Clinical trial NCT03521635
Conditions: Parkinson Disease
Sponsor: Boehringer Ingelheim
Start date: 2018-07-03; Completion date: 2020-01-07
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of the study is to explore firstly, then further evaluate and confirm the efficacy between Pramipexole Sustained Release (SR) versus Pramipexole Immediate Release (IR) on nocturnal symptoms (as measured by the change from baseline to the end of the maintenance period in Parkinson's Disease Sleep Scale 2nd version (PDSS-2) score) in L-dopa+ treated patients with advanced Parkinson's disease (PD).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pramipexole SR intervention 2: Pramipexole IR
Intervention descriptions: intervention 1: Tablets intervention 2: Tablets

Protocol documents:
Prot_000.pdf: 
ABCD
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
CLINICAL TRIAL PROTOCOL
Document Number:
c20307124-03
EudraCTNo.:
EU Trial No:
Not applicable
BI Trial No.:
0248-0686
BI Investigational 
Product(s):
Pramipexole dihydrochloride monohydrate
Title:
A two- stage multicenter, open-label, randomized, active controlled parallel 
group study comparing the efficacy and safety of Pramipexole SR versus 
Pramipexole IR administered orally over an 18-week treatment on nocturnal 
symptoms in L-Dopa+ treated patients with advanced Parkinson’s disease (PD)
Lay Title:
The SUSTAIN study compares the effects of Sustained and immediate-release 
pramipexole on the noctUrnal Symptoms of paTients with Advanced 
ParkInsoN’s diease who also take L-Dopa
Clinical Phase:
IV
Clinical Trial 
Leader:
Phone: 
Fax: 
Email: 
Coordinating 
Investigator:
Fax: 
Email:
Phone: 
          
Fax: 
Email:
Status:
Final Protocol (Revised Procotol based on global amendment 2)
Version and Date: Version:
Date:
3.0
18 Dec 2018
Page 1 of 78
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product name
Pramipexole sustained release (SR)
Active ingredient name:
Pramipexole dihydrochloride monohydrate
Protocol date
30 Nov 2017
Revision date
18 Dec 2018
Trial number
0248-0686
Title of trial:
A two- stage multicenter, open-label, randomized, active controlled parallel 
group study comparing the efficacy and safety of Pramipexole SR versus 
Pramipexole IR administered orally over an 18-week treatment on nocturnal 
symptoms in L-Dopa+ treated patients with advanced Parkinson’s disease 
(PD)
Coordinating 
Investigator:
Phone: 
          
Fax: 
Email:
Phone: 
          
Fax: 
Email:
Trial site(s):
National multi-centre trial
Clinical phase:
IV
Objective(s):
Stage I:
To explore the efficacy of Pramipexole SR versus Pramipexole IR (as 
measured by the change from baseline to week 18 in Parkinson’s disease 
Sleep Scale 2nd version (PDSS-2) total score) in treating nocturnal 
symptoms in patients on L-Dopa+ with advanced PD.
Stage II:
To further evaluate or confirm the efficacy between Pramipexole SR versus 
Pramipexole IR (as measured by the change from baseline to week 18 in 
PDSS-2 total score) in treating nocturnal symptoms in patients on L-Dopa+
with advanced PD based on the results from Stage I.
Methodology:
A two-stage multicenter, open-label, randomized, active controlled parallel 
group study design with comparison of two groups over 18 weeks
Number of patients 
Stage I: 86 randomized 


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entered: 
Stage II: To be calculated based on the results from Stage I
Number of patients on 
each treatment:
Stage I: Pramipexole SR: 43; Pramipexole IR: 43
Stage II: To be calculated based on the results from Stage I
Patients will be randomized into Pramipexole SR and Pramipexole IR 
treatments at a randomization ratio of 1:1.
Diagnosis :
Patients with idiopathic PD diagnosed
Main in- and exclusion 
criteria
•
Patients diagnosed as idiopathic PD with at least 2 years’ PD history, 
30 years of age or older at time of diagnosis, with a modified Hoehn 
and Yahr stage of 2 to 4 at on-time.
•
They must have clinically relevant sleep disturbances (i.e. PDSS-2
total score ≥18 at baseline).
•
They must feel uncomfortable at night because they were unable to 
turn around in bed or move due to immobility (i.e. the scoring of 
question 9 in PDSS-2 ≥2 that means frequency is at least 2 to 3 days 
during the past week).
•
They must have early morning off (i.e. the frequency of “feeling like 
bodily movements are poor when you wake up?” is at least 2 to 3 
days during the past week).
•
They must have motor fluctuations (at least 2 cumulative hours of 
off-time every day during waking hours, documented on a patient 
diary completed for 2 consecutive days before randomization visit). 
•
Patients must be treated with L-Dopa+ (i.e. standard and/or sustained 
release Levodopa/DDC inhibitor), or with a combination of L-Dopa+
and entacapone, at an optimized dose according to investigator’s 
judgement, this dose being stable for at least 4 weeks prior to 
randomization visit. 
•
Patients must not have been treated with sustained release 
dopaminergic drug (i.e. sustained release Levodopa/DDC inhibitor) 
after supper, or any anti-PD medication after 9 pm within 4 weeks 
prior to randomization visit.
•
Patients must not have been treated with dopamine agonists within 4 
weeks prior to randomization visit. A concomitant treatment with one 
or more of the following drugs will be allowed (at a stable dose for at 
least 4 weeks prior to randomization visit and the investigator does 
not intend to change this treatment during the treatment phase):
- anti-parkinsonian anticholinergics;
- selegiline, rasagiline, or other MAO-B-Inhibitor;
- amantadine;
- entacapone (or other COMT-Inhibitor).
Test product(s):
Pramipexole SR (tablets of 0.375 mg, and 0.75 mg)
dose:
SR Dose: 0.375 mg, 0.75mg, 1.5mg, 2.25mg, 3.0mg, 3.75mg, or 4.5mg, 
once daily, at 7-9 pm before bedtime.
The dose of Pramipexole SR should be titrated to an optimized level, to 
achieve a maximum therapeutic effect without intolerable side effects.
mode of administration:
oral (p.o.)
Comparator products:
Pramipexole IR (tablets of 0.25 mg, and 1.0 mg)
dose:
Tablets administered in equally divided doses three times per day to achieve 
a total daily dose of 0.375mg, 0.75mg, 1.5mg, 2.25mg, 3.0mg, 3.75mg, or 
4.5mg, the third dose at 7-9 pm before bedtime.


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The dose of Pramipexole IR should be titrated to an optimized level, to 
achieve a maximum therapeutic effect without intolerable side effects.
mode of administration:
oral (p.o.)
Duration of treatment:
Seven-week flexible up-titration, followed by eleven-week maintenance 
phase and one-week down-titration (if applicable).
Endpoints
Primary efficacy endpoint(to be assessed at week 18):
•
PDSS-2 total score (change from baseline).
Secondary efficacy endpoints (to be assessed at week 18):
•
Nocturnal Hypokinesia Questionnaire (NHQ) score (change from 
baseline)
•
SCOPA-Sleep score (change from baseline)
•
Early morning off (EMO) score (change from baseline)
•
Responder rate for PDSS-2 total score <18
•
Responder rate for EMO score
•
The Parkinson's disease Questionnaire (PDQ)-8 score (change from 
baseline)
•
Responder rate for Clinical Global Impression of Improvement (CGI-I)
•
Responder rate for Patient Global Impression of Improvement (PGI-I)
•
Epworth Sleepiness Scale (ESS) score (change from baseline)
Safety criteria:
Physical examination, weight, vital signs, 12-Lead ECG, laboratory tests, 
adverse events, serious adverse events, and Modified Minnesota Impulsive 
Disorders Interview (MMIDI)
Statistical methods:
Stage I:
Primary analysis: Restricted maximum likelihood (REML) - based repeated 
measures approach. Analyses will include the fixed, categorical effects of 
treatment, visit in the maintenance period, and treatment-by-visit 
interaction, as well as the continuous, fixed covariates of baseline and 
baseline-by-visit interaction.
Secondary analysis: 
For continuous endpoints, the same method as the primary analysis will be 
used. For responder rates, logistic regression analyses will be performed 
with treatment and baseline (if baseline was measured) as the independent 
variables.
Stage II:
If the decision is continuing, the sample size for Stage II will be calculated 
based on the results of Stage I. 


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FLOW CHART13
Trial Period
S1
R1
Flexible up-titration phase
Maintenance 
phase
Follow up visit after <down
titration phase/EOT>
Visit 
V1
V2
TC1
V3
TC2
V4
TC311
TC411
TC511
V5
V6
V72
V82
Week(s)
-2 to -1
0
1
2
3
4
5
6
7
8
12
18
Not applicable
Day(s)
-14 to -3
0
7
14
21
28
35
42
49
56
84
126
Last study dose +2
Time window for visits Day(s)
0
0
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
+3
Written Informed consent3

Assign patient number

Supply Trial identification card

Demographics

Medical history

Review of In-/exclusion criteria


Physical examination


BP, Pulse, Weight, Height4








Check for abnormal behavior7



MMIDI




MMSE

Modified Hoehn and Yahr stage at on-
time

Randomization

Instruct and supply patient diary

Review patient diary

EMO








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Trial Period
S1
R1
Flexible up-titration phase
Maintenance 
phase
Follow up visit after <down
titration phase/EOT>
Visit 
V1
V2
TC1
V3
TC2
V4
TC311
TC411
TC511
V5
V6
V72
V82
Weeks
-2 to -1
0
1
2
3
4
5
6
7
8
12
18
Not applicable
Days
-14 to -3
0
7
14
21
28
35
42
49
56
84
126
Last study dose +2
Time window for visits Day(s)
0
0
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
+3
CGI-I



PGI-I










ESS






PDSS-2






NHQ






SCOPA-Sleep 






PDQ-8 



Safety lab tests


8
Urine Pregnancy test9
(if applicable)


12-lead ECG


8
Dispense trial drugs






Compliance check










6
Concomitant therapy













Adverse events













Instruct and supply health economics 
questionnaire






Review health economics questionnaire10








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1.
Abbreviations are for “Screening” and “Randomization”.
2.
All assessments planned at visit 7 and visit 8 have to be done even if a patient is prematurely withdrawn from the treatment phase. For visit 8, follow up visit 
after down-titration phase or follow up visit after EOT (end of treatment) should be conducted after the end of residual effect period (i.e., 2 days after the last 
study dose)
3.
Re-consenting may become necessary when new relevant information becomes available and should be conducted according to the sponsor’s instructions.
4.
Height will only be measured at Screening (visit 1).
5.
At visit 7, for patients who want to enter a down-titration phase, study medication will be dispensed; for other patients who want to maintain their dosages, 
commercial Pramipexole IR/SR will be provided by themselves under the judgement of investigators.
6.
At visit 8, check medication compliance during the down-titration phase if applicable.
7.
In case the patient experiences any abnormal behavior, then the Modified MIDI sub-scale has to be completed.
8.
To be done at visit 8 only if abnormal at visit 7.
9.
Urine pregnancy test required for all women of child bearing potential. Pregnancy testing is one indicator of pregnancy. Changes in a subject’s menstrual cycle
that may indicate pregnancy must also be considered and a further pregnancy test can be taken if the investigator feels it to be appropriate.
10. The health economics questionnaire should be completed when any health care resources utilized and any cost for PD from 4 weeks prior to randomization visit 
to week 18. The questionnaire should be reviewed by site staff at each on-site visit. (All protocol-driven visits shall not be included unless the additional medical 
resources and costs are consumed, such as registration, disease-related lab test/examination and prescriptions)
11. From TC3 to TC5, if pramipexole dose should be adjusted due to unsatisfactory efficacy or adverse event, on-site visit should be added to adjust dose.
13. The flow chart applies only to Patients enrolled in Stage I.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
5
TABLE OF CONTENTS ........................................................................................................8
11
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........21
2.1.1
Main objectives....................................................................................................21
2.1.2
Primary endpoint(s)............................................................................................21
2.1.3
Secondary endpoint(s) ........................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................23
3.3
TRANSITION FROM STAGE I TO STAGE II..............................................23
3.4
SELECTION OF TRIAL POPULATION .......................................................24
3.4.1
Main diagnosis for trial entry ............................................................................25
3.4.2
Inclusion criteria .................................................................................................25
3.4.3
Exclusion criteria ................................................................................................26
3.4.4
Withdrawal of patients from therapy or assessments .....................................28
3.4.4.1
Withdrawal from trial treatment ...........................................................................28
3.4.4.2
Withdrawal of consent for trial participation........................................................28
3.4.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.2
Selection of doses in the trial..............................................................................31
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................32


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4.1.5.1
Blinding.................................................................................................................32
4.1.5.2
Unblinding and breaking the code ........................................................................32
4.1.6
Packaging, labelling, and re-supply...................................................................32
4.1.7
Storage conditions...............................................................................................33
4.1.7.1
Storage conditions for IR ......................................................................................33
4.1.7.2
Storage conditions for SR .....................................................................................33
4.1.8
Drug accountability.............................................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................34
4.2.1
Other treatments and emergency procedures..................................................34
4.2.2
Restrictions ..........................................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment ......................................................35
4.2.2.2
Restrictions on diet and life style..........................................................................36
4.2.2.3
Restrictions regarding women of childbearing potential ......................................36
4.3
TREATMENT COMPLIANCE........................................................................36
5.
ASSESSMENTS..................................................................................................37
5.1
........................................................................37
5.2
ASSESSMENT OF SAFETY.............................................................................40
5.2.1
Physical examination ..........................................................................................40
5.2.2
Vital signs.............................................................................................................40
5.2.3
Safety laboratory parameters ............................................................................41
5.2.4
Electrocardiogram ..............................................................................................41
5.2.5
Other safety parameters.....................................................................................41
5.2.6
Assessment of adverse events.............................................................................42
5.2.6.1
Definitions of AEs ................................................................................................42
5.2.6.2
Adverse event collection and reporting ................................................................44
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................46
5.3.1
Assessment of pharmacokinetics .......................................................................46
5.3.2
Methods of sample collection .............................................................................46
5.3.3
Analytical determinations ..................................................................................46
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................46
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................46
5.4.1
Biobanking...........................................................................................................46
5.5
OTHER ASSESSMENTS...................................................................................46
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................47
6.
INVESTIGATIONAL PLAN.............................................................................49
6.1
VISIT SCHEDULE.............................................................................................49
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................49
6.2.1
Screening period..................................................................................................49
6.2.2
Treatment period(s)............................................................................................49
6.2.2.1
Randomization visit (visit 2) at day 0...................................................................49
6.2.2.2
Up-titration phase..................................................................................................51
6.2.2.3
Maintenance phase................................................................................................53
6.2.3
Follow up period and trial completion..............................................................55


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
7.1
STATISTICAL DESIGN - MODEL.................................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................57
7.3
PLANNED ANALYSES.....................................................................................57
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................58
7.3.4
Safety analyses.....................................................................................................58
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................59
7.4
INTERIM ANALYSES ......................................................................................59
7.5
HANDLING OF MISSING DATA ...................................................................59
7.6
RANDOMISATION ...........................................................................................59
7.7
DETERMINATION OF SAMPLE SIZE .........................................................59
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION,
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........61
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................61
8.2
DATA QUALITY ASSURANCE ......................................................................62
8.3
RECORDS...........................................................................................................62
8.3.1
Source documents ...............................................................................................62
8.3.2
Direct access to source data and documents.....................................................63
8.3.3
Storage period of records ...................................................................................63
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................63
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........63
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................64
8.6
TRIAL MILESTONES.......................................................................................64
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................65
9.
REFERENCES....................................................................................................66
9.1
PUBLISHED REFERENCES............................................................................66
9.2
UNPUBLISHED REFERENCES......................................................................68
10.
APPENDICES.....................................................................................................71
10.1
ESTIMATED GFR (EGFR) USING MODIFICATION OF DIET IN 
RENAL DISEASE (MDRD) FORMULA [R02-2529].....................................71
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................72
11.1
GLOBAL AMENDMENT 1 ..............................................................................72
11.2
GLOBAL AMENDMENT 2 ..............................................................................76


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT 
Alanine Aminotransferase
AST 
Aspartate Aminotransferase
BI
Boehringer Ingelheim
CGI-I
Clinical Global Impression of Improvement
CI
Confidence Interval
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CNS
Central Nervous System
COMT
Catechol-O-Methyltransferase
CRA
Clinical Research Associate
CRF
CRO
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
Contract Research Organisation
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DB
DBL
Double-blind
Database Lock
DDC
DS
Dopa-Decarboxylase
Daytime sleepiness scale
EDC
ECDEU
Electronic Data Capture
Early Clinical Drug Evaluation Unit
ePRO
EOT
Electronic Patient Reported Outcome
End of Treatment
ESS
EMO
EU
Epworth Sleepiness Scale
Early Morning Off
European Union 
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
FDA
Flow Chart
Food and Drug Administration 
GCP
Good Clinical Practice
GGT
Gamma Glutamyl transferase
IEC
Independent Ethics Committee
IR
Immediate Release
IRB
Institutional Review Board
ISF
LPDD
Investigator Site File
Last Patient Drug Discontinuation
L-Dopa
Levodopa
L-Dopa+
Levodopa combined with a Dopa-Decarboxylase-inhibitor
MAO
MCID
Monoamine Oxydase
Minimal Clinically Important Difference


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MedDRA
Medical Dictionary for Drug Regulatory Activities
MMSE
Mini-Mental State Examination
MMIDI
NHQ
NIMP
NS
Modified Minnesota Impulsive Disorders Interview
Nocturnal Hypokinesia Questionnaire
Non-Investigational Medicinal Product
Nighttime Scale 
OL
Open Label
OPU
Operative Unit
PD
PDQ
Parkinson’s disease
The Parkinson's disease Questionnaire
PDSS-2
Parkinson’s disease Sleep Scale 2nd version
PGI-I
Patient Global Impression of Improvement
PK
Pharmacokinetics
p.o.
per os (oral)
PPX
PPS
Pramipexole
Per protocol set 
q.d.
quaque die (once a day)
REP
REML
ROP
Residual Effect Period
Restricted maximum likelihood
Randomisation operator
SAE
Serious Adverse Event
SmPC
Summary of Product Characteristics
SR
Sustained Release
SUSAR
TC
Suspected Unexpected Serious Adverse Reactions
Telephone Call
t.i.d.
TS
ter in die (3 times a day)
Treated set
TSAP
Trial Statistical Analysis Plan
UPDRS
Unified Parkinson’s disease Rating Scale
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Parkinson’s disease (PD) is a chronic degenerative disorder of the central nervous system, 
with slowly progressive degeneration of the nigrostriatal dopaminergic systems [R96-2351].
Classically, the symptoms are tremor, muscular rigidity and bradykinesia. The underlying 
Pathophysiology is a deficiency of dopamine in the basal ganglia [R96-2350].
The estimated incidence of Parkinson’s disease is 4.5 to 16/ 100.000 persons/year and PD is
associated with severe disability or death, which may be expected in 25% of patients within 5
years, in 65% of them within 10 years and in 80% of them within 15 years of onset [R02-
2068].
The management of Parkinson’s disease is specific for different stages: in early stages, the
main objective is to reduce and/or delay the disease progression, while in advanced stages
(after 5 to 7 years), the goal is to reduce and/or control functional disability, and improve 
quality of life.
In PD patients, sleep disturbances are very common, especially in patients with fluctuation 
undergoing long-term therapy. Sleep disturbances adversely affect quality of life, leading to 
considerable problems for patients as well as difficulties for caregivers [R17-4023]. 
Levodopa (combined with DDC (Dopa-Decarboxylase) inhibitor) is an effective symptomatic
therapy of PD. However, motor complications are frequent and disabling after several years
of treatment with Levodopa (L-Dopa) [P02-02651]. Motor complications involve
fluctuations, erratic or unstable responses to medications (e.g. wearing-off phenomena) and
dyskinesias or involuntary movements.
Dopamine agonists are used either in monotherapy for the treatment of PD in the early stage
of the disease (as part of L-Dopa sparing strategy to delay as much as possible the occurrence
of L-Dopa-related motor fluctuations) or in the later phase of the disease to lessen motor
complications caused by L-Dopa. The beneficial effects of dopamine agonists used as
adjuvant therapy in patients experiencing response fluctuations or diminished response to L-
Dopa are well documented.
1.2
DRUG PROFILE
Pramipexole is a non-ergot dopamine agonist with high in vitro specificity at the D2
subfamily of dopamine receptors. Pramipexole is a full agonist and exhibits higher affinity to 
the D3 receptor subtypes than to D2 or D4 receptor subtypes.
Pramipexole immediate release (IR) tablets, administered three times per day (t.i.d.), are 
indicated for the treatment of signs and symptoms of either early or advanced Parkinson's 


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disease (PD), alone (without levodopa) or in combination with levodopa. They are marketed 
under the trade-name MIRAPEX®/MIRAPEXIN®/SIFROL®/ PEXOLA®. Pramipexole IR
tablets were first authorised in the USA in 1997, followed by marketing authorisations in the 
European Union (EU), Iceland, Norway, Switzerland, Australia, New Zealand, Canada, 
Japan, Eastern European countries, South Africa, countries of the Near and Far East and 
South America.
In addition, Pramipexole IR tablets have been approved in April 2006 by the European 
Medicines Agency (EMA) and in November 2006 by the Food and Drug Administration 
(FDA) and in other countries (see above) for the treatment of moderate to severe primary 
Restless Legs Syndrome (RLS).
Boehringer Ingelheim has developed a sustained-release (SR) formulation of Pramipexole, 
that can be administered once daily (q.d.) for the treatment of signs and symptoms of 
idiopathic PD. This formulation showing a slower release of the active ingredient than that of 
the IR formulation will be beneficial to patients as it will allow patients to treat their 
symptoms with a single daily dose, instead of three doses per day, thereby increasing patient 
convenience and compliance.
Applications for Pramipexole SR for the treatment of PD have been submitted to the FDA 
and EMA in October 2008, followed by submission of applications in further countries since 
then. Pramipexole SR was approved in the EU for the treatment of early and advanced PD on 
8 October 2009. Further marketing authorisations were obtained in Iceland, Norway, 
Switzerland, Australia, Canada, Eastern European countries, countries of the Near and Far 
East and South America.
Pramipexole SR was approved in the US for the treatment of early PD on 19 February 2010 
and for the treatment of advanced PD on 19 March 2010.
The clinical trial data presented in the following is as of January 2010. In the meantime the 
two open label trials 248.633 & 248.634 and the open label part trial 248.610 have been 
finalized [U10-1624-01]. The overall patient number as well as the safety and efficacy 
evaluation of Pramipexole SR did not change.
In addition, one Phase I trial in Japanese healthy volunteers has been reported in September 
2010 (248.677) [U10-2447-01]. Dose strength bioequivalence between the Pramipexole SR 
1.5 mg x 1 tablet q.d. and Pramipexole SR 0.375 mg x 4 tablets q.d. in both fasted and fed
conditions was proven. In addition, no food effect on the bioavailability of Pramipexole after 
administration of Pramipexole SR 1.5 mg tablet was observed in this trial. No specific 
concern was noted for safety profile of Pramipexole SR.
In China two registration trials started in 2010. The Phase I trial 248.665 had been initiated in 
December 2010, the Phase III trial 248.671 in August 2010. Both of the studies have been 
finished. Pramipexole SR was approved in China for the treatment of PD in August 2014.
Pharmacokinetic:
The pharmacokinetic properties of Pramipexole IR formulation are well established.


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Additional pharmacokinetic (PK) properties for the SR formulation have been evaluated in
four Phase I PK and bioavailability (BA) trials. In addition, the steady-state pharmacokinetics 
of Pramipexole SR tablets were evaluated in patients in the early PD trial 248.524 [U08-
1904-01].
The absolute bioavailability of Pramipexole is greater than 90%, indicating that it is well 
absorbed and undergoes little presystemic metabolism [U92-0018, U91-0026]. In humans the 
protein binding of Pramipexole is very low (<20%) and the volume of distribution is large 
(400L). Pramipexole is metabolised in man only to a small extent [U92-0018].
Renal excretion of unchanged Pramipexole is the major route of elimination. Approximately 
90% of a 14C labelled dose is excreted through the kidneys while less than 2% is found in the 
faeces. The total clearance of Pramipexole is approx. 500mL/min and the renal clearance is 
approx. 400mL/min. Its terminal half-life (t1/2) is about 8 hours in the young and about 12 
hours in the elderly [U92-0018]. The terminal half-life does not change for the SR 
formulation.
In Phase I trials, Pramipexole SR tablets administered q.d. resulted in equivalent 24-hour 
exposure as Pramipexole IR tablet administered t.i.d., with about the same inter-individual 
variability. Dose proportionality was demonstrated for the final formulation of Pramipexole
SR tablets over the entire dose range from 0.375 to 4.5 mg, [U07-1551]. The Pramipexole SR 
matrix tablet formulation given q.d. did, thus, fulfil all PK requirements to allow a 
replacement of the current IR tablet given t.i.d. Concomitant food intake did not affect the PK 
of Pramipexole SR in a clinically relevant way and did not result in any irregular release and 
absorption ("dose dumping") of Pramipexole [U06-1598-01] and [U07-1551]. Accordingly, 
in the Phase III studies, the drug could be taken with or without food. Food was not identified 
as a significant covariate in the early PD trial 248.524. There is no clinically relevant 
influence of age, gender, race, or concomitant medications (e.g. drugs affecting 
gastrointestinal motility or gastric pH, or antiacids) on the PK properties of Pramipexole SR 
[U08-1904-01].
Toxicology:
For the development of Pramipexole IR tablets for PD, a non-clinical safety program has 
been completed. Repeat-dose toxicity studies with Pramipexole did not show significant 
findings which would raise serious safety concerns for further clinical trials. The major 
findings in rodent and non-rodent species (mainly involving the Central Nervous System and, 
in the rat, the female reproductive system) were probably due to an exaggerated 
pharmacodynamic effect of Pramipexole in animals. No additional toxicological studies had 
been performed with the Pramipexole SR formulation.
Safety and tolerability:
The following adverse reactions are expected under the use of Pramipexole: abnormal 
behaviours (reflecting symptoms of impulse control disorders and compulsions) such as 
binge eating, compulsive shopping, hypersexuality and pathological gambling; abnormal 
dreams, amnesia, cardiac failure, confusion, constipation, delusion, dizziness, dyskinesia, 


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dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, 
hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido disorders, nausea, 
paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; 
restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including 
diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease including 
decreased appetite, weight increase, delirium, mania, antecollis, spasms.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,778 
Parkinson's disease patients on pramipexole and 1,297 patients on placebo, adverse drug 
reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% 
of patients on placebo reported at least one adverse drug reaction.
The majority of adverse drug reactions usually start early in therapy and most tend to 
disappear even as therapy is continued.
Pramipexole IR
Early Parkinson's disease
In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, 
the most common adverse reactions (>5%) that were numerically more frequent in the group 
treated with pramipexole tablets were nausea, dizziness, somnolence, insomnia, constipation, 
asthenia, and hallucinations.
Approximately 12% of 388 patients with early Parkinson's disease and treated with 
pramipexole IR tablets who participated in the double-blind, placebo-controlled trials 
discontinued treatment due to adverse reactions compared with 11% of 235 patients who 
received placebo. The adverse reactions most commonly causing discontinuation of treatment 
were related to the nervous system (hallucinations [3.1% on pramipexole IR tablets vs 0.4% 
on placebo]; dizziness [2.1% on pramipexole IR tablets vs 1% on placebo]; somnolence 
[1.6% on pramipexole IR tablets vs 0% on placebo]; headache and confusion [1.3% and 
1.0%, respectively, on pramipexole IR tablets vs 0% on placebo]) and gastrointestinal system 
(nausea [2.1% on pramipexole IR tablets vs 0.4% on placebo]).
In a fixed-dose study in early Parkinson's disease, occurrence of the following reactions 
increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: 
postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these 
reactions was generally 2-fold greater than placebo for pramipexole doses greater than 3 
mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was 
comparable to that reported for placebo.
Advanced Parkinson's disease
In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's 
disease, the most common adverse reactions (>5%) that were numerically more frequent in 
the group treated with pramipexole IR tablets and concomitant levodopa were postural 
(orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, 
hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, 


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somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary 
frequency.
Approximately 12% of 260 patients with advanced Parkinson's disease who received 
pramipexole IR tablets and concomitant levodopa in the double-blind, placebo-controlled 
trials discontinued treatment due to adverse reactions compared with 16% of 264 patients 
who received placebo and concomitant levodopa. The reactions most commonly causing 
discontinuation of treatment were related to the nervous system (hallucinations [2.7%
on pramipexole IR tablets vs 0.4% on placebo]; dyskinesia [1.9% on pramipexole IR tablets 
vs 0.8% on placebo]) and cardiovascular system (postural [orthostatic] hypotension [2.3% on 
pramipexole IR tablets vs 1.1% on placebo]).
Pramipexole SR
Early Parkinson's disease
The most common adverse reactions (≥5% and more frequent than placebo) after 33 weeks of 
treatment with pramipexole SR tablets in the trial of early Parkinson’s disease patients were 
somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, spasms, and 
peripheral edema.
Twenty four of 223 (11%) patients treated with pramipexole SR tablets for 33 weeks 
discontinued treatment due to adverse reactions compared to 4 of 103 (4%) patients who 
received placebo and approximately 20 of 213 (9%) patients who received pramipexole IR 
tablets. The adverse reaction most commonly causing discontinuation of treatment with 
pramipexole SR tablets was nausea (2%).
A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight 
switch from pramipexole IR tablets to pramipexole SR tablets at the same daily dose in 156 
early Parkinson’s disease patients with or without levodopa. One of 104 patients switched 
from pramipexole IR tablets to pramipexole SR tablets discontinued due to adverse reactions 
(vertigo and nausea).
Advanced Parkinson's disease
The most common adverse reactions (≥5% and greater frequency than in placebo) during 18 
weeks of treatment with pramipexole SR tablets in the trial of advanced Parkinson’s disease 
patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, 
headache, and anorexia.
Eight of 164 (5%) patients treated with pramipexole SR tablets for 18 weeks discontinued 
treatment due to adverse reactions compared to 7 of 178 (4%) patients who received placebo 
and 8 of 175 (5%) patients who received pramipexole IR tablets. The most common adverse 
reactions leading to discontinuation of treatment with pramipexole SR tablets were nausea 
(1%) and hallucination (1%).
Adverse reactions can initially occur in either the titration or maintenance phase. Some 
adverse reactions developed in pramipexole SR-treated patients during the titration phase and 
persisted (≥7 days) into the maintenance phase (i.e., pramipexole SR % - placebo % = 


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treatment difference ≥2%); persistent adverse reactions were dyskinesia and insomnia.
Efficacy:
In a placebo-controlled DB trial in early PD patients, superiority of Pramipexole SR over
placebo was demonstrated at Week 18 on both the primary Unified Parkinson’s disease 
Rating Scale ((UPDRS) II+III and the key secondary Clinical Global Impression of 
Improvement (CGI-I) and Patient Global Impression of Improvement (PGI-I) responder rates
efficacy endpoints. Non-inferiority was demonstrated at Week 33 between Pramipexole SR 
and IR [U09-1232-03].
In a placebo-controlled DB trial in advanced PD patients, superiority of Pramipexole SR over
placebo was demonstrated at Week 18 on both the primary 
 and the key
secondary (percentage off-time during waking hours) efficacy endpoints [U09-1270-04].
In both the above trials, maintenance of efficacy was shown in patients treated for 33 weeks.
The efficacy of an overnight switch from Pramipexole IR to SR at the same daily dose was
evaluated in a “switch” trial conducted in early PD patients. Of 103 patients randomised to
Pramipexole SR, 87 (84.5%) were successfully switched (i.e. no worsening of the UPDRS
Parts II+III score by more than 15% from baseline and no drug-related AEs leading to
withdrawal) after a possible dose adaptation; 72 of 87 did not change the dose. An overnight
switch from Pramipexole IR to SR at the same total daily dose can be recommended [U08-
1964-01].
Lastly, long term maintenance of efficacy of Pramipexole SR in early and advanced PD
patients was demonstrated after 32 weeks of treatment in the OL long-term extension trials
248.633 and 248.634. In addition, patients with advanced PD can be safely switched
overnight from Pramipexole (PPX) IR to PPX SR at the same total daily dose, while 
maintaining efficacy [U10-1341-01] and [U10-1369-01].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This is a two-stage, multicentre, open-label, randomized, active controlled parallel group
study comparing the efficacy and safety of Pramipexole SR versus Pramipexole IR 
administered orally over an 18-week treatment on nocturnal symptoms in L-Dopa+ treated 
patients with advanced Parkinson’s disease (PD). 
As reported with other chronic disease, non-adherence of drug use (either mistimed doses or 
missed doses) is common in parkinsonian patients and may be responsible for failure to 
relieve symptoms or emergence of drug-related side effects [P04-06261]. Poorer compliance 
is associated significantly with taking more anti-parkinsonian tablets per day [P05-13388].
Sustained release formulations of several products for the treatment of Parkinson’s disease 
have been approved for registration. Sustained release formulation of Pramipexole turned out 
to be beneficial to parkinsonian patients, by improving patients’ convenience and compliance 
to the treatment.


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Concentration of SR is higher than IR in the latter night (11 pm - 4 am on second day) if 
taking Pramipexole SR once daily after dinner and IR 3 times daily which may result in 
potential benefit on nocturnal symptoms.
The general aim of study stage I is to explore the efficacy of Pramipexole SR versus 
Pramipexole IR (as measured by the change from baseline to week 18 in Parkinson’s disease 
Sleep Scale-2 (PDSS-2) total score) in treating nocturnal symptoms in patients on L-Dopa+
with advanced PD. The general aim of study stage II is to further evaluate or confirm the 
efficacy between Pramipexole SR versus Pramipexole IR (as measured by the change from 
baseline to week 18 in PDSS-2 total score) in treating nocturnal symptoms in patients on L-
Dopa+ with advanced PD based on the results from Stage I.
Patients must be treated with L-Dopa+ (i.e. standard and/or sustained release Levodopa/DDC 
inhibitor), or with a combination of L-Dopa+ and entacapone, at an optimized dose according 
to investigator’s judgment, this dose being stable for at least 4 weeks prior to randomization 
visit. Sustained release Levodopa/DDC inhibitor must not been used after supper within 4 
weeks prior to randomization visit.
Pramipexole IR will be administered in equally divided doses 3 times per day and 
Pramipexole SR will be administered once daily at 7-9pm before bedtime. After a 1- to 2-
week screening phase, patients will be randomized to one of the two treatment groups, with a 
balanced ratio of 1:1 (Pramipexole SR: Pramipexole IR). During the 7-week up-titration 
phase, the dose of study medication will be up-titrated until the optimal daily dose is reached.
The degree of improvement will be based upon the clinical judgement of the investigator. At 
the end of this up-titration phase, patients will enter the 11-week maintenance phase. The 
maintenance dose of study medication will be the optimal daily dose reached at the end of the 
up-titration phase. Following the maintenance-phase, patients will enter a short dose
reduction phase which can last for up to 7 days (depending on the daily dose administered 
during the maintenance-phase) or continue Pramipexole IR/SR treatment judged by 
investigators and patients with commercial supply at visit 7.The purposes of the dose-
reduction phase are to gradually reduce the dose of Pramipexole, to prevent possible Adverse 
Events associated with rapid dose-reduction.
The primary efficacy endpoint used to evaluate the patient’s treatment response will be
PDSS-2 total score (change from baseline to the end of the maintenance period). Secondary 
efficacy endpoints and safety endpoints are described in Section 2.1 and 2.2.
1.4
BENEFIT - RISK ASSESSMENT
The efficacy and tolerability of both Pramipexole IR and SR have been demonstrated in both
early [U95-0560; U95-0588; U00-0074; U09-1232-03] and advanced [U95-3150; U96-0232;
U09-1270-04] PD trials. In addition, non-inferiority between Pramipexole SR and
Pramipexole IR was demonstrated after 33 weeks of treatment in an international Phase III
trial in patients with early PD, at similar mean total daily dose of Pramipexole and similar
dose distribution in the two groups [U09-1232-03].


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This study is designed to explore firstly, then further evaluate or confirm the efficacy 
between Pramipexole SR versus Pramipexole IR (as measure by PDSS-2 score) in Chinese 
PD patients.
A flexible up-titration design will be used in the trial, to allow each patient to be up-titrated
until an optimal therapeutic response is achieved. The dose range for Pramipexole SR (from
0.375 mg to 4.5 mg per day) is identical to daily doses approved for Pramipexole IR [U04-
1242-06] and to the dosing scheme used in previous international and local Phase III trials for 
the clinical development of Pramipexole SR [U09-1232-03] and [U09-1270-04].
Exclusion criteria have been defined in the trial according to the Pramipexole Summary of
Products Characteristics (SmPC). At each study visit, adverse events will be elicited by 
asking the patients how they have felt since the last visit. The study duration and procedures 
do not expose the patients to any specific risk, as a treatment (Pramipexole SR or IR) will be
given to all patients, and this treatment may be taken concomitantly to any other 
antiparkinsonian treatments (anti-parkinsonian anticholinergics, MAO-B-inhibitors, 
amantadine, entacapone, L-Dopa+). In addition, patients and investigators may decide to 
discontinue the study at any time.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of the study is to explore firstly, then further evaluate or confirm the 
efficacy between Pramipexole SR versus Pramipexole IR on nocturnal symptoms (as 
measured by the change from baseline to the end of the maintenance period in PDSS-2 score) 
in L-dopa+ treated patients with advanced PD.
2.1.2
Primary endpoint(s)
The primary endpoint is the change from baseline to week 18 in PDSS-2 total score.
2.1.3
Secondary endpoint(s)
Secondary efficacy endpoints are (to be assessed at week 18):
•
Nocturnal Hypokinesia Questionnaire (NHQ) score (change from baseline);
•
SCOPA-Sleep score (change from baseline);
•
Early Morning Off (EMO) score (change from baseline);
•
Responder rate for PDSS-2 total score<18;
•
Responder rate for EMO score;
•
The Parkinson's disease Questionnaire (PDQ)-8 score (change from baseline);
•
Responder rate for Clinical Global Impression of Improvement (CGI-I);
•
Responder rate for Patient Global Impression of Improvement (PGI-I);
•
Epworth Sleepiness Scale (ESS) score (change from baseline).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a two-stage, multicentre, open-label, randomized, active controlled parallel group to 
compare the efficacy and safety of Pramipexole SR versus Pramipexole IR administered 
orally for 18 weeks in Chinese patients with advanced Parkinson’s disease (PD) treated with 
L-Dopa+(i.e. standard and/or sustained release L-Dopa /DDC inhibitor). After a 2-week 
screening phase and a 7-week flexible up-titration phase, there will be an 11-week 
maintenance phase, followed by a 1-week down titration phase. Therefore, the trial can last 
for up to 21 weeks totally. Investigators in this study will be neurologists. More details about 
the administrative structure of the trial are given in the Investigator Site File (ISF). During the 
trial, there will be 8 visits and 5 telephone calls (see Flow Chart).
The stage I part of this trial will be conducted as a pilot study to explore the difference of 
change from baseline to week 18 in PDSS-2 total score between Pramipexole SR and IR. 
Stage II will be planned as a confirmatory or exploratory design. Stage I and II are totally 
separated, and the patients in Stage I will not be used in Stage II.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial will be conducted using a two-stage, open-label, randomized, active controlled
parallel-group design.
The phase IV study was designed as two-stage due to the limited prior clinical evidences and 
the unclear deviations in the target population. Therefore, the Stage I was designed as a pilot 
to detect the signal. Based on the favorable results from Stage I, the Stage II will be 
continued for further confirmation or further evaluation.
There will be two treatment arms in this trial: Pramipexole SR as investigational medication,
Pramipexole IR as an active control. Placebo won’t be used in this study. 
A double-blinded trial requires either over-encapsulation and subsequent equivalency testing 
be completed for two distinct packaging schema of the comparator (i.e. one Aluminium-
aluminium blister in Pramipexole SR and three Aluminium-aluminium blisters-packaging in 
Pramipexole IR and unbalanced nature of different dose for each tablet between Pramipexole
IR and Pramipexole SR). Therefore, this study will be conducted in an open-label fashion. 
But this study will use randomization to minimize the potential bias incorporated.
3.3
TRANSITION FROM STAGE I TO STAGE II
The guidance described in the Table 3.3:1 serves as decision making rules for transition to 
Stage II. 


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Table 3.3:1 Guidance for decision making for transition to Stage II
Scenari
os
Result of primary endpoint in Stage I
Decision making for 
Stage II
Clinical value
Statistics
A
Achieve the minimal clinically 
important difference (MCID):
The adjusted mean difference 
<= -3.44
AND
P<0.05
Stop
B
Achieve MCID
The adjusted mean difference 
<= -3.44
AND
P>=0.05
Continue
C
Not achieve MCID
The adjusted mean difference >  
-3.44
AND
Any P
Stop
NOTE: The adjusted mean difference is the primary analyse result of the primary endpoint. 
In summary, there are 3 scenarios for decision making for transition to Stage II based on 
Stage I results as below,
•
Scenario A - Stop upon achieving MCID[R17-4026] (i.e., the adjusted mean difference 
<= -3.44 at Stage I) and statistical significance (P<0.05);
•
Scenario B - Continue upon achieving MCID (i.e., the adjusted mean difference <= -3.44 
at Stage I) and no statistical significance (P>=0.05);
•
Scenario C - Stop upon not achieving MCID (i.e., the adjusted mean difference > -3.44 at 
Stage I).
For Scenario B and C, the analysis results of Stage I in conjunction with other factors will be 
used to allow BI to make a joint decision on whether the benefit and risk support the 
continuation of the trial into Stage II. For example, in Scenario C, if there is another endpoint 
showing great benefit of SR, the trial may continue into Stage II with this endpoint as the 
primary endpoint.
3.4
SELECTION OF TRIAL POPULATION
A total of 86 eligible, male and female patients with advanced PD, Modified Hoehn and Yahr 
stages 2 to 4 at on-time with motor fluctuations and nocturnal symptoms (determined by 
PDSS-2 total score ≥18) will be randomized in stage I.
It is anticipated that approximately 102 patients will be screened and 86 eligible patients will 
be obtained for randomization in stage I (assuming a 15%-screening failure rate).
The sample size of stage II will be calculated based on the results from stage I.
Approximately 10 to 15 centers will be selected for the trial. Investigators who fail to enter at 
least one patient in the first three months after trial initiation at each center may be excluded 
from the further participation. If recruitment is delayed, additional centers can be recruited. 


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Screening of patients for this trial is competitive, i.e. screening for the trial will be stopped at 
all sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about the screening completion and will then not be allowed to screen 
additional patients for this trial.
This clinical study can fulfill its objectives only if appropriate patients are enrolled. The
following eligibility criteria are designed to select patients for whom Pramipexole treatment
is considered appropriate. All relevant medical and non-medical conditions should be taken
into consideration when deciding whether this protocol is suitable for a particular patient.
A log of all patients enrolled into the trial (i.e. who have signed the informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational product or not.
3.4.1
Main diagnosis for trial entry
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.4.2
Inclusion criteria
1. Male or female patient with advanced idiopathic PD confirmed by at least bradykinesia 
and one of the following signs: resting tremor, rigidity. 
2. Diagnosed as Parkinson’s disease, with at least 2 years’ PD history.
3. Of age ≥30 years at time of diagnosis.
4. Modified Hoehn and Yahr stage of 2 to 4 at on-time.
5. They must have clinically relevant sleep disturbances (i.e. PDSS-2 total score ≥18 at 
baseline).
6. They must feel uncomfortable at night because they were unable to turn around in bed 
or move due to immobility (i.e. the scoring of question 9 in PDSS-2 ≥2, which means 
frequency is at least 2 to 3 days during the past week).
7. They must have early morning off (i.e. the frequency of “feeling like bodily movements 
are poor when you wake up?” is at least 2 to 3 days during the past week).
8. Patients must have motor fluctuations (at least 2 cumulative hours of off-time every day 
during waking hours, documented on a patient diary completed for 2 consecutive days 
before randomization visit).
9. Patients must be treated with L-Dopa+ (i.e. standard and/or sustained release 
Levodopa/DDC inhibitor), or with a combination of L-Dopa+ and entacapone, at an 
optimized dose according to investigator’s judgment, this dose being stable for at least 4 
weeks prior to randomization visit.
10. Patients must not have been treated with sustained release dopaminergic drug (i.e. 
sustained release Levodopa/DDC inhibitor) after supper, or any anti-PD medication 
after 9pm within 4 weeks prior to randomization visit.


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11. Patients must not have been treated with dopamine agonists within 4 weeks prior to 
randomization visit. A concomitant treatment with one or more of the following drugs
will be allowed (at a stable dose for at least 4 weeks prior to randomization visit and the 
investigator does not intend to change this treatment during the treatment phase):
- Anti-parkinsonian anticholinergics;
- Selegiline, rasagiline, or other MAO-B-Inhibitor;
- Amantadine;
- Entacapone (or other COMT-Inhibitor).
12. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information.
13. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3.4.3
Exclusion criteria
1. Secondary parkinsonian syndromes due to drugs (e.g., metoclopramide, flunarizine), 
metabolic disorders (e.g., Wilson's disease), encephalitis or degenerative diseases (e.g., 
progressive supranuclear palsy).
2. Dementia, as defined by a Mini-Mental State Exam score < 24 at screening visit [R96-
2656].
3. Any psychiatric disorder according to DSM-V Diagnostic and Statistical Manual of
Mental Disorders, 5th edition criteria that could prevent compliance or completion of the
study and/or put the patient at risk if he/she takes part in the study.
4. History of psychosis, except history of drug induced hallucinations (provided the
investigator considers that participation to the trial would not represent a significant risk 
for the patient).
5. History of deep brain stimulation.
6. History of nucleus lesioning.
7. Clinically significant electrocardiogram (ECG) abnormalities at screening visit, according 
to investigator’s judgement.
8. Clinically significant hypotension (i.e. supine systolic blood pressure < 90 mmHg) and/or 
symptomatic orthostatic hypotension (i.e. clinical symptoms of orthostatic hypotension 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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associated with a decline ≥20 mmHg in systolic blood pressure and a decline ≥10 mmHg 
in diastolic blood pressure, at 1 minute after standing compared with the previous supine 
systolic and diastolic blood pressure obtained after 5 minutes of quiet rest) at screening or 
randomization visit.
9. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned within 12 months after screening, e.g. hip 
replacement.
10. Any other clinically significant disease, whether treated or not, that could put the patient 
at risk or could prevent compliance or completion of the study.
11. Serious Sleep Apnea Hypopnea Syndrome (i.e. the scoring of question 15 in PDSS-2 ≥3, 
that means frequency is at least 4 to 5 days during the past week )
12. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
13. Serum levels of AST (SGOT), ALT (SGPT), alkaline phosphatases or total bilirubin >2 
ULN (on screening lab test).
14. Patients with a creatinine clearance < 50 mL/min (estimated by the local lab / the 
investigator using the Modification of Diet in Renal Disease (MDRD, please refer to 
Appendix 10.1), and calculated on screening lab test).
15. Any hypnotic medication within 4 weeks prior to the randomization visit (i.e. diazepam, 
clonazepam, estazolam, alprazolam, zolpidem, etc.).
16. Any medication (including intra-muscular formulations) with central dopaminergic 
antagonist activity within 4 weeks prior to the randomization visit (i.e. typical 
neuroleptics, atypical antipsychotics, reserpine, methyldopa, centrally-active antiemetics, 
etc.).
17. Any of the following drugs within 4 weeks prior to randomization visit: methylphenidate,
cinnarizine, amphetamines.
18. Flunarizine within 3 months prior to randomization visit.
19. Known hypersensitivity to Pramipexole or its excipients.
20. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
21. Previous enrolment in this trial.
22. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s).
23. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial patient or unlikely to complete the trial.
24. Women who are pregnant, nursing, or who plan to become pregnant in the trial.


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3.4.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see sections 3.4.4.1 and 
3.4.4.2 below.
Every effort should be made to keep the randomised patients in the trial: if possible on
treatment, or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and Case Report Form (CRF).
3.4.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and section 6.2.2 and 
section 6.2.3. For all patients the reason for withdrawal from trial treatment (e.g. adverse 
events) must be recorded in the CRF. These data will be included in the trial database and 
reported.
3.4.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see section 3.4.4.1 
above.


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3.4.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrollment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Pramipexole SR 0.375 mg and 0.75 mg tablets, Pramipexole IR 0.25 mg and 1.0 mg tablets 
will be supplied by Boehringer Ingelheim.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1: Pramipexole SR
Substance:
Pramipexole dihydrochloride monohydrate
Pharmaceutical formulation:
Tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Germany
Unit strength:
0.375 mg and 0.75mg
Posology
0.375 mg, 0.75mg, 1.5mg, 2.25mg, 3.0mg, 3.75mg, 
or 4.5mg, once daily, at 7-9 pm before bedtime
Route of administration:
Oral (p.o.)
Table 4.1.1: 2
Test product 2: Pramipexole IR
Substance:
Pramipexole dihydrochloride monohydrate
Pharmaceutical formulation:
Tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Germany
Unit strength:
0.25 mg and 1.0 mg
Posology
0.375 mg, 0.75mg, 1.5mg, 2.25mg, 3.0mg, 3.75mg, 
or 4.5mg, 3 times daily, the third dose at 7-9pm 
before bedtime
Route of administration:
Oral (p.o.).


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4.1.2
Selection of doses in the trial
The dosing schedule for this study follows the standard doses for Pramipexole.
Doses for this study used during the up-titration and the maintenance phase consist of the 
following seven dose levels:
Pramipexole SR 0.375 mg, 0.75 mg, 1.5 mg(0.75 mg*2), 2.25 mg (0.75 mg*3), 3.0 mg (0.75 
mg *4), 3.75 mg (0.75 mg*5) or 4.5 mg (0.75 mg*6) at 7-9 pm before bedtime.
Pramipexole IR 0.375 mg (0.25mg*1/2 t.i.d.), 0.75 mg (0.25 mg t.i.d.), 1.5 mg (1.0mg*1/2 
t.i.d.), 2.25 mg (1.0 mg *1/2 t.i.d. +1.0 mg *1/4mg t.i.d.), 3.0 mg (1.0 mg t.i.d.), 3.75 mg (1.0 
mg t.i.d. + 1.0 mg *1/4mg t.i.d.), or 4.5 mg (1.0 mg t.i.d. + 1.0mg*1/2 t.i.d.)
During the 7-week up-titration phase, the need for up-titration will be assessed by the 
investigator at on-site visits and telephone contacts, based on efficacy (PGI-I) and 
tolerability. Between on-site visits, the investigator will contact the patient by phone call to 
check efficacy (PGI-I) and tolerability of the study treatment and, if necessary, decide if the 
dose level has to be up-titrated or down-titrated. The dose of study medication should be up
titrated in all patients who are not at least “a little better” on the PGI-I. If the dose is not 
increased, the reason should be given by the investigator and recorded in the eCRF (e.g. dose 
not increased due to an Adverse Event). In case of dopaminergic side effects (dyskinesia, 
psychosis, etc.) during the up-titration phase, the investigator can reduce the level of the 
study medication to the previous dose level.
4.1.3
Method of assigning patients to treatment groups
After confirming that the patient meets all the eligibility criteria at Visit 2, the patient will be 
randomly assigned to SR or IR arm (with a randomization ratio of 1:1).
The randomization list will be carried out centrally using BI randomisation operator (ROP). 
Based on the randomization list, the external vendors will implement the assignment. The BI 
standard validated random number generating system will be used to generate the 
randomization list, which will be verified by an independent statistician who is not involved 
in the trial. The access to the randomization code will be supervised by the Clinical Trial 
Support Group. Any personnel directly involved in the conduct and analysis of the trial will 
have no access to the randomization schedule prior to the database lock.
The investigators will receive a manual describing how to communicate and implement the 
assignment with the support of the external vendor.
4.1.4
Drug assignment and administration of doses for each patient
The study consists of an 18-week, active treatment phase (up to a 7-week titration phase until 
optimal response, followed by an 11-week maintenance phase). At the end of the 
maintenance phase, patients who want to enter a down-titration phase, with a final visit to 
monitor tapering of the study medication. For other patients who want to maintain their 


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dosages, commercial Pramipexole IR/SR will be provided by themselves under the 
judgement of investigators.
Study site authorized personnel (registered in the investigator site file) will dispense the study 
medication during the on-site visits.
Pramipexole IR doses will be taken orally, in equally divided doses, three times per day with
the third dose at 7-9 pm before bedtime, with a glass of water (approximately 150 mL) with 
or without food.
Pramipexole SR doses will be taken orally q.d. at 7-9 pm before bedtime. Each dose will be 
taken with a glass of water (approximately 150 mL) with or without food
Missed doses of IR will be skipped at any time.
Missed dose of SR should be taken within 12 hours after the regularly scheduled time. After 
12 hours, the missed dose should be left out and the next dose should be taken on the 
following day at the next regularly scheduled time.
The dose level determined at the end of the titration phase will be maintained throughout the 
Maintenance Phase. Patients will use their last maintenance dose on the day of visit 7.
Patients who won’t continue Pramipexole IR/SR treatment after trial completion will enter a 
down-titration phase on the day following Visit 7. Patients will take the taper medication 
during the week between visit 7 and follow-up visit 8. The medication dose will be reduced 
daily by one dose level. This tapering will take a maximum of six days (for patients treated 
with the highest dose level of 4.5 mg per day during the maintenance phase). Patients will 
return for a follow-up visit (visit 8) at last study dose + 2 days after visit 7(at least 48 hours 
after the last study drug intake in the down titration phase).
Commercial Pramipexole IR/SR is allowed to be prescribed to patients at visit 7 in the 
judgement by investigators and patients. In this case, taper process is not applicable to those 
patients. However, all other procedures at visit 7 and visit 8 will be performed as no major 
changes, except for compliance check of taper medication.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
There will be no blinding as discussed in Section 3.2.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI. For details of packaging and the 
description of the label, refer to the ISF.


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IMPs will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).Trial drug packages will have unique medication numbers which will be used 
for tracking purposes only. The medication numbers will not be linked to randomisation 
numbers.
Pramipexole SR will be supplied as film-coated tablets. Available dosage strength will be 
0.375 mg and 0.75 mg. Tablets will be supplied in Aluminium-aluminium blister sealed with 
Aluminium plastic plate containing 10 tablets.
Pramipexole IR will be supplied as film-coated tablets. Available dosage strength will be 
0.25 mg and 1.00 mg. Tablets will be supplied in Aluminium-aluminium blister sealed with
Aluminium plastic plate containing 30 tablets.
Re-supply to the sites will be managed as manually. Study site authorized personnel and
Clinical Research Associate (CRA) will monitor the IMP number in site and inform Clinical 
Trial Manager (CTM) for re-supply if the IMPs are inadequate.
4.1.7
Storage conditions
Trial medication, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined below until supplied/administered to 
patient. Temperature logs must be maintained to make certain that the drug supplies are 
stored at the correct temperature. In case temperature would be out of range, this has to be
managed based on STORM document in ISF
Only authorized personnel as documented in the <Trial Staff List> form in the ISF may 
dispense medication to trial subjects. Receipt, usage and return of the trial medication must 
be documented on the respective forms in the ISF.
4.1.7.1
Storage conditions for IR
Store sealed below 30°C (86°F), away from light. Keep out of the reach of children.
4.1.7.2
Storage conditions for SR
Pramipexole SR must be store sealed in the room temperature. Keep out of the reach of 
children.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,


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
Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. The patients will be instructed to 
return to the study site all dispensed blister packs at each on-site visit, including unused and 
partially used study medication. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates. 
The investigator / pharmacist / investigational drug storage manager will maintain records 
that document adequately that the patients were provided the doses specified by the Clinical 
Trial Protocol (CTP) and reconcile all investigational products received from the sponsor. At 
the time of return to the sponsor and/or appointed Contract Research Organisation (CRO), the 
investigator / pharmacist / investigational drug storage manager must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures

L-Dopa+ treatment:
At study entry, patients must be treated with L-Dopa+ (i.e. standard and/or sustained release 
Levodopa/DDC inhibitor), or with a combination of L-Dopa+ and entacapone, at an 
optimized dose according to investigator’s judgment, this dose being stable for at least 4 
weeks prior to visit 2. While patients have to be on a stable dose of L-Dopa+ prior visit 2 for 
at least 4 weeks, it is possible that the L-Dopa+ dose may need to be adjusted with the 
addition of Pramipexole (SR or IR) during the trial.

Other Parkinson’s disease treatments:
A concomitant treatment with one or more of the following drugs will be allowed (at a stable 
dose for at least 4 weeks prior to randomization visit and the investigator does not intend to 
change this treatment during the treatment phase):
- Anti-parkinsonian anticholinergics;
- And/or selegiline, rasagiline, or other MAO-B-Inhibitor;
- And/or amantadine;
- And/or entacapone (or other COMT-Inhibitor).


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The above list may not be exhaustive. In case another treatment is taken by the patient for his 
PD, a previous agreement should be given by the CTM before the patient can be enrolled in 
the trial.
Patients must not have been treated with sustained release dopaminergic drug (i.e. sustained 
release Levodopa/DDC inhibitor) after supper, or any anti-PD medication after 9 pm within 4 
weeks prior to randomization visit.
The timing of administration as well as the doses of these treatments will have to remain 
stable during the treatment phase.

Other concomitant treatments:
Other concomitant therapies that are not listed as restrictions will be allowed at the discretion 
of the investigator or sub-investigator. They should be limited to therapies essential for the 
care of the patient. The reason for use will be documented in the e-CRF.

Rescue medication
There is no established antidote for overdose of a dopamine agonist. If signs of central 
nervous system stimulation are present, a neuroleptic agent may be indicated. Management of 
the overdose may require general supportive measures along with gastric lavage, intravenous 
fluids, and electrocardiogram monitoring. Haemodialysis has not been shown to be helpful.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The administration of any other dopamine agonists with the study medication will necessitate 
termination of the patient’s participation in this study.
The following therapies must not be taken for the specified times prior to visit 2 and during 
the treatment phase:
- Dopamine agonist (including Pramipexole): at least 4 weeks,
- Any hypnotic medication (i.e. diazepam, clonazepam, estazolam, alprazolam, zolpidem, 
etc.): at least 4 weeks,
- Any medication with central dopaminergic antagonist activity (i.e. typical neuroleptics, 
atypical antipsychotics, reserpine, methyldopa, centrally-active antiemetics, etc.): at least 4 
weeks,
- Flunarizine: at least 3 months,
- Methylphenidate: at least 4 weeks,
- Cinnarizine: at least 4 weeks,
- Amphetamines: at least 4 weeks,
- Any other investigational drugs: at least one month or five-times the half-life of the 
investigational drug (whichever is longer).


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A previous treatment with Pramipexole IR/SR is allowed 4 weeks before visit 2, provided the 
treatment was not discontinued due to a serious/clinically significant drug related Adverse 
Event, according to investigator’s judgement.
The above list is not exhaustive. If the investigator has used or if he/she intends to use similar 
drugs not specified above, he/she should contact the sponsor to confirm patient’s 
participation to the trial / continuation in the trial.
4.2.2.2
Restrictions on diet and life style
Since somnolence is a frequent adverse event with potentially serious consequences, patients 
should neither drive a car nor engage in other potentially dangerous activities until they have 
gained sufficient experience with SIFROL® sustained release tablets and SIFROL® 
immediate release tablets to gauge whether or not it affects their mental and/or motor 
performance adversely.
4.2.2.3
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods described in the patient
information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including the empty package 
material with them at each visit. The investigator will be responsible for the assessment of 
patient compliance with study medication at each visit, by physical count of returned study 
medication. This information will be recorded and retained in the patient’s record. Percent 
compliance will be calculated based on dose in mg.
Medication compliance should be between 80-120% inclusive, at every visit. Isolated 
episodes of compliance should be evaluated on a case-by-case basis, before arbitrary 
discontinuation of a patient for non-compliance. The investigator will be encouraged to 
counsel patients on the importance of taking study medication as directed at each visit. For 
trial evaluation, handling of non-compliant patients will be described in the Trial Statistical 
Analysis Plan (TSAP). Decisions regarding patient eligibility due to poor compliance will 
finally be determined at Blinded Report Planning Meetings (BRPM), which will occur prior 
to locking of the database.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Refer to flow-chart and to Section 6 for a detailed time schedule for measurements.
Data analysis specifications for the observations mentioned below will be described in the
statistical section (Section 7) or the TSAP.
Parkinson’s disease Sleep Scale 2nd version (PDSS-2) [R04-0948]
The PDSS-2 consists of 15 questions about various sleep and nocturnal disturbances which 
are to be rated by the patients using one of five categories, from 0 (never) to 4 (very often). 
Patients will be asked to rate the severity of each question based on their experience during 
the past week (7 days) from 0 (Never) to 4 (Very often, that means 6 to 7 days a week). 
PDSS-2 total score ranges from 0 (no disturbance) to 60 (maximum nocturnal disturbance). 
There are three sub-scales from the three-factor solution, one comprising nocturnal 
movement-related problems (factor 1: “motor problems at night”), a second describing the 
disease specific symptoms (factor 2: “PD symptoms at night”) and the third representing 
sleep specific disturbances (factor 3: “disturbed sleep”). A total score of ≥18 defines 
clinically relevant PD-specific sleep disturbances. According to previous study, any 
improvements in PDSS-2 less than −3.44 points can represent clinically important changes 
for the patients. That is to say, a minimal clinically important difference (MCID) of PDSS-2
[R17-4026] is -3.44 points.
Nocturnal Hypokinesia Questionnaire (NHQ)
The Nocturnal Hypokinesia Questionnaire is designed to assess hypokinesia symptoms in 
night in PD patients, composed of two sections. Section 1 is assessed by PD patients. There 
are four domains in section 1 to assess “turning over in bed”, “getting out of bed”, 
“parkinsonian motor symptoms” and “others” separately. The domains in section 2 are the 
same with it in section 1. Section 2 is assessed by spouses or caregivers who are with the 
patients during the night.
SCOPA-Sleep [R08-5312]
The SCOPA-Sleep is a short, self-rating scale designed to evaluate nocturnal sleep quality 
and daytime sleepiness in patients with PD. It is composed of three parts: a nighttime scale 
(NS), a single-item about perceived quality of nocturnal sleep, and a daytime sleepiness scale 
(DS) that includes an item about unexpected onset of sleep.
The NS is a five-item scale with four response options (0-not at all to 3-very much) that 
addresses nighttime disturbances that “occurred in the previous month”. The five items 
include sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, and early 
wakening. Total NS score runs from 0 to 15, with higher scores reflecting more severe 
problems. The additional “quality of sleep” question assesses the overall nighttime sleep 
quality on a seven-point scale (ranging from slept very well to slept very badly). This item is 
not included in the total NS score. The DS subscale evaluates daytime sleepiness, also in the 
past month, and includes six items with four response options, from 0 (never) to 3 (often), 
and a maximum total score of 18. These DS items are addressed to how often the patient fell 


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asleep unexpectedly, but in particular situations (while sitting quietly, watching TV or 
reading, talking to someone), had difficulty to remain awake, and self-perception of daytime 
sleepiness as a problem.
Early Morning Off (EMO) [P17-11335]
The EMO is measured by the question of “do you feel like your bodily movements are poor 
when you wake up?” Patients will answer this question according to frequency during the 
past one week by scoring from 0 (“never”) to 4 (“very often” or “6 to 7 days a week”). EMO 
score should be rated before the first anti-PD drug taking in early morning, and within half an 
hour after waking up. The responder of EMO is the patient improved at least 1 comparing to 
his/her baseline condition.
Parkinson's disease Questionnaire (PDQ) -8 [R04-4222]
The PDQ-39 is a self-administered, disease specific measure of health status which covers 
eight dimensions of ill-health, and contains 39 questions. The 8 domains include:
- Mobility (e.g. fear of falling when walking): 10 items,
- Activities of daily living (e.g. difficulty cutting food): 6 items,
- Emotional well-being (e.g. feelings of isolation): 6 items,
- Stigma (e.g. social embarrassment): 4 items,
- Social support: 3 items,
- Cognition: 4 items,
- Communication: 3 items,
- Bodily discomfort: 3 items.
The PDQ-8, an 8 item self-report questionnaire derived from PDQ-39. Each item selected is 
the one most highly correlated with the overall domain score to which it contributes. The 
items were summed together and transformed onto a score from 0 to 100. The PDQ-8 has 
been shown to exhibit appropriate levels of reliability, validity and responsiveness.
Clinical Global Impression of Improvement (CGI-I) [R96-0188];
The CGI was developed by the Early Clinical Drug Evaluation Unit (ECDEU) of the 
National Institute of Mental Health as an independent, simple way for clinicians to make 
overall evaluations of a patient’s central nervous system (CNS) disease status. The ratings 
were used initially in outpatients with various psychiatric disorders. The CGI-I will be rated 
(from 1: very much improved, to 7: very much worse) by the same evaluator to assess the 
overall status of Parkinson’s disease, after interviewing the patient about the various aspects 
of the PD and after evaluating AE and concomitant treatments. The evaluator will complete 
the scale by comparing the patients’ status during the past week to their baseline condition.
The responder of CGI-I is the patient rated of any improvement (1 = Very much better, 2 =
Much better, or 3 = A little better).
Patient Global Impression of Improvement (PGI-I) [R96-0188];
The PGI-I scale is a patient-rated instrument which will be used to measure the improvement 
(from 1: very much better, to 7: very much worse) of the patient’s Parkinson disease 
symptoms throughout the study. Patients will complete the scale by comparing their status 
during the past week to their baseline condition. The responder of PGI-I is the patient rated of 
any improvement (1 = Very much better, 2 = Much better, or 3 = A little better).


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Epworth Sleepiness Scale (ESS) [R97-0791];
The ESS is a patient-rated scale about how likely one is to fall asleep during situations as 
passive and inconsequential as “watching TV” to as active as “sitting and talking to 
someone” and as consequential as “in a car, while stopped for a few minutes in traffic.” 
“Chance of dozing” is rated as an integer from 0 (no chance) to 3 (high).


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
flowchart.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling.
Vital signs (supine and standing systolic and diastolic blood pressure and pulse rate) and
weight will be measured throughout the study. The blood pressure and pulse rate will be 
determined after 5 minutes of quiet rest in supine position and after 1 minute in the standing 
position. The incidence of symptomatic and asymptomatic orthostatic hypotension will also 
be tabulated for each visit. Symptomatic orthostatic hypotension should be recorded as an 
Adverse Event (AE).


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5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the flow chart.
All analyses will be performed by the local laboratory of each site, and the respective 
reference ranges will be collected and filed in the ISF. 
Patients have to be fasted for the blood sampling for the safety laboratory. 
It is the responsibility of the investigator to evaluate the laboratory reports. The significant 
abnormality as judged by the investigator will be reported as adverse events (please refer to 
Section 5.2.6).
Table 5.2.3:1 
Safety laboratory tests
Category Test name
Category Test name
Haematology
Haematocrit, haemoglobin, erythrocyte count, white blood cell 
count (total and differential: lymphocytes, monocytes, 
neutrophils, eosinophils, basophiles), platelet count.
Serum chemistry
Urea, uric acid, creatinine, protein (total), albumin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma 
glutamyl transferase (GGT), alkaline phosphatase, total bilirubin, 
sodium, potassium, chloride, glucose, total cholesterol, 
triglycerides.
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for study. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
Modified Minnesota Impulsive Disorders Interview (MMIDI) [R06-1142]. 
The MMIDI is a semi-structured clinical interview designed to assess a number of impulse 
control disorders. This scale will be completed to evaluate impulse control disorders which 


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may potentially occur in patients treated with Pramipexole. The instrument has been modified 
by Boehringer-Ingelheim to focus on compulsive behaviours which may occur in this patient 
population (pathological gambling, compulsive buying and compulsive sexual behaviour). 
The other behaviours included in the MMIDI will not be assessed.
The MMIDI asks a series of questions to the patient and tabulates the total score as a measure 
of the probability for impulsivity. Each item is scored either “No” or “Yes”.
The MMIDI will be completed at visit 2 (week 0), visit 5 (week 8), visit 7 (week 18) and visit 
8 (follow-up). In case the patient experiences any abnormal behavior at visit 3 (week 2), visit 
4 (week 4) and visit 6 (week 12), then the Modified MIDI sub-scale has to be completed. In 
addition, at each other on-site visit, the investigator will ask the patient the following 
question: “Since the last visit, did you experience any of the following abnormal behaviours: 
Pathological gambling? Compulsive buying? Compulsive sexual behavior?” In case any of 
these questions is answered “Yes”, then MMIDI interview for relevant sub-scale(s) will be 
performed.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. 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 hospitalisation or development of dependency or abuse. 


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AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and AE reporting to sponsor and timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the Electronic Data Capture (EDC)
system. These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
No AESIs have been defined for this trial.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
-all AEs (serious and non-serious).
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should however, not be reported in the CRF.
Figure 5.2.6.2: 1
adverse event collection and reporting


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AE reporting to sponsor and timelines
The investigator must report SAEs and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique 
entry point and local PV China (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication and any possible interaction between the trial medication 
and a Non-Investigational Medicinal Product (NIMP).
The following should also be recorded as an (S) AE in the CRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been  assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy an SAE form must be completed 
in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Not applicable.
5.3.2
Methods of sample collection
Not applicable.
5.3.3
Analytical determinations
Not applicable.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
Not applicable since no pharmacodynamics data will be collected or analysed in this trial.
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable since no biomarker data will be collected and analysed in this trial.
5.4.1
Biobanking
Not applicable since no sample will be collected and analysed for biobanking in this trial.
5.5
OTHER ASSESSMENTS
Demographics, Height and Baseline Conditions: Demographics details, height and
baseline conditions will be documented.
Medical History: Medical history will be collected to assess the qualification of subjects
(including PD and concomitant diseases, if applicable).
Modified Hoehn and Yahr scale [R02-0836]: Modified Hoehn and Yahr scale will be
completed at on-time. Stages of the Parkinson’s disease will be assessed on 8 degrees 
between stage 0 (no sign of disease) to stage 5 (wheelchair bound or bedridden unless aided) 
in steps of 0, 1, 1.5, 2, 2.5, 3, 4 and 5.
Patient Diary: The cumulative hours of off-time every day during waking hours will be 
documented on a patient diary completed for 2 consecutive days before randomization visit.
Mini-Mental State Examination (MMSE) [R96-2656]: The MMSE is a patient reported
instrument which evaluates orientation, memory, attention, concentration, naming, repetition,
comprehension, ability to create a sentence, and ability to copy two intersecting polygons. A
lower score indicates more cognitive impairment.


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Urine Pregnancy Test: In women of childbearing potential, urine will be taken for 
pregnancy tests.
Concomitant Therapy (start date, end dates and changes): Concomitant therapy related to 
PD will be collected at least 3 months prior to randomization visit which should be recorded
in the eCRF. All the concomitant therapy should be recorded in the eCRF starting from the 
date of signing study informed consent, and ending at the follow up visit. After the follow up 
visit, only concomitant therapy indicated for treatment of an AE has to be reported.
Compliance: The investigator will be responsible for the assessment of patient compliance to
study drug (see also section 4.3).
5.6
APPROPRIATENESS OF MEASUREMENTS
NHQ will be used to evaluate the severity of nocturnal hypokinesia which was not covered 
by SCOPA scale. It is considered as a “non standard” criterion.


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The EMO will be used to evaluate the bodily movements when patient wakes up in the 
morning. It is considered as a “non standard” criterion. 
The rest of efficacy and safety criteria evaluated in this study are conventionally used in PD 
clinical trials. None of them could be considered as a "non standard" criterion.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The time window of all visits has been outlined in the Flow Chart.
If a patient does not appear to a visit, all efforts should be made to contact the patient. If a 
visit is conducted outside of the planned time interval, further process should be discussed 
with the sponsor.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening Period – visit 1

Obtain written informed consent

Assign patient number

Obtain comprehensive medical history and demographics to determine eligibility 
according to inclusion/exclusion criteria

Perform comprehensive physical examination (including heart, lungs, abdomen, 
extremities, height and weight, etc.) including also a skin examination

Obtain vital signs (blood pressure, pulse rate measurements),weight and height

Perform MMSE

Perform a Modified Hoehn & Yahr Scale staging at on-time

Review inclusion/exclusion criteria

Instruct the patient how to complete the diary and supply the patient with one. The diary
will be collected and reviewed at visit 2

Collect fasted blood sample for safety laboratory evaluation

Perform spot urine pregnancy test (for females with childbearing potential)

Perform a 12-lead ECG

Record concomitant therapies including PD therapies

Record any AE which might have occurred during the screening visit, after the informed 
consent was signed (e.g. if a patient gets a bleeding at the puncture site when the blood is 
drawn for the screening lab test)

Instruct and supply health economics questionnaire

Supply trial identification card
6.2.2
Treatment period(s)
6.2.2.1
Randomization visit (visit 2) at day 0
If the patient still qualifies for the study the following assessments are provided by the 
investigator:
Visit 2 (Randomisation visit) at day 0:


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
Obtain vital signs (blood pressure, pulse) and weight

Collect and review the completed patient diary. Check that the patient diary has been 
accurately completed, i.e. that there are no more than 4 double or missing entries on 
either day.
If there are more than 4 double or missing entries on one day, no other activities or 
ratings should be done, i.e. the patient is not eligible for baseline evaluation. Another 
attempt to obtain a valid baseline diary can be undertaken and the randomization visit
rescheduled.
If the diary has been accurately completed (i.e. no more than 4 double or missing entries 
on either day), documented on a patient diary completed for 2 consecutive days before 
randomization visit, the patient can be randomized.

Ask patient to complete the PDSS-2

Review use of concomitant therapies including PD therapies

Review inclusion/exclusion criteria to ensure patient still qualifies

Randomize patient

Perform MMIDI

Ask patient to score the severity of EMO

Ask patient to complete the ESS

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Ask patient to complete the quality of life assessment (PDQ-8 and EQ-5D-5L)

Dispense study medication to the patient to ensure the sufficient study medication until 
the next on-site visit with verbal instructions on how to take the medication. Remind the 
patient to take the study medication Pramipexole IR regularly three times per day with 
the third dose at 7-9 pm before bedtime or take study medication Pramipexole SR once 
daily at 7- 9 pm before bedtime. Additionally, remind the patient to bring the medication 
boxes (including all blank blister(s), unused and partially used study medication) back at 
the next scheduled on-site visit. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.
Study medication must be administered at the next day after randomization.

Record AEs or follow-up on AEs continuing from the prior visit

Schedule patient’s next contact (telephone call, TC1) to study site one week later 


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6.2.2.2
Up-titration phase
Patients will have weekly contact to the study site during the up-titration phase either as 
office visits or telephone calls. The complete seven weeks of up-titration are used to safely 
increase the study medications to the highest tolerated optimal dose for effective response. 
The investigator should use his/her clinical judgment in adjusting the dose to a dose where 
clinical improvement is reached. Furthermore, if a patient is unable to tolerate an increased 
dose level, the medication can be lowered one level.
It is possible that the L-Dopa+ dose may need to be adjusted with the addition of Pramipexole
(SR or IR) during the up-titration Phase.
Visit 3 (i.e., week 2) at day 14 ± 2:

Obtain vital signs (blood pressure, pulse) and weight

Check for abnormal behavior. The MMIDI sub-scale has to be completed if the patient 
experiences any abnormal behavior

Ask patient to score the severity of EMO

Ask patient to complete the ESS

Ask patient to complete the PDSS-2

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Ask patient to complete the PGI-I questionnaire

Perform medication compliance check

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit

Dispense study medication to the patient to ensure the sufficient study medication until 
the next on-site visit with verbal instructions on how to take the medication. Remind the 
patient to take the study medication Pramipexole IR regularly three times per day with 
the third dose at 7-9 pm before bedtime or take study medication Pramipexole SR once 
daily at 7- 9 pm before bedtime. Additionally, remind the patient to bring the medication 
boxes (including all blank blister(s), unused and partially used study medication) back at 
the next scheduled on-site visit. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.

Schedule patient’s next contact (telephone call, TC2) to study site one week later
Visit 4 (i.e., week 4) at day 28 ± 2:

Obtain vital signs (blood pressure, pulse) and weight


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
Check for abnormal behavior. The MMIDI sub-scale has to be completed if the patient 
experiences any abnormal behavior.

Perform MDS-UPDRS part IV

Perform CGI-I questionnaire

Ask patient to score MDS-UPDRS part II 

Ask patient to score the severity of EMO

Ask patient to complete the PGI-I questionnaire

Ask patient to complete the ESS 

Ask patient to complete the PDSS-2

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Perform medication compliance check

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit

Dispense study medication to ensure the sufficient study medication until the next on-site
visit the patient with verbal instructions on how to take the medication. Remind the 
patient to take the study medication Pramipexole IR regularly three times per day with 
the third dose at 7-9 pm before bedtime  or take study medication Pramipexole SR once 
daily at 7- 9 pm before bedtime.. Additionally, remind the patient to bring the medication 
boxes (including all blank blister(s), unused and partially used study medication) back at 
the next scheduled on-site visit. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.

Review the health economics questionnaire. Instruct and supply one with patient to bring 
home.

Ask a patient’s caregiver to complete CBI at on-site visit. If the caregiver absent on-site 
visit, patients should bring this questionnaire to her/his caregiver to complete it at the 
same day. If no caregiver, document it in the medical note and no need to complete CBI.

Schedule patient’s next contact (telephone call, TC3) to study site one week later

Schedule patient’s under next contact (telephone call, TC4) to study site two weeks later

Schedule patient’s fifth contact (telephone call, TC5) to study site three weeks later
Interim Telephone Calls (TC1 to TC5):
Interim telephone calls will be performed in order to avoid weekly on-site visits for the
patients. If for some instance a patient will not have telephone access at home, the patient
could perform a clinic visit. These unscheduled visits need to be reported then formally as
TC’s with a remark in the comments section of the corresponding eCRF page.
In the telephone calls the following information needs to be obtained:

Check medication compliance

Ask patient to complete the PGI-I questionnaire (the value will be recorded in the eCRF)

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit. Evaluate patient’s 
response to current dose level. If warranted, increase to next dose level. If patient is 


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already at optimal dose level, instruct patient to continue with the same dose level. If 
patient experienced side effects, the dose level can be adjusted to the next lower dose 
level.

Schedule patient’s next on-site visit.
TC5 will be the last time when the investigator can decide to down-titrate or to up-titrate the
study medication. From TC3 to TC5, if pramipexole dose should be adjusted due to 
unsatisfactory efficacy or adverse event, on-site visit should be added to adjust dose.
6.2.2.3
Maintenance phase
In this phase three on-site visits will be performed (V5 to V7). During the maintenance phase,
no dose adjustments will be allowed for the study medication. A patient’s dose will be 
adjusted for medical reasons if considered in the best interest of the patient upon agreement 
between investigators and Sponsor.
Visit 5 - week 8, day 56 ± 3:

Obtain vital signs (blood pressure, pulse) and weight

Perform CGI-I questionnaire 

Ask patient to score the severity of EMO

Ask patient to complete the PGI-I questionnaire

Ask patient to complete the ESS 

Ask patient to complete the PDSS-2

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Ask patient to complete  the quality of life assessment (PDQ-8and EQ-5D-5L)

Perform medication compliance check

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit

Dispense study medication to the patient to ensure the sufficient study medication until 
the next on-site visit with verbal instructions on how to take the medication. Remind the 
patient to take the study medication Pramipexole IR regularly three times per day with 
the third dose at 7-9 pm before bedtime or take study medication Pramipexole SR once 
daily at 7- 9 pm before bedtime. Additionally, remind the patient to bring the medication 
boxes (including all blank blister(s), unused and partially used study medication) back at 
the next scheduled on-site visit. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.


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
Schedule patient’s next visit (Visit 6) four weeks later
Visit 6 - week 12, day 84 ± 3:

Obtain vital signs (blood pressure, pulse) and weight

Check for abnormal behavior. The MMIDI sub-scale has to be completed if the patient 
experiences any abnormal behavior.

Ask patient to score the severity of EMO

Ask the patient to complete the PGI-I questionnaire

Ask patient to complete the ESS questionnaire

Ask patient to complete the PDSS-2

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Perform medication compliance check

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit

Dispense study medication to the patient to ensure the sufficient study medication until 
the next on-site visit with verbal instructions on how to take the medication. Remind the 
patient to take the study medication Pramipexole IR regularly three times per day with 
the third dose at 7-9 pm before bedtime or take study medication Pramipexole SR once 
daily at 7- 9 pm before bedtime. Additionally, remind the patient to bring the medication 
boxes (including all blank blister(s), unused and partially used study medication) back at 
the next scheduled on-site visit. The unused and partially used study medication will be 
returned to patients for treatment after drug accountability until the end of treatment.

Schedule patient’s next visit (Visit 7) six weeks later
Visit 7 - week 18, day 126 ± 3 or premature discontinuation:
All patients should complete these assessments, even those who terminate early.

Obtain vital signs (blood pressure, pulse) and weight

Perform comprehensive physical examination (including heart, lungs, abdomen, 
extremities, height and weight, etc.) including also a skin examination

Perform CGI-I questionnaire

Perform MMIDI


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
Ask patient to score the severity of EMO

Ask the patient to complete the PGI-I questionnaire

Ask patient to complete the ESS questionnaire

Ask patient to complete the PDSS-2

Ask patient to complete the NHQ Section 1. NHQ Section 2 should be completed by 
spouses or caregivers who are with the patients during the night at the same day. If no 
spouses or caregivers during the night, document it in the medical note and no need to 
complete NHQ Section 2.

Ask patient to complete the SCOPA-Sleep

Ask patient to complete the quality of life assessment (PDQ-8 and EQ-5D-5L)

Collect fasted blood sample for safety laboratory evaluation

Perform spot urine pregnancy test (for females with childbearing potential)

Perform medication compliance check

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit

Perform a 12-lead ECG

Dispense study medication to ensure the sufficient study medication for the down-
titration phase if patient won’t continue Pramipexole IR/SR treatment after trial
completion. Remind those patients to take the study medication Pramipexole IR regularly 
three times per day with the third dose at 7-9 pm before bedtime or take study medication 
Pramipexole SR once daily at 7- 9 pm before bedtime. Additionally, remind the patient 
to bring the medication boxes (including all blank blister(s), unused and partially used 
study medication) back at the next scheduled on-site visit.
Return the study medication boxes (including all blank blister(s), unused and partially 
used study medication) to study site if patient will continue Pramipexole IR/SR treatment 
after trial completion at this visit.

Schedule patient’s next visit (Visit 8) one week later.
6.2.3
Follow up period and trial completion
Visit 8 - 2 days after the last study dose +3 days:
All assessments planned at this visit must be performed by all subjects after 48 hours of the 
last intake of study medication (+3 days), including those who have been prematurely 
withdrawn from the trial. Study medication should be completely tapered according to
clinical practice at this visit except the patient who will continue the Pramipexole IR/SR
treatment. Assessments performed during visit 8 include the following:

Obtain vital signs (blood pressure, pulse) and weight

Perform MMIDI interview

Collect fasted blood sample for safety laboratory evaluation if abnormal at visit 7

Perform 12-lead ECG if abnormal at visit 7


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
Perform compliance check of taper medication

Review concomitant therapies including PD therapies

Record AEs or follow-up on AEs continuing from a prior visit
End of the trial is defined as the last visit (follow up visit) completed by each patient.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
Details of all analyses will be provided in the TSAP.
7.1
STATISTICAL DESIGN - MODEL
This is a two-stage multicentre, open-label, randomized, active controlled paralled group 
phase IV study. This two-stage study includes stage I and stage II. The stage I part of this trial 
will be conducted as a pilot study to explore the difference of change from baseline to week 
18 in PDSS-2 total score between Pramipexole SR and IR. Stage II will be planned as a 
confirmatory or exploratory design. 
 and II are totally separated, and the patients in 
Stage I will not be used in Stage II.
7.2
NULL AND ALTERNATIVE HYPOTHESES
For pilot stage I, there is no (confirmatory) hypothesis testing foreseen in a strict statistical 
sense. Analyses are descriptive in nature including two-sided p-values and confidence 
intervals throughout from statistical models used for explorative purposes.
For stage II, the assumption of the hypothesis testing will be based on the results of pilot 
stage I, which will be added once the topline results of stage I are worked out.
7.3
PLANNED ANALYSES
The analysis on the efficacy and safety endpoints will be based on the following populations:
• Treated set (TS) is defined as all patients who were dispensed study medication and were 
documented to have at least one dose of investigational treatment.
• Full analysis set (FAS) is defined as all patients who were randomized to treatment and 
received at least one dose of study drug and providing a baseline and at least one PDSS-2
total score measurement in maintenance period.
• Per protocol set (PPS) is defined as a subset of FAS, including only patients without 
important protocol violations for efficacy. Details will be provided in the TSAP.
The primary efficacy endpoint will be analyzed on the FAS (as the primary analysis) as well 
as on the PPS (as the sensitivity analysis). The secondary and further efficacy endpoints will 
be analyzed on the FAS. 
Safety endpoints will be analyzed on the TS.
Demographic and baseline characteristics will be analyzed on the TS using descriptive 
statistics.


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7.3.1
Primary endpoint analyses
Mean changes from baseline will be analyzed using a restricted maximum likelihood (REML) -
based repeated measures approach. Analyses will include the fixed, categorical effects of 
treatment, visit in the maintenance period, and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of baseline and baseline-by-visit interaction. An unstructured 
covariance structure will be used to model the within-patient measurements. 
If this analysis fails to converge, the following covariance structures will be tested in order: (UN 
ANTE (1) SP (1)). The first model to converge will be used as the primary analysis. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Descriptive p-values will be based on least-squares means using a two-sided α = 0.05 (two-sided 
95% confidence intervals). In case the model failed to converge under PROC MIXED, the 
“singular” option could be considered. The primary treatment comparisons will be the contrast 
between treatments at the endpoint visit. 
7.3.2
Secondary endpoint analyses
For continuous endpoints, the same method as the primary analysis will be used. For 
responder rates, logistic regression analyses will be performed with treatment and baseline (if 
baseline was measured) as the independent variables.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 2 days (inclusive) after the last dose of trial medication, will be assigned to the on-
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 


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residual effect period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA 
at the database lock.
Laboratory data, vital signs, physical examinations, or other safety-relevant data will be 
analysed quantitatively or qualitatively. MMIDI will be analysed descriptively. Details will 
be provided in the TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Not applicable.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Each patient will be included in the evaluation as far as his/her data are available. If a patient 
misses a visit, the missing data will not be imputed. The mixed effect model will handle 
missing data based on a likelihood method under the "missing at random” assumption. The 
individual data from patients who fail to complete the study (premature dropouts or 
withdrawals) will also be reported as far as the data are available. Details will be provided in 
the TSAP.
7.6
RANDOMISATION
After screening, eligible patients will be randomized to receive either active treatment 
Pramipexole SR or IR in a ratio of 1:1.
BI will provide the randomisation list, and the labelling of trial medication will be done by 
the external vendor. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator so that the resulting treatment will be both 
reproducible and non-predictable. The block size will be documented in the Clinical Trial 
Report. Access to the codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Stage I
The stage I part is pilot. The intent is to provide the evidence that will allow informed 
decision making in terms of the next stage’s development. Therefore, the total sample size of 


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80 was mainly determined by the trial feasibility instead of the given power. Considering the 
drop-out rate as 5%, the total randomized sample size should be 86.
Assume the common standard deviation is 8 [R17-4025]. Table 7.7: 1 summarizes the 
probabilities for the observed difference less than or equal to certain values (-3.00, -3.44)
with various true mean difference for change from baseline in PDSS-2 at Week 18 between 
Pramipexole SR and IR. All calculations were performed using R software (version 3.2.2).
For example, assuming the true mean difference between SR and IR is -4.00, the probability 
of observed difference less than or equal to the MCID [R17-4026] (i.e., -3.44) will be 62.3% 
with the sized 80. If the true mean difference between SR and IR is -5.00, the probability will 
be 80.8%.
Table 7.7: 1                  The probability (%) of the observed difference <= -3.00 and -3.44 
with various assumptions of the true mean difference and sample size
N 
Cut-off values of 
observed difference
True mean difference
-2.00
-3.00
-3.44
-4.00
-5.00
70
-3.00
30.1
50.0
59.1
69.9
85.2
-3.44
22.6
40.9
50.0
61.5
79.3
80
-3.00
28.8
50.0
59.7
71.2
86.8
-3.44
21.0
40.3
50.0
62.3
80.8
90
-3.00
27.7
50.0
60.3
72.3
88.2
-3.44
19.7
39.7
50.0
63.0
82.3
Stage II
The sample size will be updated once the Stage II is decided to continue.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs) and 
other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, end dates, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 


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be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual investigators will be notified of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring with the trial medication until 
30 days after LPDD at their site. Early termination of the trial is defined as the premature 
termination of the trial due to any reason before the end of the trial as specified in this 
protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
Two coordinating Investigators are responsible to coordinate investigators at the different 
sites participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of CTM, Clinical Research Associates 
(CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial. Data Management will be done by a CRO with which the responsibilities 
and tasks will have been agreed and a written contract filed before initiation of the clinical 
trial. Statistical Evaluation will be done by BI according to BI SOPs. IRT will not be used for 
this study. The local laboratory service at each site will be used for this study.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
[P02-02651]
Rascol O, Goetz C, Koller W, and Poewe W, Sampaio C. Treatment 
interventions for Parkinson's disease: an evidence based assessment. 
The Lancet 2002; 359(9317): 1589-1598.
[P04-06261]
Leopold NA, Polansky M, Hurka MR. Drug adherence in Parkinson's 
disease. Mov Disord 2004; 19(5):513-517.
[P05-13388] 
Grosset KA, Bone I, Grosset DG. Suboptimal medication adherence in 
Parkinson's disease. Mov Disord 2005; 20(11):1502-1507.
[P17-11335]
Onozawa R, Tsugawa J, Tsuboi Y, Fukae J, Mishima T, Fujioka S
The impact of early morning off in Parkinson's disease on patient 
quality of life and caregiver burden. J Neurol Sci 364, 1 - 5 (2016) 
[R02-0817]
Hauser R A, Friedlander J, Zesiewicz T A, Adler C H, Seeberger L C, 
O’Brien C F, et al. A home diary to assess functional status in patients 
with Parkinson’s disease with motor fluctuations and dyskinesia. 
Clinical Pharmacology 2000; 23(2): 75-81.
[R02-0836]
Lang AE, Clinical Rating Scales and Videotape Analysis. In: Koller 
WC,Paulson G, eds. Therapy of Parkinson’s disease, New York, Marcel 
Dekker 1990: 3-30.
[R02-2068]
Marion SA. The epidemiology of Parkinson's disease: current issues. In: 
Calne D, Calne S (eds.) Parkinson's Disease (Advances in Neurology, 
Vol. 86), Philadelphia, Lippincott Williams & Wilkins 2001: 163-172.
[R02-2529]
Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, et. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a 
new prediction equation. Ann Intern Med 1999. 130(6):461-470
[R03-0622]
Kind P, Dolan P, Gudex C, Williams A. Variations in population health 
ststus: results from a United Kingdom national questionnaire survey.
Br Med J 316, 736 - 741 (1998)
[R04-0948]
Chaudhuri KR, Pal S, DiMarco A, Whately-Smith C, Bridgman K, 
Mathew R. The Parkinson’s disease sleep scale: a new instrument for 
assessing sleep and nocturnal disability in Parkinson’s disease. 
J Neurol Neurosurg Psychiatry 73, 629-635(2002)
[R04-4222]
Jenkinson C, Fitzpatrick R, Peto V, Greenhall R, Hyman N.
The Parkinson's disease Questionnaire (PDQ-39): development and 
validation of a Parkinson's disease summary index score. Age Ageing 
26, 353 - 357 (1997) 
[R06-1041]
Daniel Weintraub, M.D., Katherine A. Oehlberg, B.A., Ira R. Katz, 
M.D., Ph.D., and Matthew B.Stern, M.D. Test Characteristics of the 15-


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Item Geriatric Depression Scale and, Am J Geriatr Psychiatry. 2006 
February; 14(2): 169–175
[R06-1142]
Minnesota implulsive disorders interview (MIDI) (introduction screen s 
CD: abbreviated). Provided upon request from Jon E. Grant, University 
of Minnesota, Department of Psychiatry, April (2006)
[R08-5312]
Pablo Martinez-Martin, Martine Visser, Carmen Rodriguez-Blazquez, 
SCOPA-Sleep and PDSS: Two Scales for Assessment, Movement 
Disorders Vol. 23, No. 12, 2008, pp. 1681–1688 of Sleep Disorder in 
Parkinson’s Disease
[R17-3926] 
Trenkwalder C, Kohnen R, Hoegl B, Metta V, Sixel-Doering F, 
Frauscher B, et al Parkinson's disease sleep scale - validation of the 
revised version PDSS-2 Mov Disord 26 (4), 644 - 652 (2011)
[R17-3952]
Chou KR, Jiann-Chyun L, Chu H The reliability and validity of the 
Chinese version of the Caregiver Burden Inventory.Nurs Res 51 (5), 
324 - 331 (2002)
[R17-4023]
Muntean ML, Benes H, Sixel-Doering F, Chaudhuri KR, Suzuki K, 
Hirata K, et al. Clinically relevant cut-off values for the Parkinson’s 
disease Sleep scale-2 (PDSS-2): a validation study. Sleep Med 24, 87-
92 (2016)
[R17-4025]
Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, 
et al. RECOVER Study Group Rotigotine effects on early morning
motor function and sleep in Parkinson’s disease: a double-blind, 
randomized, placebo-controlled study (RECOVER). Mov Disord 26 
(1), 90-99 (2011)
[R17-4026]
Horvath K, Aschermann Z, Acs P, Deli G, Janszky J, Komoly S, et al. 
Minimal clinically important difference on Parkinson’s Dosease Sleep 
Scale 2nd version. Parkinson’ s Dis 2015, 970534 (2015)
[R96-0188]
Guy W (Ed.) Clinical Global Impressions. ECDEU Assessment Manual 
for Psychpharmacology, Revised Ed. Rockville 1976: 218-222.
[R96-2350]
Hornykiewicz O. Chapter 6: The neurochemical basis of the 
pharmacology of Parkinson's disease. In: Calne DB (Ed.) Drugs for the 
Treatment of Parkinson's disease (Handbook of Experimental 
Pharmacology Vol.88) Berlin: Springer Verlag 1989: 185-204.
[R96-2351]
Hoehn MM, Yahr MD. Parkinsonism: Onset, progression, mortality. 
Neurology 1967; 17: (5): 427-443.
[R96-2656]
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state” A practical 
method for grading the cognitive state of patients for the clinician. J 
Psychiat Res 1975; 12(3): 189-198.
[R97-0791]
Johns M. W. A new method for measuring daytime sleepiness: the 
Epworth Sleepiness Scale. Sleep 1991; 14(6): 540-545.


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9.2
UNPUBLISHED REFERENCES
[U00-0074]
 
Parallel group, double-blind comparison study of Pramipexole and 
carbidopalevodopa in the treatment of Parkinson’s disease. BI trial No. 
248.350. 4 February 2000.
[U04-1242-06]
 Investigator's brochure: Pramipexole Extended-
release (ER) tablets Parkinson’s disease. 24 Feb 2009.
[U06-1598-01]
A single dose five-way cross-
over study to establish an in vitro/ in vivo correlation (IVIVC) for oral 
slow release (SR) tablets with 0.375 mg Pramipexole in healthy male 
volunteers. BI trial No. 248.560. 11 July 2006. Revision No. 1 dated 25 
April 2007
[U07-1551]
 
A multiple dose study with increasing Pramipexole doses (0.375 mg to 
4.5 mg q.d.) of oral sustained release (SR) tablets with a three-way 
cross comparison of 4.5 mg Pramipexole SR q.d. fasted versus 4.5 mg 
Pramipexole SR q.d. fed versus 1.5 mg Pramipexole immediate release 
tablets t.i.d. fasted in healthy male volunteers. 10 Jul 2007.
[U08-1904-01]
 Population Pharmacokinetic analysis of 
a double-blind, double-dummy, placebo-controlled, randomized, three 
parallel groups study comparing the Efficacy, Safety and Tolerability of 
Pramipexole ER versus placebo and versus Pramipexole IR 
administered orally over a 26-week maintenance phase in patients with 
early Parkinson’s disease (PD). 26 Sep 2008
[U08-1964-01]
, A double-blind, 
double-dummy, randomized, parallel groups study to assess the 
Efficacy, Safety and Tolerability of switching patients with early 
Parkinson’s disease (PD) from Pramipexole IR to Pramipexole ER or 
Pramipexole IR.
[U09-1232-03]
. A 
doubleblind double-dummy placebo-controlled randomized three 
parallel groups study comparing the Efficacy, Safety and Tolerability of 
Pramipexole ER versus placebo and versus Pramipexole IR 
administered orally over a 26-week maintenance phase in patients with 
early Parkinson’s disease (PD). 10 Jul 2009.
[U09-1270-04]
 A double-blind, double-dummy, 
placebocontrolled, randomized, three parallel groups study comparing 
the Efficacy, Safety and Tolerability of Pramipexole ER versus placebo 
and versus Pramipexole IR administered orally over a 26-week 
maintenance phase in LDopa+ treated patients with advanced 
Parkinson’s disease (PD). 9 Jul 2009


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[U10-1341-01]
. Long-term safety study of open-label pramipexole
extended release (ER) in patients with early Parkinson’s disease (PD). 
248.633 Interim analysis. 18 February 2010.
[U10-1369-01]
 Long-term safety study of open-label pramipexole
extended release (ER) in patients with advanced Parkinson’s disease 
(PD). 248.634 Interim analysis. 26 February 2010.
[U10-1624-01]
 A double-blind, 
doubledummy, randomised, parallel-group study to investigate the 
safety, tolerability, trough plasma concentration, and efficacy of 
pramipexole ER versus pramipexole IR administered orally for 12 
weeks in patients with Parkinson’s disease (PD) on L-dopa therapy, 
followed by a 52-week openlabel long-term treatment period to evaluate 
the long-term safety and efficacy of pramipexole ER. 248.610. 16 April 
2010.
[U10-2447-01]
. A multiple dose study with 
increasing dose for pramipexole extended release (ER) tablet (0.375 mg 
q.d. to 1.5 mg q.d.) in two-way crossover comparison to investigate the 
bioequivalence of 1.5 mg ER x 1 tablet q.d. versus 0.375 mg ER x 4 
tablets q.d. under fasted and fed conditions in Japanese healthy male 
volunteers. 248.677. 17 September 2010.
[U91-0026]
 et al. Pharmacokinetics and bioavailability of SND 919 
CL 2 Y, comparison of the plasma levels after intravenous (infusion, 
100 mcg), oral (tablets, 300 mcg) and oral (solution, 300 mcg) 
administration in 12 healthy volunteers (3-fold cross-over), 28 Sep 
1990.
[U92-0018]
 et al. Investigations on the pharmacokinetics and 
metabolism of SND 919 CL 2 Y after administration of single 
radioactive doses of 0.100mg intravenously and 0.300 mg orally in 6 
volunteers 30 Sep 1991.
[U95-0560]
. Double-blind, 
placebocontrolled, parallel-group comparison to assess the safety,
tolerance, and efficacy of Pramipexole in early Parkinson’s disease. 2 
November 1995.
[U95-0588]
 Parallel-group, 
placebocontrolled, dose-response tolerability, safety, and efficacy study 
of Pramipexole in early Parkinson’s disease. TR No. 7217-95-037. 13 
November 1995.
[U95-3150]
 Double-blind, 
Placebocontrolled, Parallel-group Comparison to Assess the Safety, 
Tolerance, and Efficacy of Pramipexole in Advanced Parkinson’s 
disease (0679) and to Assess Long-term Safety with Open-label 
Pramipexole (0979). BI trial No. 248.320. 11 July 1995.


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[U96-0232]
 A double-blind, 
placebocontrolled, randomised, multicentre trial to compare the safety, 
tolerance and efficacy of oral administration of Pramipexole up to 4.5 
mg and bromocriptine up to 30 mg in advanced Parkinson’s disease. BI 
trial No. 248.326. 9 August 1996.


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10.
APPENDICES
10.1
ESTIMATED GFR (EGFR) USING MODIFICATION OF DIET IN
RENAL DISEASE (MDRD) FORMULA [R02-2529]
Simplified MDRD formulation:
eGFR=186X SCr (mg/dL) -1.154 XAge -0.203 X (0.742 if female)


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 Feb 2018
EudraCT number
EU number
Not applicable
BI Trial number
0248-0686
BI Investigational Product(s)
Pramipexole dihydrochloride monohydrate
Title of protocol
A two- stage multicenter, open-label, randomized, 
active controlled parallel group study comparing 
the efficacy and safety of Pramipexole SR versus 
Pramipexole IR administered orally over an 18-
week treatment on nocturnal symptoms in L-
Dopa+ treated patients with advanced Parkinson’s 
disease (PD)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
CLINICAL TRIAL PROTOCOL
Description of change
•
Change the Lay Title from “SUSTAIN” to “The 
SUSTAIN study compares the effects of Sustained and 
immediate-release pramipexole on the noctUrnal 
Symptoms of paTients with Advanced ParkInsoN’s 
diease who also take L-Dopa” 
Rationale for change
•
Added a longer title which includes details about the 
trial for patients
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Corrected typos:
•
Changed ‘Parkinson’ to ‘Parkinson’s’
•
Changed ‘afflieted ‘to ‘affiliated’
Rationale for change
•
Revised error in previous version.
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
•
Short summary of safety criteria
Rationale for change
•
Summarized the safety criteria according to protocol 
template instruction
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
•
Clarified to have Pramipexole SR and the third dose of 
Pramipexole IR at 7- 9 pm before bedtime 
Rationale for change
•
Standardized the time to take the dose at night


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Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
•
Added NHQ as secondary efficacy endpoints
Rationale for change
•
Added NHQ to evaluate the severity of nocturnal 
hypokinesia which was not covered by SCOPA scale.
Section to be changed
FLOW CHART
Description of change
•
Added ‘Assign patient number in eCRF’ at visit 1
•
Added ‘Supply Trial identification card’ at visit 1
•
Added NHQ at all on-site visit(Visit 2-visit 7)
•
Added ‘Instruct and supply health economics 
questionnaire’ at on-site visit 1-6 
•
Added ‘superscript 11’ at TC3 and TC4 visit
•
Deleted ‘safety lab tests’ on visit 5
•
Clarified the unit of the time window
•
Clarified the urine pregnancy test is not applicable for 
all patients
•
Clarified the twelfth comment
•
Revised the timeline scheduled for visit 1
•
Revised days of Visit 2
•
Replaced ’NA’ by ‘Not applicable’
•
Separated ‘PDQ-8, EQ-5D-5L’from one line into two 
lines
Rationale for change
•
Added NHQ to evaluate the severity of nocturnal 
hypokinesia which was not covered by SCOPA scale.
•
Added and deleted study processes in flow chart 
according to study needs
•
Clarified study process to avoid any confusion
Section to be changed
ABBREVIATIONS
Description of change
•
Added NHQ abbreviation.
•
Added MCID abbreviation
•
Added EOT abbreviation
Rationale for change
•
Added the abbreviation of ‘NHQ’ , ’MCID’ and ‘EOT’ 
according to protocol template
Section to be changed
2.1.3 Secondary endpoint(s)
Description of change
•
Added NHQ (change from baseline )
•
Deleted those endpoints from the secondary endpoints:
Incidence of Adverse Events;
Proportion of withdrawals due to Adverse Events;
Change from baseline in vital signs (blood pressure and 
pulse rate) and weight;
Change from baseline in Modified Minnesota Impulsive 
Disorders Interview (MMIDI);
Safety laboratory parameters.
Rationale for change
•
Added NHQ score to evaluate the severity of nocturnal 
hypokineisa which was not covered by SCOPA scale.
•
The original listed safety secondary endpoints are 


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planned as safety criteria instead of secondary 
endpoints. Therefore, they need to be removed from this 
section.
Section to be changed
Description of change
Rationale for change
•
Added it according to study design objective
Section to be changed
Description of change
Rationale for change
•
Not required
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
•
Changed from ‘PDSS’ to ‘PDSS-2’
Rationale for change
•
Revised error in previous version.
3.3 TRANSITION FROM STAGE I TO STAGE II
Description of change
•
Changed from ‘Achieve MCID’ to ‘Achieve the 
minimal clinically important difference’
•
Changed from ‘no statistical significance (P<0.05)’ to ‘ 
no statistical significance (P>=0.05)’
Rationale for change
•
Avoided to misunderstanding of ‘MCID’
•
Revised error in previous version.
Section to be changed
3.4 SELECTION OF TRIAL POPULATION
Description of change
•
Revised the patient No to be screened.
Rationale for change
•
Revised error in previous version.
Section to be changed
3.4.3 Exclusion criteria
Description of change
•
Modified exclusion criterion 1
•
Added Exclusion criteria 6 and 11
Rationale for change
•
Clarify exclusion criterions.
Section to be changed
4.1.2 Selection of doses in the trial
Description of change
•
Changed from‘7-11pm’to’7 -9pm’
•
Changed the usage of Pramipexole IR from ‘2.25 mg 
(1.0 mg *1/2 t.i.d. +0.25mg t.i.d.), and 3.75 mg (1.0 mg 
t.i.d. + 0.25 mg t.i.d.)’ to ‘2.25 mg (1.0 mg *1/2 t.i.d. 
+1.0 mg *1/4mg t.i.d.), and 3.75 mg (1.0 mg t.i.d. + 1.0 
mg *1/4mg t.i.d.).’
Rationale for change
•
Revised error in previous version.
•
Changed the medication usage strategy according to 
medicine supply strategy.
Section to be changed
4.1.4 Drug assignment and administration of doses for 
each patient
Description of change
•
Changed from ‘7-11pm’to’7 -9pm’


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•
Clarified some patients who want to maintain their 
dosages, commercial Pramipexole IR/SR will be 
provided by themselves under the judgement of 
investigators.
•
Clarified the time window for on-site visit of visit 8 
Rationale for change
•
Revised error in previous version.
•
Clarified the study process and time window 
requirement for on-site visit after study completion
Section to be changed
4.1.7.1 Storage conditions for IR
Description of change
•
Changed the storage conditions for Pramipexole IR 
•
Clarified that STORM document will be used for 
temperature excursion
Rationale for change
•
Keep the consistence with Pramipexole IR SmPC 
•
Specified the process to manage site temperature 
excursion
Section to be changed
5.1 ASSESSMENT OF EFFICACY
Description of change
•
Added NHQ.
Rationale for change
•
Added NHQ to evaluate the severity of nocturnal 
hypokineisa which was not covered by SCOPA.
Section to be changed
5.2 FURTHER EFFICACY ASSESSMENT PART
Description of change
Deleted below two paragraphs.
•
Treatment compliance rate
The investigator will be responsible for the assessment 
of patient compliance to study drug (see also section 
4.3).
•
L-Dopa daily dose 
At study entry, the L-Dopa daily dose will be recorded 
in the eCRF on the specific page “L-Dopa concomitant 
therapy”. At each study visit, any change in the L-Dopa 
original daily dose will be recorded on the same specific 
eCRF page. The L-Dopa dose will be recorded as 
mg/day.
Rationale for change
•
Not required.
Section to be changed
5.2.5 Other safety parameters
Description of change
•
Clarified when to complete MMIDI
Rationale for change
•
Kept the consistence with flow chart
Section to be changed
5.5 OTHER ASSESSMENTST
Description of change
•
Added other assessments including demographics, 
height, baseline conditions, medical history, Modified 
Hoehn and Yahr scale, Patient Diary, MMSE, urine 
pregnancy test concomitant, therapy compliance.
•
Revised the description of Health Economics
Rationale for change
•
Revised it according to protocol general template 
Section to be changed
5.6 APPROPRIATENESS OF MEASUREMENTS
Description of change
•
Added NHQ and EMO as “non standard” criterions.


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Rationale for change
•
Revised it according to protocol general template
Section to be changed
6.2 DETAILS OF TRIAL PROCEDURES AT 
SELECTED VISITS
Description of change
•
Revised the trial process according to follow chart 
Rationale for change
•
Kept the consistence with follow chart
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
•
Changed from ‘PDSS’ to ‘PDSS-2’
Rationale for change
•
Revised error in previous version.
Section to be changed
7.6 RANDOMISATION
Description of change
•
Changed from’ and the packaging and labelling of trial 
medication will be done by the external vendor.’ to’ and 
the labelling of trial medication will be done by the 
external vendor.’
Rationale for change
•
No repackage will be done by external vendor
Section to be changed
8.3.1 Source documents
Description of change
•
Changed from ‘Concomitant therapy (start date, 
changes)’ to ‘Concomitant therapy (start date, end dates 
,changes)
Rationale for change
•
End date is required to obtain.
Section to be changed
8.7 ADMINISTRATIVE STRUCTURE OF THE TRIAL
Description of change
•
Clarified there are two coordinating Investigators are 
responsible to coordinate investigators at the different 
sites participating in this trial.
Rationale for change
•      Revised error in previous version.
Section to be changed
9.1 PUBLISHED REFERENCES
Description of change
•
Added publication information for  NHQ 
Rationale for change
•
Added publication information according to protocol 
template.
11.2
GLOBAL AMENDMENT 2
Date of amendment
18 Dec 2018
EudraCT number
EU number
Not applicable
BI Trial number
0248-0686
BI Investigational 
Product(s)
Pramipexole dihydrochloride monohydrate
Title of protocol
A two- stage multicenter, open-label, randomized, 
active controlled parallel group study comparing the 
efficacy and safety of Pramipexole SR versus 
Pramipexole IR administered orally over an 18-week 
treatment on nocturnal symptoms in L-Dopa+ treated 
patients with advanced Parkinson’s disease (PD)
To be implemented only after approval of the IRB / IEC / Competent Authorities
X
To be implemented immediately in order to eliminate hazard –


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IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
•
Clarified the in-and exclusion critieria, i.e., patients 
diagnosed as idiopathic PD with at least 2 years’ PD 
history.
Rationale for change
•
Clarified the inclusion criteria.
Section to be changed
FLOW CHART
Description of change
•
Added ‘The flow chart applies only to Patients enrolled 
in Stage I. ’ 
Rationale for change
•
Clarified study process to avoid any confusion
Section to be changed
ABBREVIATIONS
Description of change
•
Removed the abbreviation of ‘ Investigator’s Brochure ’
•
Changed TCM to CTL.
•
Changed CML to CTM.
Rationale for change
•
Not needed or revised according to company 
requirements.
Section to be changed
1.2 DRUG PROFILE
Description of change
•
Added the expected adverse reactions ‘inappropriate 
antidiuretic hormone secretion, delirium, mania, 
antecollis, spasms.’
•
Updated adverse events of 
Pramipexole observed in clinical trials
•
Deleted below sentence in protocol ‘For a more detailed 
description of the Pramipexole profile, please refer to the 
current Investigator’s Brochure (IB). ’
Rationale for change
•
Added the expected adverse reactions according to the 
update SmPCs.
•
Updated adverse events of 
Pramipexole observed in clinical trials
•
Deleted IB as a reference of the Pramipexole profile.
Section to be changed
3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING 
THE CHOICE OF CONTROL GROUP(S)
Description of change
•
Changed the ‘exploration’ to ‘further evaluation’.
Rationale for change
•
To keep the consistence between protocol synopsis and
protocol main body.
Section to be changed
3.4 SELECTION OF TRIAL POPULATION
Description of change
•
Revised ‘two months’ to ‘three months’ after trial 
initiation at each center may be excluded from the 
further participation.
Rationale for change
•
Revised it according to study real situation.


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Section to be changed
3.4.2 Inclusion criteria
Description of change
•
‘ Parkinson’s disease diagnosed for at least 2 years ’ 
changed to ‘ Diagnosed as Parkinson’s disease, with at 
least 2 years’ PD history. ’
Rationale for change
•
Clarified the inclusion criteria.
Section to be changed
3.4.4 Withdrawal of patients from therapy or assessments
Description of change
•
Corrected ‘ section 3.3.4.1 and 3.3.4.2 above ’ to 
‘ section 3.4.4.1 and 3.4.4.2 below ’
Rationale for change
•
Revised error in previous version.
Section to be changed
3.4.4.2 Withdrawal of consent for trial participation
Description of change
•
Corrected ‘ section 3.3.4.1’ to ‘ section 3.4.4.1 ’
Rationale for change
•
Revised error in previous version.
Section to be changed
4.1.7.2  Storage conditions for SR
Description of change
•
Changed ’ Pramipexole SR must be stored in the original 
package according to the instructions on the label. 
Patients will be reminded to keep the study drug out of 
the reach of children’ to ’ Pramipexole SR must be store 
sealed in the room temperature. Keep out of the reach of 
children’
Rationale for change
•
Updated wording according to Label Text Approval 
Form and kept consistence with label.
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
•
Added restrictions on life style for somnolence.
Rationale for change
•
Updated it according to SmPC.
Section to be changed
6.2.2.3 Maintenance phase
Description of change
•
Visit 5 and Visit 7 Changed ’ Ask patient to complete 
MMIDI’ to ’ Perform MMIDI ’
Rationale for change
•
MMIDI should be performed by investigator.
Section to be changed
9.1 PUBLISHED REFERENCES
Description of change
•
Added reference in section 9.
Rationale for change
•
Added reference.
Section to be changed
11.1 Estimated GFR (eGFR) using Modification of Diet in 
Renal Disease (MDRD) formula. [R02-2529]
Description of change
•
Changed the header.
Rationale for change
•
Added a reference.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20307124
3.0
clinical-trial-protocol-revision-02
A two- stage multicenter, open-label, randomized, active controlled parallel group
study comparing the efficacy and safety of Pramipexole SR versus Pramipexole IR
administered orally over an 18-week treatment on nocturnal symptoms in L-Dopa+
treated patients with advanced Parkinson's disease (PD)
Approval-Clinical Trial Leader
19 Dec 2018 08:51 CET
Approval-Biostatistics
19 Dec 2018 09:39 CET
Approval-Team Member Medical
Affairs
19 Dec 2018 14:11 CET
Approval-
 Established Core
Products
20 Dec 2018 09:46 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20307124
3.0

SAP_001.pdf: 
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TITLE PAGE 
TRIAL STATISTICAL ANALYSIS PLAN 
 
c24219582-01 
BI Trial No.: 
0248-0686 
Title: 
A two- stage multicenter, open-label, randomized, active 
controlled parallel group study comparing the efficacy and safety 
of Pramipexole SR versus Pramipexole IR administered orally 
over an 18-week treatment on nocturnal symptoms in L-Dopa+ 
treated patients with advanced Parkinson’s disease (PD) 
Investigational 
Product(s): 
Pramipexole dihydrochloride monohydrate 
Responsible trial 
statistician(s): 
Phone:
 
Date of statistical 
analysis plan: 
25 Sep 2019 SIGNED 
Version: 
“Final” 
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reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 


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1. 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
1. 
TABLE OF CONTENTS...................................................................................... 2 
LIST OF TABLES ................................................................................................................... 4 
2. 
LIST OF ABBREVIATIONS .............................................................................. 5 
3. 
INTRODUCTION ................................................................................................. 7 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...................... 8 
5. 
ENDPOINTS(S) .................................................................................................... 9 
5.1 
PRIMARY ENDPOINT(S) .................................................................................. 9 
5.2 
SECONDARY ENDPOINT(S) ............................................................................ 9 
5.2.1 
Key secondary endpoint(s) ................................................................................... 9 
5.2.2 
Secondary endpoint(s) .......................................................................................... 9 
6. 
GENERAL ANALYSIS DEFINITIONS .......................................................... 11 
6.1 
TREATMENT(S) ................................................................................................ 11 
6.2 
IMPORTANT PROTOCOL DEVIATIONS.................................................... 11 
6.3 
PATIENT SETS ANALYZED ........................................................................... 13 
6.5 
POOLING OF CENTRES ................................................................................. 14 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS .................................... 14 
6.6.1 
Determination of Observed Case (OC) values ................................................. 15 
6.6.2 
Other .................................................................................................................... 19 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS ................... 19 
7. 
PLANNED ANALYSIS ...................................................................................... 23 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......... 23 
7.2 
CONCOMITANT DISEASES AND MEDICATION ..................................... 23 
7.3 
TREATMENT COMPLIANCE ........................................................................ 23 
7.4 
PRIMARY ENDPOINT(S) ................................................................................ 24 
7.5 
SECONDARY ENDPOINT(S) .......................................................................... 25 
7.5.1 
Key secondary endpoint(s) ................................................................................. 25 
7.5.2 
(Other) Secondary endpoint(s) .......................................................................... 25 
7.7 
EXTENT OF EXPOSURE ................................................................................. 25 
7.8 
SAFETY ANALYSIS .......................................................................................... 25 
7.8.1 
Adverse events ..................................................................................................... 25 


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7.8.2 
Laboratory data .................................................................................................. 26 
7.8.3 
Vital signs ............................................................................................................. 26 
7.8.4 
ECG ...................................................................................................................... 26 
7.8.5 
Others ................................................................................................................... 26 
8. 
REFERENCES .................................................................................................... 27 
10. 
HISTORY TABLE .............................................................................................. 29 
 
 


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LIST OF TABLES 
Table 6.1: 1 
Definition of analyzing treatments: Screening ................................................. 11 
Table 6.1: 2 
Definition of analyzing treatments: On-treatment ........................................... 11 
Table 6.1: 3 
Definition of analyzing treatments: Post-treatment ......................................... 11 
Table 6.2: 1 
Important protocol deviations .......................................................................... 12 
Table 6.3: 1 
Patient sets analyzed ......................................................................................... 14 
Table 6.7: 1 
Visit structure ................................................................................................... 20 
Table 6.7: 2 
Definitions of calculated visits ......................................................................... 20 
Table 6.7: 3 
Interval definition ............................................................................................. 21 
Table 6.7: 4 
Interval definition ............................................................................................. 21 
Table 6.7: 5 
Interval definition for PGI-I ............................................................................. 21 
Table 6.7: 6 
Interval definition for CGI-I ............................................................................. 22 
Table 10: 1 
History table ..................................................................................................... 29 
 


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2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BI 
Boehringer Ingelheim 
BMI 
Body mass index 
COMT 
Catechol-O-Methyltransferase 
CRF 
Case Report Form 
CT 
Concomitant Therapy 
CTL 
Clinical Trial Leader 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
DDC 
Dopa-Decarboxylase 
ECG 
Electrocardiogram 
EMO 
Early Morning Off 
EoT 
End-Of-Text 
ESS 
Epworth Sleepiness Scale 
EX 
Exclusion criteria 
FAS 
Full Analysis Set 
L-Dopa 
Levodopa 
L-Dopa+ 
Levodopa combined with a Dopa-Decarboxylase-inhibitor 
LLT 
Lowest Level Term 
ICH 
International Conference On Harmonisation 
IN 
Inclusion criteria 
IR 
Immediate Release 
MAO 
Monoamine Oxydase 
MedDRA 
Medical Dictionary For Regulatory Activities 
MMIDI 
Modified Minnesota Impulsive Disorders Interview 
MMSE 
Mini-Mental State Examination 
MQRM 
Medical Quality Review Meeting 
Min 
Minimum 
Max 
Maximum 
N 
Number 
NHQ 
Nocturnal Hypokinesia Questionnaire 
OC 
Observed Case 
PD 
Parkinson’s Disease 
PDSS-2 
Parkinson’s Disease Sleep Scale 2nd version 
PDQ 
Parkinson's Disease Questionnaire 


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Term 
Definition / description 
ADL 
Activities of Daily Living 
PN 
Preferred Name 
PD 
Protocol Deviation 
PPS 
Per Protocol Set 
PR 
Pulse Rate 
PT 
Preferred Term 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
RPM 
Report Planning Meeting 
SAS® 
Statistical Analysis Software® 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SR 
Sustained Release 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
ToC 
Table of Contents 
TMW 
Trial Medical Writer 
TS 
Treated Set 
TSAP 
Trial Statistical Analysis Plan  
 


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3. 
INTRODUCTION 
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization. 
The TSAP is used for the two-stage study to contain the overall analysis specification. But 
there may be some modifications if this study continues to Stage II. 
SAS® Version 9.4 (or later) will be used for all analyses. 
 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
No change concerning statistical analysis has occurred since the CTP was finalized. 


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5. 
ENDPOINTS(S) 
5.1 
PRIMARY ENDPOINT(S) 
Please refer to Sections 2.1.2 and 5.1 of the CTP. 
5.2 
SECONDARY ENDPOINT(S) 
5.2.1 
Key secondary endpoint(s) 
Not applicable, since there are no key secondary endpoints specified in the protocol. 
5.2.2 
Secondary endpoint(s) 
Secondary endpoints are described in sections 2.1.3 and 5.1 of the CTP. 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENT(S) 
The definition below of the analysing treatment will be used for reporting of treatment 
emergent (On-Treatment) adverse events and to differentiate Screening and Post-Treatment 
safety data. The same labels and sort order as for the randomized treatment groups will be 
used. 
• Screening: All adverse events occurring between informed consent and first drug 
intake will be assigned to ‘screening’ (for listings only). 
Table 6.1: 1 
Definition of analyzing treatments: Screening 
Label 
Sort order 
Start date  
Stop date  
Screening 
 
Date of informed consent 
Date of first administration 
 
• On-Treatment (i.e., ‘Active + 2 days’): All adverse events occurring between first 
drug intake till 2 days after last drug intake will be assigned to ‘On-treatment’. 
Table 6.1: 2 
Definition of analyzing treatments: On-treatment 
Label 
Sort order 
Start date  
Stop date  
PPX SR 
01 
Date of first administration of 
Pramipexole SR 
Date of last administration of 
Pramipexole SR + 2 days 
PPX IR 
02 
Date of first administration of 
Pramipexole IR 
Date of last administration of 
Pramipexole IR + 2 days 
Note: An adverse event will be assigned to an analysing treatment (trt) based on start date (trt) <= 
start date (AE) < stop date (trt). 
• Post-Treatment: All adverse events occurring after last drug intake + ≥3 days will be 
assigned to ‘Post-treatment’ (for listings only). 
Table 6.1: 3 
Definition of analyzing treatments: Post-treatment 
Label 
Start date  
Stop date  
Post-Treatment 
Date of last administration + 3 days 
Date of last contact 
 
6.2 
IMPORTANT PROTOCOL DEVIATIONS 
All patients with important deviations from the protocol will be listed (Appendix 16.2 of the 
CTR). The IN/EX numbers refer to the definition given in the CTP and CRF. 


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Patients with potentially important protocol deviations (PDs) will be identified based on 
Table 6.2: 1 and documented. The table defines the different categories of important PDs. 
The final column describes which PDs will be used to exclude patients from the different 
patient analysis sets. Patients are either excluded from “All” analysis sets, the Per Protocol 
analysis set (PPS) or “None” of the analysis sets. 
The list of PDs in Table 6.2: 1 is considered a ‘working’ list, which is expected to be updated 
throughout the trial and finalized prior to the Database Lock (DBL). In any case, all 
important PDs will be tracked during the study at Medical Quality Review Meetings 
(MQRMs) or Reported Plan Meeting (RPM) to verify the quality of the inclusion and the 
conduct of the study. 
 
Table 6.2: 1 
Important protocol deviations 
Category / 
Code 
Description 
Requirements 
Exclud
ed 
from 
A 
 
Entrance criteria not met 
 
 
 
A1 
 
 
 
 
A1.1 
Not confirmed idiopathic PD or age less 
than 30 years at time of diagnosis 
Refers to IN1, IN3 
PPS 
 
A1.2* 
Not have clinically relevant sleep 
disturbances (i.e. PDSS-2 total score < 
18 at baseline) 
Refers to IN5 
PPS 
 
A1.3* 
Not feel uncomfortable at night (i.e. the 
score of question 9 in PDSS-2 < 2 at 
baseline) 
Refers to IN6 
PPS 
 
A1.4* 
Not have early morning off (i.e. the 
score <2 at baseline) 
Refers to IN7 
PPS 
 
A1.5* 
Motor fluctuations: with less than 2 
cumulative hours of off time every day 
during waking hours 
Refers to IN8 
PPS 
 
A2 
 
 
 
 
A2.1 
Neuro-psychiatrics disease 
Refers to EX1, EX2, EX3 
None 
 
A2.2 
History of psychosis (except history of 
drug induced hallucinations) 
Refers to EX4 
None 
 
A2.3* 
Serious sleep apnea hypopnea syndrome 
(i.e. the score of question 15 in PDSS-2 
≥ 3 at baseline) 
Refers to EX11 
PPS 
 
A2.4 
Participation in another clinical trial 
within one month or five time the ½ life 
of the investigational product 
Refers to EX22 
PPS 
B 
 
Informed consent 
 
 
 
B1 
Informed consent not available 
Refers to IN13 
All 
 
B2* 
Informed consent too late 
Refers to IN13 
None 
 
 
 
 
 
C 
 
Trial medication and randomization 
 
 
 
C1 
Incorrect trial medication taken 
Change in medication number 
during the trial (**) 
PPS 
 
C3 
Non-compliance 
 
 


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Category / 
Code 
Description 
Requirements 
Exclud
ed 
from 
 
C3.1* 
Overall compliance lower than 80% or 
higher than 120% 
Treatment compliance 
PPS 
Table 6.2: 1 cont. 
Important protocol deviations 
Category / 
Code 
Description 
Requirements 
Exclud
ed 
from 
 
C3.2* 
Treatment stopped before 12 weeks ± 3 
days(***) 
Treatment duration 
PPS 
 
 
 
 
 
D 
 
Concomitant medication 
 
 
 
D1 
Improper medication prior to 
randomization 
 
 
 
D1.1* 
Dopamine agonists (including 
pramipexole) within 4 weeks prior to 
randomization 
Refers to IN11 
PPS 
 
D1.2 
Sustained release dopaminergic drug (i.e. 
sustained release Levodopa/DDC 
inhibitor) after supper, or any anti-PD 
medication after 9pm within 4 weeks 
prior to randomization 
Refers to IN10 
PPS 
 
D1.3 
Any hypnotic medication within 4 weeks 
prior to the randomization 
Refers to EX15 
PPS 
 
D1.4 
Medication with central dopamine 
antagonist activity within 4 weeks prior 
to randomization 
Refers to EX16 
PPS 
 
D2 
Prohibited medication use 
 
 
 
D2.1 
Start of a prohibited medication during 
the trial (from screening to final visit for 
the analysis) 
Refers to Section 4.2.2.1 in CTP 
PPS 
 
 
 
 
 
 
E 
Missing primary endpoint data 
 
 
 
E1* 
Patient has baseline PDSS-2 missing, or 
all maintenance period PDSS-2 missing 
 
FAS 
Note that for these important protocol deviations, there may be exceptions which will be 
discussed during the MQRM or RPM. 
* IPDs will be identified programmatically. 
** Unless the corresponding study treatment turns out to be identical. 
*** Premature discontinuation will on technical level be handled as PD, although a premature 
discontinuation due to an AE does strictly speaking not “deviate” the protocol. 
 
6.3 
PATIENT SETS ANALYZED 
CTP, Section 7 defined the patient sets used for analyses as below distinct Table 6.3: 1. 
 
 


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Table 6.3: 1 
Patient sets analyzed 
 
Patient set 
Class of endpoint 
Treated set 
(TS) 
Full analysis set 
(FAS) 
Per protocol set 
(PPS) 
Primary endpoint 
 
primary analysis 
sensitivity analysis 
secondary and further endpoints  
 
X 
 
Safety endpoints  
X 
 
 
Demographic/baseline endpoints 
X 
 
 
The number of patients with available data for an endpoint may differ. For details, see Section 6.6. 
6.5 
POOLING OF CENTRES 
This section is not applicable because center is not included in the statistical model. 
 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
For all efficacy scales, there is initially no intention to estimate missing efficacy data. 
However, depending on the amount and pattern of missing data detected during MQRMs, the 
decision for missing data imputation will be taken. This decision will be taken latest during 
the final Report Planning Meeting (RPM). If the choice is to replace missing items, then the 
rules described in section 6.6.1 will be applied.  


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6.6.1 
Determination of Observed Case (OC) values 
For the derivation of OC type values for intermediate sub-scores or total scores of composite 
scales, the following simple (non-model-based) approaches (could be) used for imputation of 
missing answers to single questions: 
• 
best-case imputation: perform scoring as if the question had been answered in the sense 
of the best possible outcome; 
• 
worst-case imputation: perform scoring as if the question had been answered in the sense 
of the worst possible outcome; 
• 
linear up-scaling (for sum scores): in the first step, compute the (partial) sum score based 
on the available answer scores; in the second step, perform an up-scaling of this partial 
sum score to the full number of planned answers - the up-scaled score is given as: 
 
Illustrative example: if there are four questions in total, with answer scores ranging from 0 to 
5 for the first two questions, and from 1 to 4 for the last two questions, and if only the first 
and the third question have been answered with scores of 5 and 3, respectively, then the 
partial sum score of 8 = (5+3) would be up-scaled to 16 = 2 + (18 - 2) * (8 - 1) / (9 - 1). 
In the special case when the scores for all answers have the same range, linear up-scaling is 
equivalent to imputing the mean of the available answer scores for each of the missing 
answer scores. 
For all scales/scores, approximately 80% of available answers have been decided to be the 
threshold to impute missing items.  
6.6.1.1 Parkinson’s Disease Sleep Scale-2 (PDSS-2) 
If PDSS-2 is not completely answered, the missing questions will be imputed according to 
the linear upscaling as long as 12 of the 15 questions are available. If less than 12 questions 
of the 15 questions for PDSS-2 are available, the derived score PDSS-2 will be set to missing. 
Three subscales of PDSS-2 “Disturbed sleep” (items 1–3, 8, and 14); “Motor symptoms at 
night” (items 4–6, 12, and 13); and “PD symptoms at night” (items 7, 9–11, and 15) will use 
the imputed items to do the analysis. 


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6.6.1.2 Nocturnal Hypokinesia Questionnaire (NHQ) 
If NHQ is not completely answered, the missing questions will be imputed according to the 
linear upscaling as long as 8 of the 10 questions are available. If less than 8 questions of the 
10 questions for NHQ are available, the derived score NHQ will be set to missing.  
6.6.1.3 SCOPA-Sleep 
NS (night-time sleep) subscale of B-section: 4-point Likert ranging from 0: “not at all” to 3: 
“a lot”; Additional item: 7-point Likert scale ranging from “slept very well” to “slept very 
badly”; and DS (daytime sleepiness) subscale of D-section: 4-point Likert scale ranging from 
0: “never” to 3: “often”. The NS subscale score ranges from 0 to 15. The DS subscale score 
ranges from 0 to 18. Sum all the answers for each subscale to have the NS subscale score and 
the DS subscale score.   
When more than one answer is ticked by the patient, the item score is considered missing. If 
only one score is missing in either the B- or D-sections of the scale, the score of the missing 
items is replaced by the non-weighted average of the non-missing items of that scale. If 2 or 
more scores are missing, a summary score is not calculated and considered missing. 
6.6.1.4 Parkinson’s Disease Quality of Life Questionnaire (PDQ) -8 
If PDQ-8 is not completely answered, the missing questions will not be imputed.  
6.6.1.5 Epworth Sleepiness Scale (ESS) 
If ESS is not completely answered, the missing questions will be imputed according to the 
linear up-scaling as long as 7 questions of the 8 questions are available. If less than 7 
questions of the 8 questions for ESS are available, the derived score ESS will be set to 
missing.   


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6.6.1.11 Patient diary  
This is clearly not a scale, but the question of handling missing partial data is virtually the 
same as for scales: 
• In case of multiple entries for a half-hour, the worst case imputation will be applied. 
• If a diary is not completely answered, the computation of percentages will be based 
on the set of half-hour intervals for which information is given (equivalent to linear 
upscaling or mean imputation for those half-hour intervals where no information is 
given) as long as at least 42 of the 48 half-hours intervals are available. If less than 42 
half-hours of the 48 half-hours are available, the diary will be considered to invalid, 
and derived endpoints will be set to missing. 
If derived endpoints are available for the two days (equivalent to two valid diaries), the 
derived endpoints for the visit will be the mean of the derived endpoints available for diaries 
(equivalent to compute the means for the available days). 
If derived endpoints are only available for one day (equivalent to only one valid diary), the 
derived endpoints available will be set for this visit (equivalent to compute the means for the 
available days).  
Intermediate variables will be computed for the calculation: 


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• The total on time period is the sum of half-hour periods that have been coded as “on” 
without dyskinesia, or as “on” with dyskinesia. 
• The percent “off” during waking hours for day i with i=1, 2 (denoted DIAI) is equal 
to: 
 
•  “Off” time + “On” time duration (=∑”off” and “on” half-hour periods) for day i, 
where, the half-hours periods that are either missing or “asleep” are not taken into 
account for the denominator. 
• Finally, the evaluation of percent “off” during waking hours for a visit (denoted 
DIAPO) will be calculated as the average of day 1 and 2, i.e. DIAPO is equal to 
arithmetic mean of DIA1 and DIA2. 
• For each of the following times, the same derivation rules will be used to calculate the 
percent values: 
– “on without dyskinesia” 
– “on with dyskinesia” 
Application: 
If a patient reports the following in his/her diary for the visit (called X): 
• 
Day 1: 44 half-hours filled in: 12 half-hours asleep/ 14 half-hours “off” / 4 half-
hours “on without dyskinesia” / 14 half-hours “on with dyskinesia”  
• 
Day 2: 45 half-hours filled in: 11 half-hour asleep/ 10 half-hours “off” / 8 half-hours 
“on without dyskinesia” / 16 half-hours “on with dyskinesia”  
For Day 1, the diary is considered acceptable so the percent “off” during waking hours 
(called DIAPO1) will be DIAPO = 14/((14)+(4+14))*100=43.75%;  
For Day 2, the diary is considered acceptable so the percent “off” during waking hours 
(called DIAPO2) will be DIAPO2 = 10/((10)+(8+16)) *100=29.41%;  
So, for this visit X, the percent ”off” during waking hours (called DIAPO) is: DIAPO= 
(DIAPO1+DIAPO2)/2=(43.75%+29.41%)/2=36.58%.  


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6.6.2 
Other 
6.6.2.1 Handling of partial and missing Adverse Event (AE) and dates 
Missing or incomplete AEs’ start dates are imputed according to BI standards (see “Handling 
of missing and incomplete AE dates”) (2). 
6.6.2.2 Handling of partial and missing Concomitant Therapy (CT) dates 
The aim of the algorithm is to apply the “worst case scenario”, i.e., to allocate the CT to the 
“On-Treatment” period.  
6.6.2.3 Handling of partial trial indication date 
When deriving time since trial indication variable, then the following rule will be applied: If 
day is missing then day=’15’. If month and day are missing then month=’07’ and day=’01’. If 
this substitution results in a negative duration, then the duration is set to 0 year. 
 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
It is initially not planned to work on calculated visits; however timing deviations will be 
carefully checked during MQRMs. If there are too many important timing deviations then the 
following rules will be applied (this decision will be taken at the latest during the final 
RPM).Primary and secondary efficacy analyses will be based on calculated visits which will 
be labelled by ‘Week X’ in tables, listings and figures. A calculated visit is a visit that 
corresponds to a time interval based on relative days. The calculated visits form a set of 
exhaustive, non-overlapping time intervals covering the entire duration of the trial. 
Calculated visits will usually have a one-to-one correspondence with planned visits. 
If two or more data points of a patient fall into the same interval, the following rules will be 
used: 
• 
Pre-treatment period: use the last value 
• 
Treatment period: use the closest value to the planned day  
• 
Post-treatment period: use first value 
In case where two visits fall in the same interval and at equal distance to the planned visit, the 
first one will be taken for the analysis. 
The following first table presents the visit structure according to the study flowchart: 
 
 


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Table 6.7: 1 
Visit structure  
Trial Period Screening Random 
Treatment 
Flexible up-titration phase 
Maintenance 
Follow up 
Visit 
V1 
V2 
TC1 
V3 
TC2 
V4 
TC3 
TC4 
TC5 
V5 
V6 
V7 
V8 
Week(s) 
-2 to -1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
12 
18 
NA 
Day(s) 
-14 to-3 
0 
7 
±2 
14 
±2 
21 
±2 
28 
±2 
35 
±2 
42 
±2 
49 
±2 
56 
±3 
84 
±3 
126 
±3 
Last dose+2 
+3 
Description 
Screen 
Baseline Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
12 
Week 
18 
End 
Taper 
 
The following tables shows how measurements will be assigned as calculated visit based on 
the day (relative to first study drug intake) on which measurements were made. Below are 
different patterns for interval definition of different types of endpoints:  
• 
PDSS-2, NHQ, SCOPA-sleep, EMO, ESS, 
 (refer to 
Table 6.7: 2)  
• 
 
• 
PDQ-8, 
 (refer to Table 6.7: 4) 
• 
PGI-I (refer to Table 6.7: 5) 
• 
CGI-I (refer to Table 6.7: 6) 
Table 6.7: 2 
Definitions of calculated visits 
 
Visit No Planned day 
Interval definition 
Visit description 
Example 
From 
To 
Actual day Calculated visit 
V2 
0 
-∞ 
0 
Baseline 
0 
V2 
V3 
14 
1 
20 
Week 2 
17 
V3 
V4 
28 
21 
41 
Week 4 
28 
V4 
V5 
56 
42 
69 
Week 8 
54 
V5 
V6 
84 
70 
104 
Week 12 
100 
V6 
V7 
126 
105 
+∞ 
Week 18 
120 
V7 
 
The “Actual day” column lists an example of actual days. The “Calculated visit” column 
shows how the algorithm would be applied to these actual days. In the example, actual day 3 
and 17 fall in the same interval from day 1 to 20, so they should both be categorized under 
calculated visit 3 (Week 2). By default, the value for day 17 will be used for the visit 3 
because it is the closest value to the planned day. 
In accordance with the corresponding rules for safety data, measurements up to 2 days 
(inclusive) after last intake of study medication (during up-titration, maintenance or down-
titration periods) will be considered as on-treatment for the statistical analysis. This decision 
might be modified at the final RPM at the latest. 


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Even if we do not use the calculated visit for the analysis, a variable “Study Day” will be 
added for all over time data in the analysis data set, representing the time since first drug 
administration. In any case, the VISIT 8 for prematurely discontinued patients will need to be 
re-structured following those rules.  
 
Table 6.7: 3 
Interval definition 
 
Visit No Planned day 
Interval definition 
Visit description 
From 
To 
V2 
0 
-∞ 
0 
Baseline 
V4 
28 
1 
41 
Week 4 
V5 
56 
42 
90 
Week 8 
V7 
126 
91 
+∞ 
Week 18 
 
Table 6.7: 4 
Interval definition 
 
Visit No Planned day 
Interval definition 
Visit description 
From 
To 
V2 
0 
-∞ 
0 
Baseline 
V5 
56 
47 
90 
Week 8 
V7 
126 
91 
+∞ 
Week 18 
 
Table 6.7: 5 
Interval definition for PGI-I   
Visit No Planned day 
Interval definition 
Visit description 
From 
To 
TC1 
7 
0 
9 
Week 1 
V3 
14 
10 
17 
Week 2 
TC2 
21 
18 
24 
Week 3 
V4 
28 
25 
31 
Week 4 
TC3 
35 
32 
38 
Week 5 
TC4 
42 
39 
45 
Week 6 
TC5 
49 
46 
52 
Week 7 
V5 
56 
53 
69 
Week 8 
V6 
84 
70 
104 
Week 12 
V7 
126 
105 
+∞ 
Week 18 
 
 
 


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Table 6.7: 6 
Interval definition for CGI-I   
Visit No Planned day 
Interval definition 
Visit description 
From 
To 
V4 
28 
26 
48 
Week 4 
V5 
56 
49 
90 
Week 8 
V7 
126 
91 
+∞ 
Week 18 
 


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7. 
PLANNED ANALYSIS 
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.  
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not).  
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers. 
The category missing will be displayed only if there are actually missing values. 
Baseline refers to the last assessment of a variable prior to first trial drug intake. 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Only descriptive statistics are planned for this section of the report. Demographic and 
baseline characteristics will be displayed for TS by treatment group and for the total.  
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Concomitant diseases and medication on-treatment period will be displayed for TS 
population. Only descriptive statistics are planned for this section of the report. 
Concomitant diseases will be displayed by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and preferred term (PT) by treatment group and for 
the total. Concomitant non PD therapy medication will be displayed by Anatomical 
Therapeutic Chemical level 2 (ATC2) and Preferred Names (PNs) respectively by treatment 
group and for the total. A frequency table will be provided for the concomitant Anti-PD 
therapy and added (i.e., new added) Anti-PD therapies with their ATC4 and PN.  
Tables will also describe the concomitant L-Dopa therapies. The L-Dopa daily dose/ L-Dopa 
equivalent daily dose and the percentage of patients with L-Dopa dose/ L-Dopa equivalent 
daily dose ≤400mg or >400mg will be described. 
7.3 
TREATMENT COMPLIANCE 
Only descriptive statistics are planned for this section of the report. The compliance will be 
displayed separately by visit interval and total. Treatment compliance will be displayed for 
the TS population. 


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7.4 
PRIMARY ENDPOINT(S) 
The analysis of the primary endpoint will be conducted in accordance with Section 7.3.1 of 
the CTP. The statistical model will be as follows: 
 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Tests will be based on least-squares means using a two-sided α = 
0.05 (two-sided 95% confidence intervals).The primary treatment comparison will be the 
contrast between treatments at the endpoint visit. 
The primary analysis will be performed on FAS. The sensitivity analysis will be performed 
on PPS. 
The only stratification factor, i.e., site, will be excluded from the primary model, because it is 
simply be done for the convenience of running the trial ("organizational strata") due to the 
manual envelop randomization. It is performed to minimize the amount of unused supplies at 
each site and thereby simplify stock control. Therefore, site needs not be included per default 
in the primary analysis model. 
In the event of non-convergence, the following methods will be attempted (in order) to 
overcome it: 
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50. 
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations. 
4. Include the statement ‘performance nothread’ – this removes multi-threading from the 
calculations. 
5. Provide starting values for covariance parameters using a ‘parms’ statement. 
Estimates will be obtained from by prior knowledge or possibly by first running the model 
using a simpler covariance matrix.  
6. Use a simpler covariance matrix: Should none of the previous methods work, the 
covariance matrix will be changed from unstructured to Toeplitz with heterogeneous 
variances (TOEPH). Should this also not converge, a standard Toeplitz matrix (TOEP) will 


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be fitted. Finally, if convergence still does not occur, then an order-1 autoregressive matrix 
(AR(1)) will be fitted. 
The primary model will be also evaluated by subgroup (refer to section 6.4) and on the PPS 
population.  
7.5 
SECONDARY ENDPOINT(S) 
7.5.1 
Key secondary endpoint(s) 
This section is not applicable as no key secondary endpoint has been specified in the 
protocol. 
7.5.2 
(Other) Secondary endpoint(s) 
Continuous endpoints will be analyzed using a MMRM model with the same effects as the 
primary endpoint, but using the respective baseline of the continuous endpoint as covariate. 
Logistic regression analyses will be performed with treatment and baseline (if baseline was 
measured) as the independent variables. 
7.7 
EXTENT OF EXPOSURE 
Extent of exposure will be displayed for the TS. The standard descriptive statistical 
parameters on duration and doses of study drug administration will be calculated and 
displayed separately for all treatment groups.  
Frequencies will be also prepared for the following categories : < 1 week, 1 - <4 weeks, 4 - 
<8 weeks, 8 - <12weeks, and >=12 weeks. And mean final dose and cumulative dose will be 
calculated and the final dose distribution for daily doses and categories (low, median, high) 
will be displayed. 
7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the TS population. 
7.8.1 
Adverse events 
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs. 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies: 


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• 
All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, and outcome). 
• 
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day after 
the end of the first occurrence). 
For further details on summarization of AE data, please refer to (2, 3). 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + 2 days will be assigned to the randomized treatment. All adverse events occurring 
before first drug intake will be assigned to ‘screening’ and all adverse events occurring after 
the last drug intake +2 days will be assigned to ‘post-treatment’ (for listings only). For details 
on the treatment definition, see Section 6.1. 
An overall summary of adverse events will be presented. 
The frequency of patients with adverse events will be summarized by treatment, primary 
System Organ Class (SOC) and Preferred Term (PT) (mention MedDRA levels to be 
displayed in the tables). Separate tables will be provided for some kinds of adverse events. 
The SOCs will be sorted alphabetically; PTs will be sorted by frequency (within SOC). 
7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (4). 
7.8.3 
Vital signs 
Only descriptive statistics are planned for this section of the report. 
7.8.4 
ECG 
Not applicable. 
7.8.5 
Others 
The number and frequency of MMIDI, MMIDI for compulsive sexual behaviour, for 
compulsive buying, and for pathological gambling and abnormal behaviour will be displayed. 


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8. 
REFERENCES 
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version. 
2. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON. 
3. 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON. 
4. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON. 
 


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10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-MMM-
YY) 
Author 
Sections 
changed 
Brief description of change 
Initial 
22-Jun-18 
None 
This is the initial TSAP with necessary 
information for trial conduct 
Final 
25-Sep-19 
None 
This is the final TSAP with all 
information for trial phase I conduct