
 
ORIENTATION TO PLACE 
MMS102E 
MMSE: What Is the Floor 
 
REGISTRATION 
MMS103A 
MMSE: Repeat Word 1 
 
REGISTRATION 
MMS103B 
MMSE: Repeat Word 2 
 
REGISTRATION 
MMS103C 
MMSE: Repeat Word 3 
 
ATTENTION AND CALCULATION 
MMS104 
MMSE: Attention and Calculation Subtotal 
 
ATTENTION AND CALCULATION 
MMS104AA 
MMSE: What is 100 Take Away 7 
Attention and 
Calculation: 
Option 1 
ATTENTION AND CALCULATION 
MMS104AB 
MMSE: Keep Subtracting 7 Step 2 
ATTENTION AND CALCULATION 
MMS104AC 
MMSE: Keep Subtracting 7 Step 3 
ATTENTION AND CALCULATION 
MMS104AD 
MMSE: Keep Subtracting 7 Step 4 
ATTENTION AND CALCULATION 
MMS104AE 
MMSE: Keep Subtracting 7 Step 5 
ATTENTION AND CALCULATION 
MMS104BA 
MMSE: Spell Backward Letter 1 


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Subcategory for Question 
Parameter Code 
Parameter 
Comment 
ATTENTION AND CALCULATION 
MMS104BB 
MMSE: Spell Backward Letter 2 
Attention and 
Calculation: 
Option 2 
ATTENTION AND CALCULATION 
MMS104BC 
MMSE: Spell Backward Letter 3 
ATTENTION AND CALCULATION 
MMS104BD 
MMSE: Spell Backward Letter 4 
ATTENTION AND CALCULATION 
MMS104BE 
MMSE: Spell Backward Letter 5 
ATTENTION AND CALCULATION 
MMS104Derived 
Attention and Calculation Subtotal 
 
RECALL 
MMS105A 
MMSE: Recall Word 1 
 
RECALL 
MMS105B 
MMSE: Recall Word 2 
 
RECALL 
MMS105C 
MMSE: Recall Word 3 
 
NAMING 
MMS106A 
MMSE: Naming Object 1 
 
NAMING 
MMS106B 
MMSE: Naming Object 2 
 
REPETITION 
MMS107 
MMSE: Repeat What I Say 
 
COMPREHENSION 
MMS108A 
MMSE: Take in Right Hand 
 
COMPREHENSION 
MMS108B 
MMSE: Fold in Half 
 
COMPREHENSION 
MMS108C 
MMSE: Put on Floor (or Table) 
 
READING 
MMS109 
MMSE: Read This and Do What It Says 
 
WRITING 
MMS110 
MMSE: Write a Sentence 
 
DRAWING/COPYING 
MMS111 
MMSE: Copy This Design 
 
MMSE 
MMS112 
MMSE: Total Score 
 
TOTAL MMSE 
MMS112Derived 
Total MMSE Score 
 
LEVEL OF CONSCIOUSNESS 
MMS113 
MMSE: Level of Consciousness 
Text Description 
11.7 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
Two versions of C-SSRS questionnaires were used in the study as described below:  
• C-SSRS-Baseline/Screening Version   
The Columbia-Suicide Severity Rating Scale Screening/Baseline Version (C-
SSRS-BL) was taken at screening. List of questionnaire items is provided below: 
Subcategory for Question 
Question Short Name 
Question Name* 
SUICIDAL IDEATION 
CSS0401A 
CSS04-Wish to be Dead-Life 
SUICIDAL IDEATION 
CSS0401B 
CSS04-Wish to be Dead-P_M 
SUICIDAL IDEATION 
CSS0401C 
CSS04-Wish to be Dead, Describe 
SUICIDAL IDEATION 
CSS0402A 
CSS04-Non-Spec Suicid Thought-Life 
SUICIDAL IDEATION 
CSS0402B 
CSS04-Non-Spec Suicid Thought-P_M 
SUICIDAL IDEATION 
CSS0402C 
CSS04-Non-Spec Suicid Thought, Describe 
SUICIDAL IDEATION 
CSS0403A 
CSS04-Idea, No Intent, No Plan-Life 
SUICIDAL IDEATION 
CSS0403B 
CSS04-Idea, No Intent, No Plan-P_M 
SUICIDAL IDEATION 
CSS0403C 
CSS04-Idea, No Intent, No Plan, Describe 
SUICIDAL IDEATION 
CSS0404A 
CSS04-Idea, Intent, No Plan-Life 
SUICIDAL IDEATION 
CSS0404B 
CSS04-Idea, Intent, No Plan-P_M 
SUICIDAL IDEATION 
CSS0404C 
CSS04-Idea, Intent, No Plan, Describe 
SUICIDAL IDEATION 
CSS0405A 
CSS04-Idea, Plan, Intent-Life 
SUICIDAL IDEATION 
CSS0405B 
CSS04-Idea, Plan, Intent-P_M 
INTENSITY OF IDEATION 
CSS0406A 
CSS04-Most Severe Idea-Life 
INTENSITY OF IDEATION 
CSS0406B 
CSS04-Most Severe Idea, Desc-Life 
INTENSITY OF IDEATION 
CSS0406C 
CSS04-Most Severe Idea-P_M 
INTENSITY OF IDEATION 
CSS0406D 
CSS04-Most Severe Idea, Desc-P_M 


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Subcategory for Question 
Question Short Name 
Question Name* 
INTENSITY OF IDEATION 
CSS0407A 
CSS04-Most Severe Idea, Frequency-Life 
INTENSITY OF IDEATION 
CSS0407B 
CSS04-Most Severe Idea, Frequency-P_M 
INTENSITY OF IDEATION 
CSS0408A 
CSS04-Most Severe Idea, Duration-Life 
INTENSITY OF IDEATION 
CSS0408B 
CSS04-Most Severe Idea, Duration-P_M 
INTENSITY OF IDEATION 
CSS0409A 
CSS04-Most Severe Idea, Control-Life 
INTENSITY OF IDEATION 
CSS0409B 
CSS04-Most Severe Idea, Control-P_M 
INTENSITY OF IDEATION 
CSS0410A 
CSS04-Most Severe Idea, Deterrents-Life 
INTENSITY OF IDEATION 
CSS0410B 
CSS04-Most Severe Idea, Deterrents-P_M 
INTENSITY OF IDEATION 
CSS0411A 
CSS04-Most Severe Idea, Reasons-Life 
INTENSITY OF IDEATION 
CSS0411B 
CSS04-Most Severe Idea, Reasons-P_M 
SUICIDAL BEHAVIOR 
CSS0412A 
CSS04-Actual Attempt-Life 
SUICIDAL BEHAVIOR 
CSS0412B 
CSS04-Actual Attempt-P_Y 
SUICIDAL BEHAVIOR 
CSS0413A 
CSS04-Number of Actual Attempts-Life 
SUICIDAL BEHAVIOR 
CSS0413B 
CSS04-Number of Actual Attempts-P_Y 
SUICIDAL BEHAVIOR 
CSS0414A 
CSS04-Non-suicidal Self-injur Behav-Life 
SUICIDAL BEHAVIOR 
CSS0414B 
CSS04-Non-suicidal Self-injur Behav-P_Y 
SUICIDAL BEHAVIOR 
CSS0415A 
CSS04-Interrupted Attempt-Life 
SUICIDAL BEHAVIOR 
CSS0415B 
CSS04-Interrupted Attempt-P_Y 
SUICIDAL BEHAVIOR 
CSS0416A 
CSS04-Number of Interrupt Attempts-Life 
SUICIDAL BEHAVIOR 
CSS0416B 
CSS04-Number of Interrupt Attempts-P_Y 
SUICIDAL BEHAVIOR 
CSS0417A 
CSS04-Aborted Attempt-Life 
SUICIDAL BEHAVIOR 
CSS0417B 
CSS04-Aborted Attempt-P_Y 
SUICIDAL BEHAVIOR 
CSS0418A 
CSS04-Number of Aborted Attempts-Life 
SUICIDAL BEHAVIOR 
CSS0418B 
CSS04-Number of Aborted Attempts-P_Y 
SUICIDAL BEHAVIOR 
CSS0419A 
CSS04-Preparatory Acts/Behavior-Life 
SUICIDAL BEHAVIOR 
CSS0419B 
CSS04-Preparatory Acts/Behavior-P_Y 
SUICIDAL BEHAVIOR 
CSS0419C 
CSS04-Preparatory Acts/Behav, Descr 
SUICIDAL BEHAVIOR 
CSS0420A 
CSS04-Suicidal Behavior-Life 
SUICIDAL BEHAVIOR 
CSS0420B 
CSS04-Suicidal Behavior-P_Y 
* Question name ends with “-Life” relates to lifetime interval,  those end with “-P_M” or to “-P_Y” relate to past 6 
months interval 
 
 


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• C-SSRS-SLV (Since Last Visit Version) 
The Columbia-Suicide Severity Rating Scale Since Last Visit (C-SSRS-SLV) was 
assessed at baseline and at each schedule visit afterwards (except at end of week 4 
visit). List of questionnaire items is provided below: 
Subcategory for Question 
Question Short Name Question Name 
SUICIDAL IDEATION 
CSS0201 
CSS02-Wish to be Dead 
SUICIDAL IDEATION 
CSS0201A 
CSS02-Wish to be Dead, Describe 
SUICIDAL IDEATION 
CSS0202 
CSS02-Non-Specific Suicidal Thought 
SUICIDAL IDEATION 
CSS0202A 
CSS02-Non-Specific Suicid Thought, Descr 
SUICIDAL IDEATION 
CSS0203 
CSS02-Suicidal Ideation-No Intent 
SUICIDAL IDEATION 
CSS0204 
CSS02-Ideation With Intent, No Plan 
SUICIDAL IDEATION 
CSS0205 
CSS02-Ideation With Plan/Intent 
INTENSITY OF IDEATION 
CSS0206 
CSS02-Most Severe Ideation 
INTENSITY OF IDEATION 
CSS0206A 
CSS02-Most Severe Ideation, Description 
INTENSITY OF IDEATION 
CSS0207 
CSS02-Most Severe Ideation, Frequency 
INTENSITY OF IDEATION 
CSS0208 
CSS02-Most Severe Ideation, Duration 
INTENSITY OF IDEATION 
CSS0209 
CSS02-Most Severe Ideation, Control 
INTENSITY OF IDEATION 
CSS0210 
CSS02-Most Severe Ideation, Deterrents 
INTENSITY OF IDEATION 
CSS0211 
CSS02-Most Severe Ideation, Reasons 
SUICIDAL BEHAVIOR 
CSS0212 
CSS02-Actual Attempt 
SUICIDAL BEHAVIOR 
CSS0213 
CSS02-Number of Actual Attempts 
SUICIDAL BEHAVIOR 
CSS0214 
CSS02-Non-suicidal Self-injurious Behav 
SUICIDAL BEHAVIOR 
CSS0215 
CSS02-Interrupted Attempt 
SUICIDAL BEHAVIOR 
CSS0216 
CSS02-Number of Interrupted Attempts 
SUICIDAL BEHAVIOR 
CSS0217 
CSS02-Aborted Attempt 
SUICIDAL BEHAVIOR 
CSS0218 
CSS02-Number of Aborted Attempts 
SUICIDAL BEHAVIOR 
CSS0219 
CSS02-Preparatory Acts/Behavior 
SUICIDAL BEHAVIOR 
CSS0220 
CSS02-Suicidal Behavior 
SUICIDAL BEHAVIOR 
CSS0221 
CSS02-Suicide 
SUICIDAL BEHAVIOR 
CSS0222C 
CSS02-Most Lethal Attempt Potential 
 
• Definition of “Suicidal behavior”, “Suicidal Ideation” and “Suicidal Behavior 
or Ideation” at Baseline 
The Columbia-Suicide Severity Rating Scale Screening/Baseline Version (C-
SSRS-BL) was taken at screening. The Columbia-Suicide Severity Rating Scale 
Since Last visit Version (C-SSRS-SLV) was taken at baseline visit which was 
scheduled to be performed before first study drug administration.   
Any “Yes” answer to the suicidal behavior items at screening or at baseline visit 
identifies a subject as with “Suicidal Behavior at Baseline”.  
Similarly, any “Yes” to its suicidal ideation items at screening or at baseline 
identifies 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. 


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• Definition of “Suicidal behavior”, “Suicidal Ideation” and “Suicidal Behavior 
or Ideation” Post Baseline 
The Columbia-Suicide Severity Rating Scale Since Last Visit Version (C-SSRS-
SLV) was taken at each visit post baseline.  
Any “Yes” answer to its suicidal behavior items at any post baseline visit identifies 
a subject as with “Suicidal Behavior Post Baseline”.  
Similarly, any “Yes” answer to its suicidal ideation items identifies a subject as 
with “Suicidal Ideation Post Baseline”.  
A subject identified with either “Suicidal Behavior Post Baseline” or with 
“Suicidal Ideation Post Baseline” will also be classified as with “Suicidal Behavior 
or Ideation Post Baseline”. 
11.8 
PARKINSON’S DISEASE QUALITY OF LIFE QUESTIONNAIRE (PDQ39) 
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):  
• 0 = Never 
• 1 = Occasionally 
• 2 = Sometimes 
• 3 = Often 
• 4 = Always 
 
List of PDQ39 questionnaire (QSCAT= PDQUALIF in QS STDM domain) items are 
listed in the below table along with their 8 dimensions: 
PDQ-39 Subscales 
Question Short Name 
Question Name 
Mobility 
PDQ3901 
Had difficulty doing leisure activities? 
Mobility 
PDQ3902 
Had difficulty looking after your home? 
Mobility 
PDQ3903 
Had difficulty carrying shopping bags? 


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PDQ-39 Subscales 
Question Short Name 
Question Name 
Mobility 
PDQ3904 
Had problems walking half a mile? 
Mobility 
PDQ3905 
Had problems walking 100 yards? 
Mobility 
PDQ3906 
Had problems getting around the house? 
Mobility 
PDQ3907 
Had difficulty getting around in public? 
Mobility 
PDQ3908 
Needed someone else to accompany you? 
Mobility 
PDQ3909 
Felt frightened about falling in public? 
Mobility 
PDQ3910 
Been confined to the house more? 
Activities of daily living (ADL) 
PDQ3911 
Had difficulty washing yourself? 
Activities of daily living (ADL) 
PDQ3912 
Had difficulty dressing yourself? 
Activities of daily living (ADL) 
PDQ3913 
Had problems doing up your shoe laces? 
Activities of daily living (ADL) 
PDQ3914 
Had problems writing clearly? 
Activities of daily living (ADL) 
PDQ3915 
Had difficulty cutting up your food? 
Activities of daily living (ADL) 
PDQ3916 
Difficulty holding drink without spill? 
Emotional well being 
PDQ3917 
Felt depressed? 
Emotional well being 
PDQ3918 
Felt isolated and lonely? 
Emotional well being 
PDQ3919 
Felt weepy or tearful? 
Emotional well being 
PDQ3920 
Felt angry or bitter? 
Emotional well being 
PDQ3921 
Felt anxious? 
Emotional well being 
PDQ3922 
Felt worried about your future? 
Stigma 
PDQ3923 
Felt you had to conceal your PD? 
Stigma 
PDQ3924 
Avoided situations - eating or drinking? 
Stigma 
PDQ3925 
Felt embarrassed in public due to PD? 
Stigma 
PDQ3926 
Felt worried by other people's reaction? 
Social support 
PDQ3927 
Problems with personal relationships? 
Social support 
PDQ3928 
Lacked support from spouse or partner? 
Social support 
PDQ3929 
Lacked support from family or friends? 
Cognitive impairment (Cognitions) 
PDQ3930 
Unexpectedly fallen asleep during day? 
Cognitive impairment (Cognitions) 
PDQ3931 
Had problems with your concentration? 
Cognitive impairment (Cognitions) 
PDQ3932 
Felt your memory was bad? 
Cognitive impairment (Cognitions) 
PDQ3933 
Distressing dreams or hallucinations? 
Communication 
PDQ3934 
Had difficulty with your speech? 
Communication 
PDQ3935 
Felt unable to communicate with people? 
Communication 
PDQ3936 
Felt ignored by people? 
Bodily discomfort 
PDQ3937 
Had painful muscle cramps or spasms? 
Bodily discomfort 
PDQ3938 
Had aches and pains in joints or body? 
Bodily discomfort 
PDQ3939 
Felt unpleasantly hot or cold? 
 
Derivation of Scores: 
• Each dimension is calculated as a scale from 0 to 100, where 0 is indicative of no 
problem at all and 100 is the maximum level of problem. 
• If the response to a question is missing, no scale score is calculated for that 
individual for that dimension. This will preclude calculation of the PDQ39 single 
index score from the eight domains. 
• Mobility: [(sum of scores of questions 1 to 10) / (4 x 10)] x 100 


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• Activities of daily living: [(sum of scores of questions 11 to 16) / (4 x 6)] x100 
• Emotional wellbeing: [(sum of scores of questions 17 to 22) / (4 x 6) ]x 100 
• Stigma: [(sum of scores of questions 23 to 26) / (4 x 4)] x 100 
• Social support: [(sum scores of questions 27 to 29) / (4 x 3)] x 100 
note: if respondents indicate that they do not have a spouse or partner on question 
28 then social support can be calculated as follows: 
Social support = [(scores of questions 27+29) / (4 x 2)] x 100 
• Cognitions: [(sum of scores of questions 30 to 33) / (4 x 4)] x 100 
• Communication: [(sum of scores of questions 34 to 36) / (4 x 3)] x 100 
• Bodily discomfort: [(sum scores of questions 37 to 39) / (4 x 3)] x 100 
• Total Score of PDQ39:  Sum of dimension scores / 8 
11.9 
EPWORTH SLEEPINESS SCALE (ESS) 
The ESS is a self-administered questionnaire with 8 questions taken at baseline and at 
end of Weeks 5, 8 and 12. It provides a measure of a person’s general level of daytime 
sleepiness, or their average sleep propensity in daily life. The ESS asks people to rate, 
on a 4-point scale (0 – 3), their usual chances of dozing off or falling asleep in 8 
different situations or activities that most people engage in as part of their daily lives, 
although not necessarily every day.  
The total ESS score is the sum of 8 item-scores and can range between 0 and 24. The 
total ESS score is the sum of 8 item-scores. If one or more item-scores are missing, 
that ESS is invalid as it is not feasible to interpolate missing item-scores. 
List of ESS questionnaire items are listed in the below table: 
Question Name 
Question Short Name 
ESS01-Sitting and Reading 
ESS0101 
ESS01-Watching TV 
ESS0102 
ESS01-Sitting Inactive in a Public Place 
ESS0103 
ESS01-Passenger for Hour Without Break 
ESS0104 
ESS01-Lying Down to Rest In Afternoon 
ESS0105 
ESS01-Sitting and Talking to Someone 
ESS0106 
ESS01-Sitting Quietly After Lunch 
ESS0107 
ESS01-In Car Stopped Few Minutes Traffic 
ESS0108 
 
Derivation of Scores: 
• The total ESS score is the sum of 8 item-scores and can range between 0 and 24. 
• ESS score >10: A subject with ESS score>10 at any time post baseline will be 
classified as having “Post-Baseline ESS>10”. Otherwise (precluding missing 
values), the subject will be classified as “Otherwise”. 


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• Shift from Baseline in ESS Score: A subject with baseline ESS≤10 and at least one 
ESS>10 post baseline will be classified as “ESS<10→ESS>10”. Otherwise 
(precluding missing values) subject will be classified as “Otherwise”.   
11.10 
ORTHOSTATIC HYPOTENSION SYMPTOMS ASSESSMENT (OHSA) QUESTION 1 
OHSA question 1 (“Dizziness, lightheadedness, feeling faint or feeling as though you 
might pass out”) will be completed only by subjects experiencing orthostatic 
hypotension.   
The OHSA Q1 item value ranges from 0 to 10 where 0=None and 10=Worst Possible 
that best rates how severe were the symptoms from low blood pressure have been on 
average over the past week. 
List of OHSA questionnaire item and derived items are listed in the below table: 
Category of Question 
Question Short Name Question Name 
OHSA 
OHSA101 
OHSA Question 1. Dizziness 
OHSA 
OHSADerived1 
OHSA Q1 Score>0 
OHSA 
OHSADerived2 
OHSA Q1 Post Baseline Maximal Score 
 
Derivation of Scores: 
• OHSADerived1: Each Q1 item value either taken before or after first study dose 
will be classified as =0 indicative of no clinical symptoms or >0 with clinical 
symptoms at any level. 
• OHSADerived2: The post baseline OHSA Maximal Score will be derived on a by 
subject basis. 
11.11 
IMPULSIVE-COMPULSIVE DISORDERS IN PARKINSON'S DISEASE (QUIP-RATING 
SCALE) 
The questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease, 
(QUIP-Rating Scale) will be collected at 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. 
The QUIP-RS consists of an instruction sheet and a second sheet with four questions 
which have to be answered for each 7 disorders on a 5-point Likert scale where 
0=Never, 1=Rarely, 2=Sometimes, 3=Often and 4=Very Often.  
The subcategories of the QUIP-RS originally provided in the SDTM SAS® database 
were modified in line with QUIP-RATING SCALE [Version 1.0 (7/01/09) Copyright© 
University of Pennsylvania 2009].  
 
 


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List of QUIP-RS questionnaire subscales and items are listed in the below table along 
with their modified 6 dimensions (hobbyism and punding are combined): 
QUIP-RS Dimension 
Question Short Name Question Short Name 
I. GAMBLING 
QUI101A 
Think about:Gambling? 
I. GAMBLING 
QUI102A 
Excessive:Gambling? 
I. GAMBLING 
QUI103A 
Controlling:Gambling? 
I. GAMBLING 
QUI104A 
Engage:Gambling? 
II. SEX 
QUI101B 
Think about:Sex? 
II. SEX 
QUI102B 
Excessive:Sex? 
II. SEX 
QUI103B 
Controlling:Sex? 
II. SEX 
QUI104B 
Engage:Sex? 
III. BUYING 
QUI101C 
Think about:Buying? 
III. BUYING 
QUI102C 
Excessive:Buying? 
III. BUYING 
QUI103C 
Controlling:Buying? 
III. BUYING 
QUI104C 
Engage:Buying? 
IV. EATING 
QUI101D 
Think about:Eating? 
IV. EATING 
QUI102D 
Excessive:Eating? 
IV. EATING 
QUI103D 
Controlling:Eating? 
IV. EATING 
QUI104D 
Engage:Eating? 
V. HOBBYISM-PUNDING 
QUI101E 
Think about:Performing tasks or hobbies? 
V. HOBBYISM-PUNDING 
QUI102E 
Excessive:Performing tasks or hobbies? 
V. HOBBYISM-PUNDING 
QUI103E 
Controlling:Performing tasks or hobbies? 
V. HOBBYISM-PUNDING 
QUI104E 
Engage:Performing tasks or hobbies? 
V. HOBBYISM-PUNDING 
QUI101F 
Think about:Repeating simple activities? 
V. HOBBYISM-PUNDING 
QUI102F 
Excessive:Repeating simple activities? 
V. HOBBYISM-PUNDING 
QUI103F 
Controlling:Repeating simple activities? 
V. HOBBYISM-PUNDING 
QUI104F 
Engage:Repeating simple activities? 
VI. MEDICATIONS 
QUI101G 
Think about:Taking your PD medications? 
VI. MEDICATIONS 
QUI102G 
Excessive:Taking your PD medications? 
VI. MEDICATIONS 
QUI103G 
Controlling:Taking your PD medications? 
VI. MEDICATIONS 
QUI104G 
Engage:Taking your PD medications? 
 
Derivation of Scores: 
• Total QUIP-RS Score: Sum of 28 items (ranges from 0-112). If the response to a 
question is missing, no Total QUIP-RS Score will be calculated. 
• The total scores for each dimension will be calculated as the sum of corresponding 
items. If the response to a question is missing, no scale score is calculated for that 
individual for that dimension 
• Gambling: 4 items ranges 0-16. 
• Sex: 4 items ranges 0-16. 
• Buying: 4 items ranges 0-16. 
• Eating: 4 items ranges 0-16. 
• Hobbyism-Punding: 8 items ranges 0-32. 


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• Medications: 4 items ranges 0-16. 
• ICD Score: Sum of gambling, sex, buying and eating, ranges 0-60 
11.12 
HEALTH-RELATED QUALITY OF LIFE (HRQOL) SF-12V2 
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 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. 
Originally eCRF items provided in SDTM database which were used by data 
management to derive the norm based scores are listed below: 
Question Short Name Question Name 
SF12101 
SF12: Would You Say Your Health Is 
SF12102A 
SF12: Typical day : Moderate activities 
SF12102B 
SF12: Typical day : Climbing stairs 
SF12103A 
SF12: Physical health : Accomplish less 
SF12103B 
SF12: Physical health : Limited 
SF12104A 
SF12: Emotional prob : Accomplish less 
SF12104B 
SF12: Emotional prob : Less carefully 
SF12105 
SF12: How much did pain interfere 
SF12106A 
SF12: Past4wks : Felt calm and peaceful? 
SF12106B 
SF12: Past4wks : Have a lot of energy? 
SF12106C 
SF12: Past4wks : Felt Downhearted? 
SF12107 
SF12: Interfered with social activities 
 
List of the norm based derived items (with the addition of ‘_Derived’ to each) provided 
in SDTM database are listed below: 
Question Short Name 
Question Name 
BP_Derived 
Bodily Pain 0-100 Score 
BP_NBS_Derived 
Bodily Pain Norm-Based Score 
GH_Derived 
General Health 0-100 Score 
GH_NBS_Derived 
General Health Norm-Based Score 
MCS_Derived 
Mental Component Score 
MH_Derived 
Mental Health 0-100 Score 
MH_NBS_Derived 
Mental Health Norm-Based Score 
PCS_Derived 
Physical Component Score 
PF_Derived 
Physical Functioning 0-100 Score 
PF_NBS_Derived 
Physical Functioning Norm-Based Score 
RE_Derived 
Role Emotional 0-100 Score 
RE_NBS_Derived 
Role Emotional Norm-Based Score 
RP_Derived 
Role Physical 0-100 Score 
RP_NBS_Derived 
Role Physical Norm-Based Score 
SF_Derived 
Social Functioning 0-100 Score 


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Question Short Name 
Question Name 
SF6D_R2_Derived 
SF-6D_R2 (Utility Index Release 2) Score 
SF_NBS_Derived 
Social Functioning Norm-Based Score 
VT_Derived 
Vitality 0-100 Score 
VT_NBS_Derived 
Vitality Norm-Based Score 
Scores to be used in exploratory analyses: 
• Mental Component Summary Score (MCS_Derived). 
• Physical Component Summary Score (PCS_Derived). 
 
 


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 12 
PLANNED SUBGROUPS ANALYSES 
This study was not powered for subgroup analyses and therefore all of the below 
proposed analyses will be conducted in an exploratory manner. 
As the study was not powered for subgroups analyses, the below proposed subgroups 
assessments will be limited to the descriptive presentation of the primary endpoint 
treatment effect magnitude and to the overall incidence of TEAEs and serious TEAEs. 
Other post-hoc assessments might also be reported in the CSR based on clinical 
relevance.  
Subgroups descriptive statistical assessment for the primary efficacy endpoint is 
described in more detail as part of the sensitivity analyses planned for the primary 
endpoint is described in Descriptive Subgroups Analysis. 
The descriptive assessment of TEAEs and serious TEAEs will be provided in summary 
tables displaying the incidence (no. of subjects and percentages) and frequency (no. of 
events) of the observed TEAEs. 
Subgroups analyses will be conducted according to the below factors: 
• Gender. 
• Study population (North Americans or Non North Americans) 
• Age (<=Median ITT Age, > Median ITT Age) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Race (White, Other) 
 
 
 
 
 


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 13 
EFFICACY ENDPOINTS 
13.1 
PRIMARY EFFICACY ENDPOINT 
Change from Baseline (Derived) to End of Week 12 Visit in the total UPDRS (UPDRS 
part II+III) score. 
13.2 
SECONDARY EFFICACY ENDPOINTS 
Secondary efficacy endpoints will be analyzed in the order of hierarchy testing (See 
Significance Level and Multiplicity Adjustment): 
1. Change from Baseline (Derived) to End of Week 12 Visit in Epworth Sleepiness 
Scale (ESS) score. 
2. Change from Baseline (Derived) to End of Week 12 Visit in Motor UPDRS (part 
III) score. 
3. Change from Baseline (Derived) to End of Week 12 Visit in ADL UPDRS (part II) 
score. 
4. Change from Baseline (Derived) to End of Week 12 in ADL subscale score of 
PDQ39. 
5. Change from Baseline (Derived) to End of Week 12 Visit in Total PDQ39 score. 
13.3 
EXPLORATORY ENDPOINTS 
Exploratory endpoints and pre-defined analyses are displayed in Exploratory 
Endpoints and Analyses (P2B001 Vs. Components). 
13.4 
ADDITIONAL EXPLORATORY ENDPOINTS 
Additional exploratory endpoints and pre-defined analyses are displayed in Additional 
Exploratory Endpoints and Analyses (P2B001 VS. Prami-ER). 
 
 
 


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 14 
SIGNIFICANCE LEVEL AND MULTIPLICITY ADJUSTMENT 
One (1) primary endpoint and five (5) secondary endpoints are pre-defined for this 
study. The overall significance level for this study will be 5% using two-tailed tests 
utilizing the hierarchical gate keeping method to control the overall Type I error rate.  
A total of 12 contrasts are pre-planned for the primary and secondary endpoints 
altogether.  Testing will be performed according to the below order and rules: 
Order  
Contrasts to be Tested in the Order Listed 
1st 
Primary Endpoint: Change from Baseline (Derived) to End of Week 12 Visit in the 
Total UPDRS (UPDRS part II+III) score: P2B001 vs. pramipexole 0.6 mg (PPX) and 
P2B001 vs. rasagiline (RAS) contrasts. 
The primary endpoint will be considered as met only if both contrasts favor P2B001 at 
a two-tailed significance level of 5% each. 
2nd 
1st Secondary Endpoint: Change from Baseline (Derived) to Week 12 Visit in the 
Total ESS Score: P2B001 vs. Pramipexole ER (PramiER) contrast. 
This endpoint will formally be tested only if the primary endpoint (two contrasts) is 
met.  
This endpoint will be considered as met if the analysis favors P2B001 at a two-tailed 
significance level of 5%. 
3rd 
2nd Secondary Endpoint: Change from Baseline (Derived) to End of Week 12 Visit in 
Motor UPDRS score (UPDRS part III): P2B001 vs. PPX and P2B001 vs. RAS 
contrasts. 
This endpoint will formally be tested only if the primary endpoint (two contrasts) and 
the 1st secondary endpoint (one contrast) and are all met. 
This endpoint will be considered as met only if both contrasts favor P2B001 at a two-
tailed significance level of 5% each 
4th  
3rd Secondary Endpoint: Change from Baseline (Derived) to End of Week 12 Visit in 
ADL UPDRS score (UPDRS part II): P2B001 vs. PPX and P2B001 vs. RAS contrasts. 
This endpoint will formally be tested only if the primary endpoint (two contrasts), the 
1st secondary endpoint (one contrast) and the 2nd secondary endpoint (two contrasts) are 
all met. 
This endpoint will be considered as met only if both contrasts favor P2B001 at a two-
tailed significance level of 5% each. 
5th  
4th Secondary Endpoint: Change from Baseline (Derived) to Week 12 Visit in the 
ADL subscale score of PDQ39: P2B001 vs. PramiER contrast. 
This endpoint will formally be tested only if the primary endpoint (two contrasts), the 
1st secondary endpoint (one contrast), the 2nd secondary endpoint (two contrasts) and 
the 3rd secondary endpoint (two contracts) are all met. 
This endpoint will be considered as met if the analysis favors P2B001 at a two-tailed 
significance level of 5%. 


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6th 
4th Secondary Endpoint: Change from Baseline (Derived) to Week 12 Visit in the 
ADL subscale score of PDQ39: P2B001 vs. PPX and P2B001 vs. RAS contrasts. 
This endpoint will formally be tested only if the primary endpoint (two contrasts), the 
1st secondary endpoint (one contrast), the 2nd secondary endpoint (two contrasts), the 
3rd secondary endpoint (two contrasts) and the 4th secondary endpoint (P2B001 vs. 
PramiER contrast) are all met. 
This endpoint will be considered as met if both contrasts favor P2B001 at a two-tailed 
significance level of 5% each. 
7th 
5th Secondary Endpoint: Change from Baseline (Derived) to End of Week 12 Visit in 
the Total PDQ39 score: P2B001 vs. PPX and P2B001 vs. RAS contrasts.  
This endpoint will formally be tested only if the primary endpoint (two contrasts), the 
1st secondary endpoint (one contrast), the 2nd secondary endpoint (two contrasts), the 
3rd secondary endpoint (two contrasts) and the 4th secondary endpoint (three contrasts) 
are all met. 
This endpoint will be considered as met only if both contrasts favor P2B001 at a two-
tailed significance level of 5% each. 
Nominal p-values will be reported in the CSR in the case of failure to reach the above 
defined statistical significance. 
 
 


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 15 
ESTIMANDS AND MULTIPLE IMPUTATIONS 
15.1 
PRIMARY ESTIMAND (MAIN SUPPORTIVE ESTIMAND) 
The Primary Estimand will be the efficacy Estimand and is based on efficacy 
assumption (de-jure).  
The Primary Estimand construction elements are:  
1. Treatment of Interest: Will be the initially randomized treatment taken as 
planned:  P2B001 vs. pramipexole 0.6mg and P2B001 vs. rasagiline. 
2. Population: Subjects with Early Parkinson’s Disease that were randomized to the 
study. 
3. Variable of interest: change from Baseline (Derived) to End of Week 12 in the 
total UPDRS score. 
4. Inter-current events: Subjects that ETT for whatever reason, or, for whom 
treatment with rescue therapy was initiated during the double-blind treatment 
period.  
5. Population-level summary: The between groups (P2B001 vs. pramipexole 0.6mg 
and P2B001 vs. rasagiline) difference in the change from Baseline (Derived) to 
End of Week 12 in the total UPDRS score. 
The treatment effect under the Primary Estimand will be attributed to subjects with 
Early Parkinson’s Disease that were randomized to the study, assuming that subjects 
treated with P2B001 or with pramipexole 0.6mg ceased to have the additional benefit 
over rasagiline (its treatment effect is expected to be less prominent among all 4 study 
arms; see Per-Protocol Sample Size and Power Considerations) following the use of 
rescue therapy. Treatment effect for subjects ETT due to whatever reason receiving no 
rescue therapy will be assumed as if those subjects did not discontinue and had full 
adherence to treatment. The incorporation of the Primary Estimand implies that 
observations collected post rescue therapy initiation, as well as post ETT for whatever 
reason will not be included in the analysis and will be multiply imputed as described 
below: 
1. Missing values following rescue therapy uptake will multiply be imputed using 
rasagiline (RAS 0.75) based imputation as control reference assuming missing not 
at random (MNAR).  
2. Missing values following ETT due to whatever reason for subjects receiving no 
rescue therapy will multiply be imputed under MAR assumption. 
The analysis related to the Primary Estimand will use the mITT Analysis Set and 
will be considered as the Main Supportive Estimand for the principal analysis of the 
primary endpoint. 
 
 


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 15.2 
SECONDARY ESTIMAND (ADDITIONAL SUPPORTIVE ESTIMAND) 
The Secondary Estimand will be the effectiveness Estimand and is based on the 
effectiveness assumption (de-facto).  
The Secondary Estimand construction elements are:  
1. Treatment of Interest: Will be the initially randomized treatment as actually 
taken: P2B001 vs. pramipexole 0.6mg and P2B001 vs. rasagiline. 
2. Population: Subjects with Early Parkinson’s Disease that were randomized to the 
study. 
3. Variable of interest: change from Baseline (Derived) to End of Week 12 in the 
total UPDRS score. 
4. Inter-current events: Subjects that ETT due to treatment related reason, ETT due 
to non-treatment related reason, or, for whom treatment with rescue therapy was 
initiated during the double-blind treatment period. 
5. Population-level summary: The between groups (P2B001 vs. pramipexole 0.6mg 
and P2B001 vs. rasagiline) difference in the change from Baseline (Derived) to 
End of Week 12 in the total UPDRS score. 
The treatment effect under the Secondary Estimand will be attributed to subjects with 
Early Parkinson’s Disease that were randomized to the study, assuming that subjects 
treated with P2B001 or with pramipexole 0.6mg ceased to have the additional benefit 
over rasagiline (its treatment effect is expected to be less prominent among all 4 study 
arms; see Per-Protocol Sample Size and Power Considerations) following the use of 
rescue therapy or following ETT due to treatment related reasons. Treatment effect for 
subjects ETT due to non-treatment related reasons receiving no rescue therapy will be 
assumed as if those subjects did not discontinue and had full adherence to treatment. 
The incorporation of the Secondary Estimand implies the following: 
3. Observations collected post rescue therapy initiation and/or post ETT will not be 
included in the analysis and will be multiply imputed as described below.  
4. Missing values following ETT due to treatment related reasons and/or following 
rescue therapy uptake will multiply be imputed using rasagiline (RAS 0.75) based 
imputation as control reference assuming missing not at random (MNAR).  
5. Missing values following ETT due to non-treatment related reasons for subjects 
receiving no rescue therapy will multiply be imputed under MAR assumption. 
The analysis related to the Secondary Estimand for the mITT Analysis Set will be 
considered as the Additional Supportive Estimand for the principal analysis of the 
primary endpoint.   


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 15.3 
TERTIARY ESTIMAND (SENSITIVITY ESTIMAND) 
The Tertiary Estimand will have the same construction elements as described for the 
Primary Estimand with the exception that all data collected in database, regardless if 
collected following of rescue therapy initiation and/or ETT for whatever reason will 
be included in the calculation of the population level summary. Any post-baseline 
missing data will be multiply imputed under MNAR, altogether reflecting the worst-
case scenario. 
The analysis related to the Tertiary Estimand for the mITT Analysis Set will be 
considered as a Sensitivity Estimand to the Main Supportive Estimand.   
15.4 
MULTIPLE IMPUTATIONS  
General comment: In the case of obtaining an error message due to the choice of the 
below specified seed value, the MINMAXITER=1000 option will be used and the 
last two digits of the specified seed will be added to the pre-specified value until error 
resolution. 
15.4.1 
Multiple Imputations for the Primary Estimand 
1. Step 1: At the initial stage, a dataset (named “MIin1stEst”) will be constructed, 
including, per ITT subject (in one dataset record) the following: treatment arm to 
which subject was randomized to (TRTP), Pooled Country/Geographical Region 
(CGR1), initiation date of rescue therapy, treatment termination reason, date of last 
P2B001/Placebo treatment and Total UPDRS as measured at Baseline (Derived), 
End of Week 5, End of Week 8 and End of Week 12. Observations in MIin1stEst 
collected post rescue therapy initiation, as well as post last P2B/Placebo 
administration date of ETT subjects for whatever reason will be set to missing 
values. 
2. Step 2: Using the previously described “MIin1stEst” dataset, the Markov Chain 
Monte Carlo (MCMC) methodology for creating a monotone missingness pattern 
imputation model will be used to generate multiply imputed datasets for 
intermittent missing values. Treatment (TRTP) will be used in the BY statement 
and the Total UPDRS scores at Baseline (Derived), End o Week 5, End of Week 8 
and End of Week 12 will be identified in the VAR statement. The number of 
imputations will be 100 and the procedure will use a seed of 1234 for this 
imputation step under the MAR assumption. The SAS® code for this step is 
provided below: 
PROC MI DATA=MIin1stEst OUT=TMP NIMPUTE=100 seed=1234 
     minimum=0 0 0 0 maximum=160 160 160 160; 
     by trtp; 
     VAR BL W5 W8 W12; 
     MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE; 
run; 


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3. Step 3: For each of the 100 intermittent imputed datasets, the remaining missing 
data will then be imputed using the method for monotone regression missingness. 
Treatment (TRTP) will be used in the BY statement and the Total UPDRS scores 
at Baseline (Derived), End o Week 5, End of Week 8 and End of Week 12 as well 
as CGR1 will be identified in the VAR statement. The number of imputations will 
be 1 and the procedure will use a seed of 2345 for this imputation step. The SAS® 
code for this step is provided below: 
PROC MI data=TMP out=TMP1 NIMPUTE=1 seed=2345 
     minimum=. 0 0 0 0 maximum=. 160 160 160 160; 
     by trtp; 
     class cgr1; 
     VAR cgr1 BL W5 W8 W12; 
     monotone regression; 
run; 
4. Step 4: Scores multiply imputed in previous step under MAR following rescue 
therapy will then be set to missing values in all 100 imputed datasets for the 
purpose of MI under MNAR. Thereafter, for each of the 100 imputed datasets, 
multiple imputations using the method for monotone regression missingness will 
be performed with rasagiline (RAS 0.75) based imputation as control reference 
under MNAR as its treatment effect is expected to be less prominent among all 4 
study arms. Total UPDRS scores at Baseline (Derived), End of Week 5, End of 
Week 8, and End of Week 12 as well as CGR1 will be identified in the VAR 
statement. The number of imputations will be 1 and the procedure will use a seed 
of 2345 for this imputation step. The SAS® code for this step is provided below: 
 
PROC MI data=TMP1 out=MIout2ndEst NIMPUTE=1 seed=2345 
     minimum=. . 0 0 0 0 maximum=. . 160 160 160 160; 
     class trtp cgr1; 
     VAR cgr1 BL W5 W8 W12; 
     monotone regression; 
     MNAR model (W5 W8 W12/modelobs=(trtp='RAS 0.75')); 
     by _imputation_; 
run; 
 
5. Step 5: For each subject within each of the 100 imputed datasets the change from 
Baseline (Derived) to the End of Week 12 (CHG) will be calculated to be used in 
the statistical analysis of the change from baseline to Week 12 visit in the total 
UPDRS score employing the mITT referring to the Primary Estimand. 
 
 


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 15.4.2 
Multiple Imputations for the Secondary Estimand 
1. Step 1: At the initial stage, a dataset (named “MIin2ndEst”) will be constructed, 
including, per ITT subject (in one dataset record) the following: treatment arm to 
which subject was randomized to (TRTP), Pooled Country/Geographical Region 
(CGR1), initiation date of rescue therapy, treatment termination reason, date of last 
P2B001/Placebo treatment and Total UPDRS as measured at Baseline (Derived), 
End of Week 5, End of Week 8 and End of Week 12. Observations in MIin2ndEst 
collected post rescue therapy initiation will be set to missing values. 
2. Step 2: Using the previously described “MIin2ndEst” dataset, the Markov Chain 
Monte Carlo (MCMC) methodology for creating a monotone missingness pattern 
imputation model will be used to generate multiply imputed datasets for 
intermittent missing values. Treatment (TRTP) will be used in the BY statement 
and the Total UPDRS scores at Baseline (Derived), End o Week 5, End of Week 8 
and End of Week 12 will be identified in the VAR statement. The number of 
imputations will be 100 and the procedure will use a seed of 3456 for this 
imputation step under the MAR assumption. The SAS® code for this step is 
provided below: 
PROC MI DATA=MIin2ndEst OUT=TMP NIMPUTE=100 seed=3456 
     minimum=0 0 0 0 maximum=160 160 160 160; 
     by trtp; 
     VAR BL W5 W8 W12; 
     MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE; 
run; 
3. Step 3: For each of the 100 intermittent imputed datasets, the remaining missing 
data will then be imputed using the method for monotone regression missingness. 
Treatment (TRTP) will be used in the BY statement and the Total UPDRS scores 
at Baseline (Derived), End o Week 5, End of Week 8 and End of Week 12 as well 
as CGR1 will be identified in the VAR statement. The number of imputations will 
be 1 and the procedure will use a seed of 4567 for this imputation step. The SAS® 
code for this step is provided below: 
PROC MI data=TMP out=TMP1 NIMPUTE=1 seed=4567 
     minimum=. 0 0 0 0 maximum=. 160 160 160 160; 
     by trtp; 
     class cgr1; 
     VAR cgr1 BL W5 W8 W12; 
     monotone regression; 
run; 
4. Step 4: Scores multiply imputed in previous step under MAR following rescue 
therapy and/or following ETT due to treatment related reasons will then be set to 
missing values in all 100 imputed datasets for the purpose of MI under MNAR. 
Thereafter, for each of the 100 imputed datasets, multiple imputations using the 
method for monotone regression missingness will be performed with rasagiline 
(RAS 0.75) based imputation as control reference under MNAR as its treatment 


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effect is expected to be less prominent among all 4 study arms. Total UPDRS 
scores at Baseline (Derived), End o Week 5, End of Week 8, and End of Week 12 
as well as CGR1 will be identified in the VAR statement. The number of 
imputations will be 1 and the procedure will use a seed of 4567 for this imputation 
step. The SAS® code for this step is provided below: 
PROC MI data=TMP out=MIout2ndEst NIMPUTE=1 seed=4567 
     minimum=. . 0 0 0 0 maximum=. . 160 160 160 160; 
     class trtp cgr1; 
     VAR cgr1 BL W5 W8 W12; 
     monotone regression; 
     MNAR model (W5 W8 W12/modelobs=(trtp='RAS 0.75')); 
     by _imputation_; 
run; 
5. Step 5: For each subject within each of the 100 imputed datasets the change from 
Baseline (Derived) to the End of Week 12 (CHG) will be calculated to be used in 
the statistical analysis of the change from baseline to Week 12 visit in the total 
UPDRS score employing the mITT referring to the Secondary Estimand. 
15.4.3 
Multiple Imputations for the Tertiary Estimand 
1. Step 1: At the initial stage, a dataset (named “MIin3rdEst”) will be constructed, 
including, per ITT subject (in one dataset record) the following: treatment arm to 
which subject was randomized to (TRTP), Pooled Country/Geographical Region 
(CGR1) and Total UPDRS as measured at Baseline (Derived), End of Week 5, End 
of Week 8 and End of Week 12.  
2. Step 2: Using the previously described “MIin3ndEst” dataset, the MI procedure 
using the FCS method with the regression method of classification will be used to 
generate missing baseline values under the MAR assumption. The number of 
imputations will be 100 and the procedure will use a seed of 5678 for this 
imputation step. The SAS® code for this step is provided below: 
PROC MI DATA=MIin3rdEst OUT=TMP NIMPUTE=100 seed=5678 
     minimum=. . 0 maximum=. . 160; 
     CLASS trtp CGR1; 
     VAR trtp CGR1 bl; 
     FCS REG(BL =trtp cgr1);  
   run; 
3. Step 3: Thereafter, for each of the 100 imputed datasets, multiple imputations using 
the method FCS regression missingness will be performed with rasagiline (RAS 
0.75) based imputation as control reference under MNAR as its treatment effect is 
expected to be less prominent among all 4 study arms. The number of imputations 
will be 1 and the procedure will use a seed of 67891011 with 
MINMAXITER=1000 for this imputation step. The SAS® code for this step is 
provided below: 
 
 


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PROC MI data=TMP out=MIout3rdEst NIMPUTE=1 seed=67891011 
MINMAXITER=1000 
     minimum=. . 0 0 0 0 maximum=. . 160 160 160 160; 
     class trtp cgr1; 
     VAR cgr1 BL W5 W8 W12; 
     FCS regression; 
     MNAR model (W5 W8 W12/modelobs=(trtp='RAS 0.75')); 
     by _imputation_; 
run; 
4. Step 4: For each subject within each of the 100 imputed datasets the change from 
Baseline (Derived) to the End of Week 12 (CHG) will be calculated to be used in 
the statistical analysis of the change from baseline to Week 12 visit in the total 
UPDRS score employing the mITT referring to the Tertiary Estimand. 
 
 


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 16 
PRIMARY EFFICACY ENDPOINT AND ANALYSES 
The primary efficacy endpoint for this trial will be the change from baseline to Week 
12 visit in the total UPDRS score (see for score calculation definition: Unified 
Parkinson's Disease Rating Scale (UPDRS), defined as sum of UPDRS parts II and III. 
The mITT analysis set will be used as the principal analysis for efficacy analysis and 
inference. Main supportive, additional supportive and sensitivity analysis to the main 
supportive analyses will be conducted with reference to the Primary Estimand, 
Secondary Estimand and Tertiary Estimand, respectively.  
Formal analysis will employ two contrasts: P2B001 vs. PPX and P2B001 vs. RAS.  
16.1 
PRINCIPAL ANALYSIS OF THE PRIMARY ENDPOINT 
The mITT analysis set will be used for the principal analysis of the primary 
endpoint. A Mixed Model for Repeated Measures (MMRM) (SAS® MIXED 
procedure with REPEATED sub-command) will be used for the analysis of this 
endpoint. The model will include the following fixed effects: categorical scheduled 
week by treatment interaction, CGR1, and baseline total 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 scheduled changes from baseline (derived) to post-baseline visits (weeks 5, 8, 
and 12) will be used as response in the model and differences between the treatments 
groups at week 12 will be estimated using contrasts.  
The SAS® code planned for the analysis is outlined below: 
proc mixed Data=ADQS Method=REML; 
     ods output LSMeans=LSMmixed Diffs=Diffsmixed;  
     Class TRTp visit CGR1; 
     Model CHG=TRTp*visit CGR1 BL /DDFM=KR Solution; 
     Repeated visit              /Subject=SubjID Type=un; 
     LSMeans  TRTp*visit         /Pdiff CL; 
where mITT='Yes' and param='Total UPDRS' and Visit in('End of Week 
5','End of Week 8','End of Week 12'); 
run;quit; 
In case that the model does not converge the strategy outlined in Convergence Issues 
and Pre-Planned Strategy will be employed. 
16.2 
MAIN SUPPORTIVE ANALYSIS FOR THE PRIMARY ENDPOINT 
This analysis related to the Primary Estimand employing the mITT Analysis Set 
will be considered as the main supportive analysis for the principal analysis of the 
primary endpoint.   
The MIout1stEst multiply imputed dataset referring to the Primary Estimand will 
be used in this analysis. The response variable, namely the change from Baseline 
(Derived) to End of Week 12 visit in the total UPDRS score, of each of the 100 imputed 


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datasets, will be analyzed using the Analysis of Covariance (ANCOVA) employing 
the SAS® MIXED procedure. The model will include the planned treatment group 
(TRTP), CGR1 and baseline total UPDRS score as explanatory variables.  
The outcome results of the analyses of the 100 imputed datasets will be combined 
using the Robin’s rules, employing the SAS® MIANALYZE which will be used to 
derive the combined least squares means (LSM) estimates of the study groups, the 
between groups contrasts estimates as well as the corresponding 95% CI’s and p-
values for inference. The SAS® code to be used is outlined below: 
 
proc mixed Data=MIout1stEst Method=REML; 
     ods output LSMeans=LSmeans1stEst Diffs=Diffs1stEst;  
     Class TRTp CGR1; 
     Model CHG=TRTp CGR1 BL /Solution; 
     LSMeans  TRTp          /Pdiff CL; 
 
 by _imputation_; 
run;quit; 
 
* Combining LSmeans *; 
*********************; 
PROC MIANALYZE DATA=LSmeans1stEst; 
     by trtp; 
     ODS OUTPUT PARAMETERESTIMATES=LSM1stEstComb; 
     MODELEFFECTS estimate; 
     STDERR       StdErr; 
RUN; 
 
* Combining Between Groups Contrasts *; 
**************************************; 
PROC MIANALYZE DATA=Diffs1stEst; 
     ODS OUTPUT PARAMETERESTIMATES=Contrasts1stEst; 
     MODELEFFECTS estimate; 
     STDERR       StdErr  ; 
 
  by trtp _trtp; 
RUN; 
16.3 
ADDITIONAL SUPPORTIVE ANALYSIS FOR THE PRIMARY ENDPOINT 
This analysis related to the Secondary Estimand employing the mITT Analysis Set 
will be considered as an additional supportive analysis for the principal analysis of the 
primary endpoint. 
The MIout2ndEst multiply imputed dataset referring to the Secondary Estimand will 
be used in this analysis. The analysis of the change from Baseline (Derived) to End of 
Week 12 visit in the total UPDRS score will be repeated for this multiply imputed 
dataset as outlined in Section 16.2 with the difference that PROC MIXED will employ 
the mITT Analysis Set, in line with reasons detailed in Randomized Subjects Early 
Study Terminated During Screening/Baseline Visits and in Missing Observations due 
to COVID-19. 


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 16.4 
SENSITIVITY ANALYSES FOR THE PRINCIPAL ANALYSIS OF THE PRIMARY 
ENDPOINT 
The below sensitivity analyses will be performed to assess the robustness of the results 
and conclusions derived from the principal analysis of the primary endpoint and its 
supportive analyses. 
16.4.1 
Sensitivity Analysis to the Main Supportive Analysis using the Tertiary 
Estimand 
This analysis related to the Tertiary Estimand employing the mITT Analysis Set 
will be considered as as a sensitivity analysis to the main supportive analysis. 
The MIout3rdEst multiply imputed dataset referring to the Tertiary Estimand will 
be used in this analysis. The analysis of the change from Baseline (Derived) to End of 
Week 12 visit in the total UPDRS score will be repeated for this multiply imputed 
dataset as outlined in Section 16.2 with the difference that PROC MIXED will employ 
the mITT Analysis Set, in line with reasons detailed in Randomized Subjects Early 
Study Terminated During Screening/Baseline Visits and in Missing Observations due 
to COVID-19. 
16.4.2 
Additional Sensitivity Analysis to the Main Supportive Analysis using the CO 
Analysis Set 
The MIout1stEst multiply imputed dataset referring to the Primary Estimand 
employing the CO Analysis Set will be used in this analysis. The analysis of the 
change from Baseline (Derived) to End of Week 12 visit in the total UPDRS score will 
be repeated for this multiply imputed dataset as outlined in Section 16.2 with the 
difference that PROC MIXED will employ the CO Analysis Set. 
16.4.3 
Additional Sensitivity Analysis to the Main Supportive Analysis using the PP 
Analysis Set 
The MIout1stEst multiply imputed dataset referring to the Primary Estimand 
employing the PP Analysis Set will be used in this analysis. The analysis of the change 
from Baseline (Derived) to End of Week 12 visit in the total UPDRS score will be 
repeated for this multiply imputed dataset as outlined in Section 16.2 with the 
difference that PROC MIXED will employ the PP Analysis Set. 
16.4.4 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint using the 
CO Analysis Set 
The principal analysis of the primary endpoint described in 16.1 will be repeated for 
the CO Analysis Set. 


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 16.4.5 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint using the 
PP Analysis Set 
The principal analysis of the primary endpoint described in 16.1 will be repeated for 
the PP Analysis Set. 
16.4.6 
Sensitivity Analysis to the Principal Analysis of the Primary Endpoint 
Accounting for the Potential Unblinding Incident 
FDA proposed to “… repeat the primary efficacy analyses in which all UPDRS Parts 
2+3 ratings on affected individuals are treated as missing for all visits taking place 
after their respective sites received the potentially compromised clinical supplies. For 
those affected individuals, use the last Parts 2+3 total score prior to the receipt of the 
unblinded packing lists carried forward to Week 12.”. However, since drug was 
dispensed at baseline visit, it implies that all post first dose assessments are subjected 
to the apparent potential unblinding and therefore exclusion of subjects will be 
performed on a by subject basis. 
FDA further proposed to “… perform the same sensitivity analysis for the secondary 
efficacy outcome UPDRS Part 2 total score.”. 
Accordingly, the following will be performed as part of the sensitivity analysis: 
• The principal analysis of the primary endpoint described in 16.1 will be repeated 
for the mITT Analysis Set excluding subjects with potential unblinding incident. 
• 
The primary analysis for the secondary endpoint, the change from baseline 
(derived) to end of week 12 in motor UPDRS (part III) score described in Section 
17.2 will be repeated for the mITT Analysis Set excluding subjects with potential 
unblinding incident.  
• The primary analysis for the secondary endpoint, the change from baseline to end 
of week 12 in ADL UPDRS score described in Section 17.3 will be repeated for 
the mITT Analysis Set excluding subjects with potential unblinding incident.  
16.4.7 
Tipping Point Analysis 
The Tipping Point Analysis will use the Primary Estimand multiply imputed 
MIout1stEst dataset described in Section 15.4.1 with the aim of exploring the possible 
impact of missing values on the results and conclusions derived from the main 
supportive analysis of the primary endpoint performed with reference to the mITT 
Analysis Set for the Primary Estimand. This analysis will be performed according to 
the following steps: 
1. Missing changes from baseline to week 12 calculated following multiple 
imputation of missing values for subjects of the P2B001 arm will artificially be 
increased (negative change from baseline reflects improvement) by the value of δ 
(δ>0). 
2. The main supportive analysis for the primary endpoint as described in Section 16.2 
will be employed for the two contrasts: P2B001 vs. RAS and P2B001 vs. PPX. 


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The maximal p-value derived from the two contrasts as well as the minimal p-value 
will be accumulated for each value of δ. 
3. Steps 1 and 2 will be repeated by steps of 0.1 increasing increments of δ. Note that 
δ=0 corresponds to results obtained according to Section 16.2 avoiding artificially 
increasing the missing values multiply imputed values of the P2B001 subjects. The 
first δ in which significance is lost for the maximal p-value (endpoint is met only 
if both contrasts are met) will then be considered as the tipping point. 
4. The maximal p-values and the minimal p-values obtained for the grid of δ will 
graphically be displayed to visualize this sensitivity analysis. 
16.4.8 
Descriptive Subgroups Analysis 
This study was not powered for subgroup analyses and therefore all of the analyses 
proposed below will be conducted in an exploratory manner. 
The descriptive statistics of changes from baseline in the total UPDRS for the mITT 
Analysis Set will be displayed for the following subgroups: 
• Gender. 
• Study population (North Americans or Non North Americans) 
• Age (<=Median ITT Age, > Median ITT Age) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Race (White, Other) 
 
 
 


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SECONDARY EFFICACY ENDPOINT AND ANALYSES 
The mITT analysis set will be used as the primary analysis set for efficacy analysis 
and inference for the secondary endpoints defined below. Supportive analyses for these 
secondary endpoints will be conducted using the Primary Estimand. Endpoints and 
analyses are governed by the order of contrasts testing according to Significance Level 
and Multiplicity Adjustment. 
17.1 
1ST SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF WEEK 
12 IN TOTAL ESS SCORE 
The ESS analyses will use definitions outlined in Epworth Sleepiness Scale (ESS).  
Formal analysis will test the P2B001 vs. PramiER contrast in the change from Baseline 
(Derived) to End of Week 12 in Epworth Sleepiness Scale (ESS). 
The primary statistical analysis for this secondary endpoint will use the mITT Analysis 
Set employing the MMRM model as described in the Principal Analysis of the Primary 
Endpoint. BL, W5, W8 and W12 values are those referred to the Total ESS Score.  
Supportive analysis for this secondary endpoint will use: 
•  Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with one difference: maximal imputed values at BL, W5, W8 and W12 
will be bounded by the maximal value of 24. 
• Statistical analysis of 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts. 
17.2 
2ND SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE (DERIVED) TO 
END OF WEEK 12 IN MOTOR UPDRS (PART III) SCORE 
The Motor UPDRS analyses will use definitions outlined in Unified Parkinson's 
Disease Rating Scale (UPDRS).  
The primary statistical analysis for this secondary endpoint will use the MMRM model 
as described in the Principal Analysis of the Primary Endpoint. BL, W5, W8 and W12 
values are those referred to the Motor UPDRS Score.  
Supportive analysis for this exploratory endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with one difference: maximal imputed values at BL, W5, W8 and W12 
will be bounded by the maximal value of 108. 


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• Statistical analysis of the 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts.  
17.3 
3RD SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF WEEK 
12 IN ADL UPDRS SCORE 
The ADL UPDRS analyses will use definitions outlined in Unified Parkinson's Disease 
Rating Scale (UPDRS).  
Formal analysis will test the change from Baseline (Derived) to End of Week 12 visit 
in ADL UPDRS Score employing two contrasts: P2B001 vs. PPX and P2B001 vs. 
RAS. 
The primary statistical analysis for this secondary endpoint will use the mITT Analysis 
Set employing the MMRM model as described in the Principal Analysis of the Primary 
Endpoint. BL, W5, W8 and W12 values are those referred to the ADL UPDRS Score. 
Supportive analysis for this secondary endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with one difference: maximal imputed values at BL, W5, W8 and W12 
will be bounded by the maximal value of 52. 
• Statistical analysis of 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts.  
17.4 
4TH SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END OF WEEK 
12 IN ADL SUBSCALE SCORE OF PDQ39 
The ADL subscale of the PDQ39 analyses will use definitions outlined in Parkinson’s 
Disease Quality of Life Questionnaire (PDQ39).  
Formal analysis will test the change from Baseline (Derived) to End of Week 12 visit 
in ADL subscale score of PDQ39 employing three contrasts according to the testing 
order specified in Significance Level and Multiplicity Adjustment: Firstly, P2B001 vs. 
PramiER and thereafter, if met, P2B001 vs. PPX and P2B001 vs. RAS. BL and W12 
values are those referred to the ADL subscale of PDQ39.   
The primary statistical analysis for this secondary endpoint will use the mITT Analysis 
Set using the Analysis of Covariance (ANCOVA) employing the SAS® MIXED 
procedure. The model will include the planned treatment group (TRTP), CGR1 and 
baseline score as explanatory variables. The least squares means (LSM) estimates of 
the study groups, the between groups contrasts estimates as well as the corresponding 


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95% CI’s and p-values for inference will be displayed. The SAS® code to be used is 
outlined below: 
proc mixed Data=&dataset Method=REML; 
     ods output LSMeans=LSmeans Diffs=Diffs;  
     Class TRTp CGR1; 
     Model CHG=TRTp CGR1 BL /Solution; 
     LSMeans  TRTp          /Pdiff CL; 
run;quit; 
 
Supportive analysis for this secondary endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with the following differences:  
✓ As PDQ39 was  collected at Baseline Visit and at the End of Week 12 the SAS® 
code referring to W5 and W8 will be omitted. 
✓ Maximal imputed values at BL and W12 will be bounded by the maximal value 
of 100. 
• Statistical analysis of 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts. 
17.5 
5TH SECONDARY EFFICACY ENDPOINT: CHANGE FROM BASELINE TO END 
OF WEEK 12 IN TOTAL PDQ39 SCORE 
The ADL subscale of the PDQ39 analyses will use definitions outlined in Parkinson’s 
Disease Quality of Life Questionnaire (PDQ39).  
Formal analysis will test the change from Baseline (Derived) to End of Week 12 visit 
in total PDQ39 score employing two contrasts according to the testing order specified 
in Significance Level and Multiplicity Adjustment: P2B001 vs. PPX and P2B001 vs. 
RAS. BL and W12 values are those referred to the total PDQ39 score.   
Primary statistical analysis for this secondary endpoint as well as supportive analysis 
for this secondary endpoint will be conducted as described in Section 17.4. 
 
 
 
 
   
 
 


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EXPLORATORY ENDPOINTS AND ANALYSES (P2B001 VS. 
COMPONENTS) 
Analyses of the exploratory endpoints will provide additional insight into the 
therapeutic effect of P2B001 as compared to its two components. The mITT 
Analysis Set will be used as the primary analysis set for effectiveness analysis for the 
below exploratory endpoints. Supportive assessments for these exploratory endpoints 
will be conducted using the Primary Estimand employing the mITT. Results will be 
provided displaying the model derived estimates and 95% CIs, the magnitude of 
treatment effect and 95% CIs, as well as nominal p-values. 
The exploratory endpoints to be analyzed are: 
18.1 
END OF WEEK 12 CGI-S RESPONDERS ANALYSIS 
The End of Week 12 Responders analyses for CGI-S will use definitions outlined in 
Clinical Global Impression – Severity Scale (CGI-S). 
18.1.1 
Primary CGI-S Responders Analysis  
The primary statistical analysis for this exploratory endpoint will use logistic 
regression (SAS® PROC LOGISTIC) and model will include the following fixed 
effects: TRTp, CGR1, and baseline CGI-S Score (as 1 df variable). The response 
classification (“Responder”/”Non-Responder”) will be used as response in the model.  
The SAS® code to be used is outlined below: 
proc logistic data=&dataset order=internal descending; 
     ODS output CLOddsWald=CLOddsWald Diffs=Diffs LSmeans=LSMeans; 
     class cgr1;  
     class TRTp (ref='P2B001') / param=ref param=glm; 
     model Response = TRTp CGR1 BL  / cl risklimits expb; 
 
 lsmeans TRTp / cl ilink pdiff; 
run;quit; 
18.1.2 
Supportive CGI-S Responders Analysis 
Supportive analysis for this exploratory endpoint will be conducted with reference to 
the Primary Estimand as described below: 
18.1.2.1 Multiple Imputations (CGI-S Responders Analysis) 
1. Step 1: At the initial stage, a dataset (named “MIin1stEst”) will be constructed, 
including, per mITT subject (in one dataset record) the following: treatment arm 
to which subject was randomized to (TRTP), Pooled Country/Geographical Region 
(CGR1) and CGI-S at Baseline (Derived) and at End of Week 12. Observations of 
MIin1stEst collected post rescue therapy initiation, as well as post last 
P2B/Placebo administration date of ETT for whatever reason will be set to missing 
values. 


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2. Step 2: The MI procedure, using the FCS method (SAS® MI procedure with the 
logistic method of classification variables) will be used for MI under the missing 
at random (MAR) assumption. The number of imputations will be 100 and 
procedure will use a seed of 1357. The SAS® code for this step is provided below: 
proc MI Data=MIin1stEst Out=TMP Nimpute=100 Seed=1357; 
     Class TRTp CGR1 W12;   
     Var TRTp CGR1 BL W12; 
     FCS logistic(W12 = TRTp CGR1 BL); 
    run;quit; 
 
3. Step 3: Scores multiply imputed in previous step under MAR following rescue 
therapy will then be set to missing values in all 100 imputed datasets for the 
purpose of MI under MNAR. Thereafter, for each of the 100 imputed datasets, 
multiple imputations using the method for monotone regression missingness will 
be performed with rasagiline (RAS 0.75) based imputation as control reference 
under MNAR. The number of imputations will be 1 and the procedure will use a 
seed of 3579 for this imputation step. The SAS® code for this step is provided 
below: 
PROC MI data=TMP1 out=MIout1stEst NIMPUTE=1 seed=3579 
     minimum=. . 0 0 maximum=. . 7 7; 
     class trtp cgr1; 
     VAR cgr1 BL W12; 
     monotone regression; 
     MNAR model (W12/modelobs=(trtp='RAS 0.75')); 
     by _imputation_; 
run; 
4. Step 4: For each subject within each of the 100 imputed datasets the change from 
Baseline (Derived) to the End of Week 12 (CHG), following the rounding to 
nearest integer of imputed values, will be calculated and the subject will be 
classified as a “Responder” or a “Non-Responder” as outlined in Clinical Global 
Impression – Severity Scale (CGI-S). 
18.1.2.2 Statistical Analysis of the Multiply Imputed Datasets (CGI-S Responders 
Analysis) 
The statistical analysis of the multiply imputed datasets will be conducted as outlined 
below:  
1. Step 1: Each of the 100 imputed datasets will be analyzed for the between groups 
contrasts in this response variable. Analyses will use logistic regression (SAS® 
PROC LOGISTIC) and model will include the following fixed effects: TRTp, 
CGR1, and baseline CGI-S Score (as 1 df variable). The response classification 
(“Responder”/”Non-Responder”) will be used as response in the model.  
The SAS code to be used at this stage is: 
 
 


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proc logistic data=MIout1stEst order=internal descending; 
     ODS output CLOddsWald=CLOddsWaldMI 
                ParameterEstimates=ParameterEstimatesMI 
                LSmeans=LSMeansMI; 
     class cgr1;  
     class TRTp (ref='P2B001') / param=ref param=glm; 
     model Response = TRTp CGR1 BL  / cl risklimits expb; 
    lsmeans TRTp / cl ilink; 
     by _imputation_; 
run;quit; 
2. Step 2: Then, the 100 WALD test statistics will directly be combined applying the 
Wilson-Hilferty transformation to normalize the test statistic and results will be 
combined using Rubin’s rule to obtain the p-value using the below SAS code:  
* Wilson-Hilferty Transformation to the WALD Statistics *; 
data WALD;set ParameterEstimatesMI; 
     WALD_value_WilHil=((WaldChiSq/DF)**(1/3) –  
                       (1-2/(9*DF)))/SQRT(2/(9*DF)); 
     WALD_sterr_WilHil=1.0; 
     if classval0 in('PramiER','PPX 0.6','RAS 0.75'); 
     contrast=trim(classval0)||' vs P2B001'; 
     keep contrast WaldChiSq DF WALD_sterr_WilHil 
                                WALD_value_WilHil; 
    run; 
 
* Combine Results *; 
PROC MIANALYZE data=WALD; 
     by contrast; 
     ODS output ParameterEstimates=MI_p_value; 
     modeleffects WALD_value_WilHil; 
     stderr       WALD_sterr_WilHil; 
run; 
 
* Compute p-value from the Combined CMH Test *; 
data MI_p_value;set MI_p_value; 
     if tValue>0 then Prob_upper=Probt/2; 
      else Prob_upper=1-probt/2; 
      keep contrast Prob_upper; 
run; 
3. Step 3: The magnitude of treatment effect will use the Odds Ratio. As the odds-
ratio is not expected to be normally distributed, analysis will be conducted on the 
log transformed odds-ratio. Standard error will be derived from the log transformed 
confidence interval of the odds-ratio. Back transformed estimate and its 95% 
confidence interval will be used to derive the combined estimate (Rubin’s Rules). 
The SAS code to be used for these procedures is provided below:  
 
 


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* Log-transform odds ratio estimates and obtain SE from CI *; 
data CLOddsWaldMI;SET CLOddsWaldMI; 
     log_or_value=LOG(OddsRatioEst); 
     log_or_se=(LOG(UpperCL)-LOG(LowerCL))/(2*1.96); 
     if effect in('TRTP PramiER  vs P2B001', 
                  'TRTP PPX 0.6  vs P2B001', 
                  'TRTP RAS 0.75 vs P2B001'); 
 
 contrast=left(tranwrd(Effect,'TRTP ','')); 
 
 keep contrast log_or_value log_or_se; 
    run; 
 proc sort data=CLOddsWald;by contrast;run; 
 
* Combine the Log-transformed Odds-Ratio *; 
PROC MIANALYZE DATA=CLOddsWaldMI; 
     by contrast; 
     ODS OUTPUT PARAMETERESTIMATES=PARAMETERESTIMATES_OR; 
     MODELEFFECTS log_or_value; 
     STDERR       log_or_se; 
run; 
  
* Back-transform combined values *; 
DATA PARAMETERESTIMATES_OR;SET PARAMETERESTIMATES_OR; 
     Estimate_back = EXP(ESTIMATE);            
     LCL_back=Estimate_back*EXP(-1.96*STDERR); 
     UCL_back=Estimate_back*EXP(+1.96*STDERR); 
         keep contrast Estimate_back LCL_back UCL_back; 
run; 
 
4. Step 4: The model adjusted combined (Rubin’s Rules) estimated proportion of 
responders will then be obtained using the below SAS code: 
* Combined LSMeans for model adjusted responders proportions *; 
proc sort data=LSMeansMI;by TRTp;run; 
PROC MIANALYZE DATA=LSMeansMI; 
     by TRTp; 
     ODS OUTPUT PARAMETERESTIMATES=PARAMETERESTIMATES_LSmeans; 
     MODELEFFECTS Mu; 
     STDERR       StderrMu; 
run; 
18.2 
END OF WEEK 12 TOTAL UPDRS RESPONDERS ANALYSIS 
The End of Week 12 Responders analyses for Total UPDRS responder’s analysis will 
use definitions outlined in Unified Parkinson's Disease Rating Scale (UPDRS). 
The primary statistical analysis for this exploratory endpoint will be conducted as 
described in Section 18.1.1 with the difference of using the Total UPDRS Response 
variable (“Responder”/”Non-Responder”)  adjusted to baseline Total UPDTS score. 
Supportive analysis for this exploratory endpoint will be conducted with reference to 
the Primary Estimand as described below: 


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• Multiple Imputations will be conducted as outlined in Section 15.4.1 with the 
following addition to Step 4:  The change from Baseline (Derived) to the End of 
Week 12 (CHG)  will be used to define the Total UPDRS binary response variable: 
A subject with an improvement of 4 points or more will be classified as a 
“Responder”. Otherwise, the subject will be defined as a “Non-Responder”. 
• 
Statistical analyses of the multiply imputed data sets will be conducted as outlined 
in Section 18.1.2.2 with the difference of using the Total UPDRS binary response 
variable (“Responder”/”Non-Responder”)  and the Total UPDRS baseline value. 
18.3 
CHANGE FROM BASELINE TO END OF WEEK 12 IN TOTAL ESS SCORE 
The analysis of the change from Baseline to End of Week 12 in the Total ESS score is 
detailed in 1st Secondary Efficacy Endpoint: Change from Baseline to End of Week 
12 in Total ESS Score. The analyses of the P2B001 vs. its components will accordingly 
be conducted as an exploratory endpoint analysis. 
18.4 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE PDQ39 
SUBSCALES SCORES 
The analyses of the PDQ39 subscales will use definitions outlined in Parkinson’s 
Disease Quality of Life Questionnaire (PDQ39).  
Please note that the analysis plan for the change from baseline (derived) to End of 
Week 12 in the PDQ39 ADL subscale and in the Total PDQ39 score were already 
outlined as part of the analyses of the secondary endpoints and therefore are not 
repeated in this section. Within this work frame of exploratory endpoints analyses, the 
following subscales will be analyzed, each separately: 
• Mobility Score 
• Emotional Well-Being Score 
• Stigma Score 
• Social Support Score 
• Cognitive Impairment Score 
• Communications Score 
• Bodily Discomfort Score 
Analysis of each of the above subscales will be performed as outlined in 4th Secondary 
Efficacy Endpoint: Change from Baseline to End of Week 12 in ADL Subscale Score 
of PDQ39. 
 
 


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 18.5 
CHANGE FROM BASELINE (DERIVED) IN THE IMPULSIVE-COMPULSIVE DISORDERS 
IN PD (QUIP-RS) TOTAL SCORE AND SUBSCALES SCORES  
The QUIP-RS analyses will use definitions outlined in Impulsive-Compulsive 
Disorders in Parkinson's Disease (QUIP-Rating Scale).  
Within this scope of work, a total of 8 aggregate metrics will be analyzed, each 
separately for the Change from Baseline (Derived) to End of Week 12: 
• Total QUIP-RS Score 
• Total ICD Score 
• Total Gambling Score 
• Total Sex Score 
• Total Buying Score 
• Total Eating Score 
• Total Hobbyism-Punding Score 
• Total Medications Score 
The statistical analysis for each of these 8 aggregated exploratory endpoints will use 
the MMRM model as described in the Principal Analysis of the Primary Endpoint. BL, 
W3, W5, W12 and W14 values are those referred to the each of the aggregate metrics 
above listed. 
18.6 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE SUMMARY 
SCORES OF HEALTH-RELATED QUALITY OF LIFE (HRQOL) SF-12V2 
The HRQOL SF-12v2 analyses of the two summary scores will use definitions 
outlined in Health-Related Quality of Life (HRQOL) SF-12v2.  
Within this scope of work, two norm based scores will be analyzed, each separately: 
• Mental Component Summary Score. 
• Physical Component Summary Score. 
The primary statistical analysis for each of these exploratory endpoints will use the 
mITT Analysis Set using the Analysis of Covariance (ANCOVA) employing the SAS® 
MIXED procedure. The model will include the planned treatment group (TRTP), 
CGR1 and baseline score as explanatory variables. The least squares means (LSM) 
estimates of the study groups, the between groups contrasts estimates as well as the 
corresponding 95% CI’s and nominal p-values will be displayed. The SAS® code to 
be used is outlined below: 
 
 


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proc mixed Data=&dataset Method=REML; 
     ods output LSMeans=LSmeans Diffs=Diffs;  
     Class TRTp CGR1; 
     Model CHG=TRTp CGR1 BL /Solution; 
     LSMeans  TRTp          /Pdiff CL; 
run;quit; 
Supportive analysis for each of these exploratory endpoints will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with the following differences:  
✓ As SF-12V2 was  collected at Baseline Visit and at the End of Week 12 the 
SAS® code referring to W5 and W8 will be omitted. 
✓ Maximal imputed values at BL and W12 will be bounded by the maximal value 
of 100. 
• Statistical analysis of 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts. 
18.7 
END OF WEEK 12 CGI-I  RESPONDERS ANALYSIS 
The End of Week 12 Responders analyses for CGI-I responders analysis will use 
definitions outlined in Clinical Global Impression – Improvement Scale (CGI-I). 
The primary statistical analysis for this exploratory endpoint will use the GLIMMIX 
procedure for binary outcome measure with logit link function. The model will include 
the interaction between the treatment group and visit and CGR1 as fixed factors and 
the response classification (“Responder”/”Non-Responder”) will be used as response 
in the model. Note that Analysis will model the probability of “Responder”. The SAS® 
code to be used is outlined below: 
 
proc glimmix data=ADQS; 
     ODS output Diffs=Diffs LSmeans=LSMeans; 
     class SubjID TRTp VISIT cgr1;  
     model Response(event='Responder') = TRTp*Visit CGR1 / 
           LINK=LOGIT DIST=binary DDFM=KR;  
     RANDOM INT / sub=SubjID; 
 
 lsmeans Visit*TRTp / cl ilink pdiff oddsratio; 
     where mITT='Yes' and QSCAT='CGI' and Param='CGI-Improvement' 
     and Visit in('End of Week 5','End of Week 8','End of Week 12'); 
run;quit; 
 
Supportive analysis for this exploratory endpoint will be conducted with reference to 
the Primary Estimand as described below: 
• Multiple Imputations will be conducted as outlined below: 


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1. Step 1: At the initial stage, a dataset (named “MIin1stEst”) will be constructed, 
including, per mITT subject (in one dataset record) the following: treatment 
arm 
to 
which 
subject 
was 
randomized 
to 
(TRTP), 
Pooled 
Country/Geographical Region (CGR1) and CGI-I at End of Week 5, End of 
Week 8 and at End of Week 12. Observations of MIin1stEst collected post 
rescue therapy initiation, as well as post last P2B/Placebo administration date 
of ETT for whatever reason will be set to missing values. 
2. Step 2: The MI procedure, using the FCS method (SAS® MI procedure with 
the logistic method of classification variables) will be used for MI under the 
missing at random (MAR) assumption. The number of imputations will be 100 
and procedure will use a seed of 3579. The SAS® code for this step is provided 
below: 
* Multiple Imputations for the Primary Estimand *; 
proc MI Data=MIin1stEst Out=TMP Nimpute=100 Seed=3579; 
     Class TRTp CGR1 W12;   
     Var TRTp CGR1 W5 W8 W12; 
     FCS logistic(W12 =TRTp CGR1); 
run;quit; 
3. Step 3: Scores multiply imputed in previous step under MAR following rescue 
therapy will then be set to missing values in all 100 imputed datasets for the 
purpose of MI under MNAR. Thereafter, for each of the 100 imputed datasets, 
multiple imputations using the method for monotone regression missingness 
will be performed with rasagiline (RAS 0.75) based imputation as control 
reference under MNAR. The number of imputations will be 1 and the 
procedure will use a seed of 57911 for this imputation step. The SAS® code for 
this step is provided below: 
PROC MI data=TMP1 out=MIout1stEst NIMPUTE=1 seed=57911 
     minimum=. . 0 0 0 maximum=. . 7 7 7; 
     class trtp cgr1; 
     VAR cgr1 W5 W8 W12; 
     monotone regression; 
     MNAR model (W5 W8 W12/modelobs=(trtp='RAS 0.75')); 
     by _imputation_; 
run; 
4. Step 3: For each subject within each of the 100 imputed datasets, following the 
rounding to nearest integer of imputed values, a subject will be classified as a 
“Responder” or a “Non-Responder” as outlined  in Clinical Global Impression 
– Improvement Scale (CGI-I). 
• 
Statistical analyses of the CGI-I multiply imputed data sets will be conducted as 
outlined in Section 18.1.2.2 with the difference of using the Total CGI-I binary 
response variable at 'End of Week 12’ while omitting BL value in the PROC 
LOGISTIC model statement. 


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 19 
ADDITIONAL EXPLORATORY ENDPOINTS AND ANALYSES (P2B001 VS. 
PRAMI-ER) 
Analyses of the additional exploratory endpoints will provide further insight into the 
therapeutic effect of P2B001 as compared PramiER. The mITT Analysis Set will be 
used as the primary analysis set for effectiveness analysis for the below additional 
exploratory endpoints and supportive assessments for these will be conducted using 
the Primary Estimand. Results will be provided displaying the model derived 
estimates and 95% CIs, the magnitude of treatment effect and 95% CIs, as well as 
nominal p-values. 
The additional exploratory endpoints to be analyzed are: 
19.1 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN TOTAL UPDRS 
(PART II AND III) SCORE 
The Total UPDRS analyses will use definitions outlined in Unified Parkinson's 
Disease Rating Scale (UPDRS).  
The primary statistical analysis for this exploratory endpoint will use the MMRM 
model as described in the Principal Analysis of the Primary Endpoint. BL, W5, W8 
and W12 values are those referred to the Total UPDRS Score.  
Supportive analysis for this exploratory endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand. 
• Statistical analysis of the 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts.  
19.2 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN MOTOR UPDRS 
(PART III) SCORE 
The Motor UPDRS analyses will use definitions outlined in Unified Parkinson's 
Disease Rating Scale (UPDRS).  
The primary statistical analysis for this exploratory endpoint will use the MMRM 
model as described in the Principal Analysis of the Primary Endpoint. BL, W5, W8 
and W12 values are those referred to the Motor UPDRS Score.  
Supportive analysis for this exploratory endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with one difference: maximal imputed values at BL, W5, W8 and W12 
will be bounded by the maximal value of 108. 


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• Statistical analysis of the 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts.  
19.3 
CHANGE FROM BASELINE TO END OF WEEK 12 IN ADL UPDRS SCORE 
The ADL UPDRS analyses will use definitions outlined in Unified Parkinson's Disease 
Rating Scale (UPDRS).  
The primary statistical analysis for this exploratory endpoint will use the MMRM 
model as described in the Principal Analysis of the Primary Endpoint. BL, W5, W8 
and W12 values are those referred to the Motor UPDRS Score.  
Supportive analysis for this exploratory endpoint will use: 
• Multiple Imputations step as described in Multiple Imputations for the Primary 
Estimand with one difference: maximal imputed values at BL, W5, W8 and W12 
will be bounded by the maximal value of 52. 
• Statistical analysis of the 100 multiply imputed datasets for the Primary Estimand 
will use an ANCOVA as described in the Main Supportive Analysis for the 
Primary Endpoint and will be followed by two MIANALYZE steps to combine the 
least square means and the between groups contrasts.  
19.4 
END OF WEEK 12 CGI-S RESPONDERS ANALYSIS 
The End of Week 12 Responders analysis for CGI-S for the P2B001 vs. Prami ER 
contrast will use the methodology outlined in Section 18.1 using the mITT Analysis 
Set. 
19.5 
END OF WEEK 12 TOTAL UPDRS RESPONDERS ANALYSIS 
The End of Week 12 total UPDRS responders analysis for the P2B001 vs. Prami ER 
contrast will use the methodology outlines in Section 18.2 using the mITT Analysis 
Set. 
19.6 
END OF WEEK 12 CGI-I  RESPONDERS ANALYSIS 
The End of Week 12 Responders analysis for CGI-I for the P2B001 vs. Prami ER 
contrast will use the methodology outlines in Section 18.7 using the mITT Analysis 
Set. 
 
 
 


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 19.7 
CHANGE FROM BASELINE (DERIVED) TO END OF WEEK 12 IN THE PDQ39 
SUBSCALES SCORES 
The analyses of the change from baseline (Derived) to the end of Week 12, evaluating 
the P2B001 vs. PramiER contrast will be conducted for all of the PDQ39 aggregate 
scores excluding the PDQ39 ADL subscale which was already outlined as part of the 
analyses of the secondary endpoints and therefore is not repeated in this section.  
Analysis of each of these aggregates will be performed as outlined in 5th Secondary 
Efficacy Endpoint: Change from Baseline to End of Week 12 in Total PDQ39 Score.  
19.8 
PROPORTION (%) OF PATIENTS WITH POST-BASELINE ESS SCORE >10 
The analysis of this binary outcome measure  will use definitions outlined in Epworth 
Sleepiness Scale (ESS). Analysis will be conducted using the mITT Analysis Set. 
The primary statistical analysis for this exploratory endpoint will use logistic 
regression (SAS® PROC LOGISTIC) and model will include the following fixed 
effects: TRTp, CGR1, and baseline Total ESS Score (as 1 df variable). The response 
classification (“Post-Baseline ESS>10”/”Otherwise”) at any time post baseline will be 
used as response in the model. Note that Analysis will model the probability of (“Post-
Baseline ESS>10”. The SAS® code to be used is outlined below: 
proc logistic data=&dataset order=internal descending; 
     ODS output CLOddsWald=CLOddsWald 
         ParameterEstimates=ParameterEstimates LSmeans=LSMeans; 
     class cgr1;  
     class TRTp (ref='P2B001') / param=ref param=glm; 
     model Response = TRTp CGR1 BL  / cl risklimits expb; 
     lsmeans TRTp / cl ilink; 
run;quit; 
Supportive analysis for this exploratory endpoint will be conducted with reference to 
the Primary Estimand as described below: 
• Multiple Imputations will be conducted as outlined in Section 15.4.1 but Step 4 
will read as follows: 
Step 4: For each subject within each of the 100 imputed datasets, any post baseline 
observation of Total ESS >10 will identify a subject as “Post-Baseline ESS>10”. 
Otherwise, a subject will be classified as ” Otherwise”. 
• 
Statistical analyses of the multiply imputed data sets will be conducted as outlined 
in Section 18.1.2.2 with the difference of using this binary response variable and 
the Total ESS baseline value. 
 
 


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 19.9 
PROPORTION (%) OF PATIENTS WITH ESS SCORE ≤10 AT BASELINE AND ESS 
SCORE >10 POST-BASELINE 
The analysis of this binary outcome measure  will use definitions outlined in Epworth 
Sleepiness Scale (ESS). Analysis will be conducted using the mITT Analysis Set. 
The primary statistical analysis for this exploratory endpoint will use logistic 
regression (SAS® PROC LOGISTIC) and model will include the following fixed 
effects: TRTp, CGR1, and baseline Total ESS Score (as 1 df variable). The response 
classification (“ESS<10→ESS>10”/” Otherwise ”), namely the shift from baseline to 
any time post-baseline, will be used as response in the model. Note that Analysis will 
model the probability of “ESS<10→ESS>10”. The SAS® code to be used is outlined 
below: 
proc logistic data=&dataset order=internal descending; 
     ODS output CLOddsWald=CLOddsWald 
         ParameterEstimates=ParameterEstimates LSmeans=LSMeans; 
     class cgr1;  
     class TRTp (ref='P2B001') / param=ref param=glm; 
     model Response (event='ESS<=10 -> ESS>10') = TRTp CGR1 BL  / 
           cl risklimits expb; 
     lsmeans TRTp / cl ilink; 
run;quit; 
Supportive analysis for this exploratory endpoint will be conducted with reference to 
the Primary Estimand as described below: 
• Multiple Imputations will be conducted as outlined in Section 15.4.1 but Step 4 
will read as follows: 
Step 4: For each subject within each of the 100 imputed datasets, any post baseline 
of observation >10 with baseline measurement <10 will identify a subject as 
“ESS<10→ESS>10”. Otherwise, a subject will be classified as ” Otherwise”. 
• 
Statistical analyses of the multiply imputed data sets will be conducted as outlined 
in Section 18.1.2.2 with the difference of using this binary response variable and 
the Total ESS baseline value. 
 
 
 
 
 
 
 
 
 


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 20 
SAFETY ANALYSES 
All safety analyses specified herein pertain to the ST Analysis Set using the ST 
Analysis Set denominator unless otherwise specified. 
20.1 
ANALYSES OF ADVERSE EVENTS 
20.1.1 
Treatment Emergent AEs 
Adverse events were recorded from the time when a subject has signed the Informed 
Consent Form till the then end of the safety follow-up visit. The MedDRA dictionary 
was used to standardize the terms used by the investigator to describe the Adverse 
Events (AEs). 
The following will be incorporated into the analysis of adverse events: 
• All analyses to be provided will include only coded AEs. 
• Adverse events analyses will include only the Treatment Emergent Adverse Events 
(TEAEs), namely, those events which started on the day of first study IP 
administration or afterwards. Both TEAEs and non-TEAES will be listed. 
The following AEs analyses will be provided: 
• The incidence (no. of patients) and frequency (no. of events) of TEAEs will be 
provided when broken down by System Organ Class (SOC), and by SOC and 
Preferred Term (PT) according to MedDRA dictionary. Note that PT is referred 
to the database Dictionary derived term. 
• Breakdowns of TEAEs by all of the AEs attributes will also be provided. 
• The derived dictionary used in the analyses displaying the MedDRA System Organ 
Class (SOC), the Preferred Term (PT) and the AE Verbatim Term as specified by 
the Investigator, will be provided. 
•  SAEs, if any, as captured in the clinical database will be listed. 
• Summary tables of TEAEs including TEAEs reported for those subjects that EST 
or ETT will also be provided. 
• Summary tables of TEAEs including TEAEs reported for those subjects that EST 
or ETT due to adverse events will also be provided. 
20.1.2 
TEAEs of Special Interest 
The incidence and frequency of TEAE of special interest will also be summarized 
using descriptive statistics. These include: 
• Sleep Related (e.g., PT terms: Disturbances in sleep phase rhythm, Poor quality 
sleep, Disturbances in initiating and maintaining sleep (Insomnia), Parasomnias, 
Sleep disorder, Narcolepsy and associated conditions) 


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• Dopaminergic AEs (e.g., PT terms: somnolence, nausea, vomiting, Orthostatic 
hypotension, Hallucinations, hallucinations gustatory, hallucination visual, 
hallucinations auditory, Gambling disorder, Compulsive shopping, Obsessive 
thoughts, 
Obsessive-compulsive, 
Impulsive 
behaviour, 
impulsive–control 
disorder) 
• Depression/Mood: (e.g., PT terms: Depression, Anxiety symptoms, Depressed 
mood, Major depression, Restlessness, Apathy) 
• ICD/OCD: (e.g., PT terms: Gambling disorder, Compulsive shopping, Obsessive 
thoughts, Obsessive-compulsive, Impulsive behavior, impulsive– control disorder) 
• GI Disorders: (e.g., PT terms: Nausea, Vomiting, Diarrhoea, Constipation, 
Abdominal 
pain 
upper, 
Abdominal 
discomfort, 
Gastritis, 
Dyspepsia,  
Gastroesophageal reflux disease, Flatulence) 
• OH Related: (e.g., PT terms: Dizziness, Orthostatic hypotension, Dizziness 
postural, Dizziness exertional, Fall, Hypotension, Syncope) 
• Daytime Sleepiness Related: (e.g., Sudden onset of sleep, Somnolence) 
Temporal pattern of AEs of special interest will also be displayed when broken down 
by the time to events onset as described in 20.1.3 and in 20.1.4. 
20.1.3 
Time to Event Onset (Temporal Pattern of AEs) 
Time to events onset analyses will use the following categories: 
• <=7 Days, >7 Days 
For these time categories, the incidence and frequency of TEAE by time category in 
which TEAEs were reported will be displayed using descriptive statistics. 
20.1.4 
Further Temporal Pattern of AEs  
TEAEs of special interest (see TEAEs of Special Interest) will be displayed using 
graphical presentations as proposed by Olanow et al [Movement Disorders, 2018, 
wileyonlinelibrary.com DOI: 10.1002/mds.27497] 
20.2 
ANALYSES OF LABORATORY DATA 
Safety laboratory tests (chemistry, hematology, coagulation and urinalysis), 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 for sites in 
Europe and Eurofins Central Laboratory US for sites in USA and Canada.  
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 


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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.) 
Laboratory data analyses will include the following: 
• Shift Analysis: Assessments of laboratory was based on classification of each 
measurement with reference to the normal ranges (“Low”, “Normal” or “High”). 
Summary tables for each parameter tested providing the shift from Baseline 
(Derived) to End of Week 14 assessment will be provided by treatment group and 
visit. 
• Quantitative Analysis: Summary statistics of results measurements and changes 
from Baseline (Derived) to End of Week 14 will be presented by treatment group 
and by visit. Note that quantitative results provided in database according to the 
cutoff values; e.g., '<0.13' the value of 0.13 will be used in the analysis. List of 
these cutoffs and related parameters will be provided. 
• Incidence of Potential Clinically Significant (PCS): Incidence of post-baseline 
laboratory data of PCS will be summarized using descriptive statistics according 
to the cutoff’s values detailed below. 
Potentially Clinically Significant (PCS) Laboratory Values 
Parameter 
High/Low PCS 
Alanine Aminotransferase (U/L) 
>3x ULN* 
Aspartate Aminotransferase (U/L) 
>2x ULN* 
Bilirubin (umol/L) 
>2x ULN* 
Urea Nitrogen (mmol/L) 
>2x ULN* 
Alkaline Phosphatase (U/L) 
>2x ULN* 
Creatinine (umol/L) 
>1.5x ULN* 
Creatinine Clearance (mL/min) 
<50 
* ULN – Upper Limit of age-sex matched normal range 
 
 


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 20.3 
ANALYSES OF 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 (OH) is defined as a reduction of systolic blood pressure of at 
least 20 mmHg or 10 mmHg in diastolic blood pressure within 3 minutes of quiet 
standing. Height will be measured at screening only and weight will be measured at 
all visits.  Orthostatic Hypotension Clinical Evaluation was also been conducted as 
described below: 
1. On baseline and visits 4, 5 and 6, subjects that have OH will be asked to answer 
one question of the orthostatic hypotension activity scale (OHAS) which inquiries 
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.   
Analyses of vital signs will be performed as described below: 
• Summary statistics of results measurements and changes from Baseline (Derived) 
to each scheduled visit will be presented by treatment group and by visit in which 
measurement was taken. 
• Proportion (%) of subjects with orthostatic hypotension at each scheduled visit and 
at any time following first study drug dose (see Definition of Date of First Study 
Drug Treatment) will be presented by treatment group. The denominator for this 
analysis will by all subjects included in the ST Analysis Set. 
• Proportion (%) of subjects with clinically significant orthostatic hypotension 
following first study drug dose (see Definition of Date of First Study Drug 
Treatment) will be presented by treatment group. The denominator for this analysis 
will by all subjects included in the ST Analysis Set. 
• Incidence and listing of measurements of Potential Clinical Significance (PCS) 
value after first study dose will be presented by treatment group. The denominator 
for this analysis will by all subjects included in the ST Analysis Set with post-
baseline measurements. 
 
 


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Potentially Clinically Significant (PCS) Vital Signs Ranges 
Parameter 
Criteria for Potentially Clinically Significant* 
Heart Rate (bpm) 
>120 and Increase >30 
<50 and Decrease >30 
Systolic** BP (mmHg) 
>160 and Increase >30 
<80 and Decrease >30 
Diastolic** BP (mmHg) 
>100 and Increase >20 
<50 and Decrease >20 
* Increases / Decreases relative to Baseline (Derived) measurement 
**   For both measurements taken at supine and at standing 
20.4 
ANALYSES OF 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 initiated and dated by the Investigator. 
Analyses of ECG evaluations will be performed in the following manner: 
• Descriptive statistics of quantitative 12-Lead ECG parameters measured at 
scheduled visits by treatment group will be provided along with changes from 
baseline.  
• Proportion (%) of subjects with abnormal ECG at each scheduled visit and at any 
time following first study drug dose (see Definition of Date of First Study Drug 
Treatment) will be presented by treatment group. The denominator for this analysis 
will be all subjects included in the ST Analysis Set. 
• Proportion (%) of subjects with clinically significant abnormal ECG following first 
study drug dose (see Definition of Date of First Study Drug Treatment) will be 
presented by treatment group. The denominator for this analysis will be all subjects 
included in the ST Analysis Set. 
• Shift analysis of Investigator assessment from Baseline (Derived) to each scheduled 
visit and to last observed assessment will also be performed. 


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• Incidence and listings of individual subject’s ECG findings of Potential Clinical 
Significance (PCS) will be provided. The denominator for this analysis will be all 
subjects included in the ST Analysis Set. 
 
Potentially Clinically Significant ECG Ranges 
Parameter 
Criteria for Potentially Clinically Significant (PCS) 
QTcF interval (msec) 
Prolonged QTcF interval (QTcF >450) 
Heart Rate (bpm) 
 
Tachycardia (HR >120) 
Bradycardia (HR <50) 
PR interval (msec) 
Prolonged PR (PR>200) 
Short PR (PR<120) 
QRS Interval (msec) 
Wide QRS (QRS>120) 
Narrow QRS (QRS<70) 
RR Interval (msec) 
Short RR interval (RR<500) 
Long RR interval (RR>1200) 
 
20.5 
ANALYSES OF PHYSICAL EXAMINATION 
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.  
The distribution of physical examination assessments at Baseline (Derived) and at the 
End of Week 14 according to protocol pre-defined body systems. The denominator 
will be the number of subjects of the ST Analysis Set.  
Shift analysis from Baseline (Derived) to End of Week 14 for each body system will 
be performed. The denominator for this analysis will be the subjects of the ST Analysis 
Set. 
Individual subjects’ data listings providing all the physical assessments results will 
also be provided. 
 
 


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 20.6 
ANALYSES OF SUICIDALITY (COLUMBIA-SUICIDE SEVERITY RATING SCALE) 
Suicidality analysis will use definitions outlined in Columbia-Suicide Severity Rating 
Scale (C-SSRS).  
The distribution of the number of subjects identified with either “Suicidal behavior”, 
“Suicidal Ideation” or “Suicidal Behavior or Ideation” at screening/baseline and during 
study will be provided.  
Summary table, for each of the above classifications, displaying the shift from 
screening/baseline to the post baseline period, using the worst case scenario, will be 
provided displaying number and percentages of subjects in each category when broken 
down by treatment groups. The denominator for this analysis will be the number of 
subjects with baseline and post-baseline assessments. 
Individual subjects’ data listings providing the full questionnaire details will also be 
provided. 
20.7 
ANALYSES OF ORTHOSTATIC HYPERTENSION SYMPTOMS ASSESSMENT (OHSA) 
Q1 
OHSA Q1 analysis will use definitions outlined in Orthostatic Hypotension Symptoms 
Assessment (OHSA) question 1. 
Please note that the questionnaire was completed sporadically only by subjects 
experiencing orthostatic hypotension. 
The distribution of no. of subjects by OHSA Q1 categorical score [=0 (no symptoms) 
or >0) will be provided by study period and by planned scheduled visits will be 
provided. The denominator for this analysis will be the number of subjects included in 
the ST Analysis Set. 
A summary table, displaying the distribution of no. of subjects by OHSA Q1 Post 
Baseline Maximal Score will be displayed and individual subjects’ data listings will 
also be provided. 
20.8 
TOLERABILITY AND DROP-OUT ASSESSMENTS 
Tolerability analysis will be based on the number (%) of subjects who: 
• Early terminated treatment. 
• Early terminated study. 
• Early terminated treatment due to adverse events. 
• Early terminated study due to adverse events. 


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NCT03329508 
 
The denominator for this analysis will be the number of subjects included in the ITT 
Analysis Set. 
Time to withdrawal will be presented by Kaplan-Meier curves broken down by 
treatment groups. Censoring of untreated subjects will use event day 0. 
21 
DEVIATION FROM STATISICAL ANALYSIS PLAN (SAP) 
Any deviation from this Statistical Analysis Plan (SAP) will be reported in the Clinical 
Study Report. 
 
 
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