Clinical trial NCT06457204
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2024-07-02; Completion date: 2024-08-12
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to establish the bioequivalence of Sifrol® tablets manufactured at two different sites.

Detailed description:

Arms: arm 1: Subjects received the reference product followed by the test product, the treatments were separated by a wash-out phase of at least 3 days.

Reference product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.

Test product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours. arm 2: Subjects received the test product followed by the reference product, the treatments were separated by a wash-out phase of at least 3 days.

Test product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.

Reference product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.
Interventions: intervention 1: Pramipexole manufactured in Ingelheim intervention 2: Pramipexole manufactured in Ennigerloh
Intervention descriptions: intervention 1: 1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours. intervention 2: 1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.

Protocol documents:
Prot_000.pdf: 
BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c43506074-02
EU Trial No.
UTN
2024-510764-23-00
U1111-1303-3852
BI Trial No.
0248-0689
BI Investigational
Medicinal Product
Sifrol®, pramipexole
Title
Bioequivalence of two Sifrol® tablets following oral 
administration in healthy subjects (an open-label, randomised, 
single-dose, two-way crossover trial)
Lay Title
A study in healthy people to compare two different Sifrol®
tablets  
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Investigator
Phone: 
 / Fax: 
Current Version, Date
Version 2.0, 29 Apr 2024
Original Protocol Date
23 Feb 2024
Page 1 of 55
Proprietary confidential information
© 2024 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
Original protocol date
23 February 2024
Revision date
29 April 2024
BI trial number
0248-0689
Title of trial
Bioequivalence of two Sifrol® tablets following oral administration in healthy 
subjects (an open-label, randomised, single-dose, two-way crossover trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
The manufacturing of Sifrol® tablets will be outsourced to 
 
This trial targets to establish bioequivalence between Sifrol®
tablets produced at the current (Ingelheim) and alternative (Ennigerloh) 
manufacturing site.
Trial objective
To establish the bioequivalence of Sifrol® tablets containing 0.088 mg pramipexole
manufactured by BI in Ingelheim (reference) and by
 
 (test). 
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of pramipexole
Secondary endpoints: AUC0-of pramipexole
Trial design
Randomised, open-label, two-way crossover design
Number of subjects 
total entered
28
on each treatment
28
Diagnosis
Not applicable
Main inclusion criteria
Healthy male and female subjects, age of 18 to 55 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product
Sifrol® 0.088 mg tablets (Ennigerloh)
dose
1 x 1 tablet (= 0.088 mg pramipexole)
mode of administration
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product
Sifrol® 0.088 mg tablets (Ingelheim)
dose
1 x 1 tablet (= 0.088 mg pramipexole)
mode of administration
Oral with 240 mL of water after an overnight fast of at least 10 h


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Duration of treatment
One day (single dose) for each treatment
Statistical methods
The assessment of bioequivalence will be based upon 2-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (test/reference) for the primary 
and secondary endpoints using an acceptance range of 80.00 to 125.00%. This
method corresponds to the two one-sided t-tests procedure, each at a 5% 
significance level. The statistical model will be an analysis of variance (ANOVA) 
on the logarithmic scale including effects for sequence, subjects nested within
sequences, period and treatment. CIs will be calculated based on the residual error 
from the ANOVA and quantiles from the t-distribution.
The secondary endpoint will be analysed with the same statistical method as for the 
primary endpoints.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory8
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
1/2 (two identical periods separated by a wash-out of at 
least 3 days between drug administrations
2/3
-1
-12:00
20:00
Admission to trial site7
x5, 7
x7
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
x2
x2
x2
0:00
08:00
Drug administration, start bed rest
0:15
08:15
x
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, end of bed rest, 
thereafter lunch3
x
x
x
5:00
13:00
x
6:00
14:00
x
8:00
16:00
x
10:00
18:00
x
11:00
19:00
Dinner3
12:00
20:00
x
x
2
24:00
08:00
Breakfast (voluntary) 3, discharge from 
trial site
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
FU
4
3-24
End of study (EoS) examination4
B
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test in women), demographics (including determination of body height and weight, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
.Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, pregnancy test in women, recording of AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
The time is approximate; all procedures must be completed no later than 10 hours before planned drug administration on 
Day 1.
8.
The laboratory parameters to be determined in safety lab A and B are detailed in chapter 5.2.3.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS AND DEFINITIONS........................................................9
1.
INTRODUCTION.................................................................................... 11
1.1
MEDICAL BACKGROUND............................................................................11
1.2
DRUG PROFILE...............................................................................................12
1.2.1
Clinical pharmacokinetics (PK) of pramipexole................................12
1.2.2
Safety and tolerability of pramipexole................................................12
1.2.3
Residual Effect Period..........................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................14
1.4
BENEFIT - RISK ASSESSMENT ...................................................................14
1.4.1
Benefits...................................................................................................14
1.4.2
Risks .......................................................................................................14
1.4.3
Benefit risk assessment.........................................................................15
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 16
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......16
2.1.1
Main objectives......................................................................................16
2.1.2
Primary endpoint..................................................................................16
2.1.3
Secondary endpoint ..............................................................................16
2.2.2.2
Safety and tolerability..............................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 18
3.1
OVERALL TRIAL DESIGN............................................................................18
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................18
3.3
SELECTION OF TRIAL POPULATION ......................................................18
3.3.1
Main diagnosis for trial entry..............................................................19
3.3.2
Inclusion criteria...................................................................................19
3.3.3
Exclusion criteria ..................................................................................19
3.3.4
Withdrawal of subjects from treatment or assessments ...................21
3.3.4.1
Withdrawal from trial treatment ..............................................21
3.3.4.2
Withdrawal of consent to trial participation ............................22
3.3.4.3
Discontinuation of the trial by the sponsor..............................22


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3.3.5
Replacement of subjects .......................................................................22
4.
TREATMENTS........................................................................................ 23
4.1
INVESTIGATIONAL TREATMENTS ..........................................................23
4.1.1
Identity of the Investigational Medicinal Products ...........................23
4.1.2
Selection of doses in the trial................................................................23
4.1.3
Method of assigning subjects to treatment groups ............................23
4.1.4
Drug assignment and administration of doses for each subject .......24
4.1.5
Blinding and procedures for unblinding ............................................24
4.1.6
Packaging, labelling, and re-supply ....................................................25
4.1.7
Storage conditions.................................................................................25
4.1.8
Drug accountability ..............................................................................25
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................26
4.2.1
Other treatments and emergency procedures....................................26
4.2.2
Restrictions............................................................................................26
4.2.2.1
Restrictions regarding concomitant treatment .........................26
4.2.2.2
Restrictions on diet and life style.............................................26
4.2.2.3
Contraception requirements.....................................................27
4.3
TREATMENT COMPLIANCE.......................................................................27
5.
ASSESSMENTS....................................................................................... 28
5.1
ASSESSMENT OF EFFICACY.......................................................................28
5.2
ASSESSMENT OF SAFETY............................................................................28
5.2.1
Physical examination ............................................................................28
5.2.2
Vital signs...............................................................................................28
5.2.3
Safety laboratory parameters..............................................................28
5.2.4
Electrocardiogram................................................................................31
5.2.5
Other safety parameters.......................................................................31
5.2.6
Assessment of adverse events...............................................................31
5.2.6.1
Definitions of adverse events...................................................31
5.2.6.1.1 Adverse event ............................................................31
5.2.6.1.2 Serious adverse event ................................................32
5.2.6.1.3 AEs considered ‘Always Serious’.............................32
5.2.6.1.4 Adverse events of special interest .............................33
5.2.6.1.5 Intensity (severity) of AEs.........................................33
5.2.6.1.6 Causal relationship of AEs ........................................33
5.2.6.2
Adverse event collection and reporting ...................................34
5.2.6.2.1 AE collection.............................................................34
5.2.6.2.2 AE reporting to the sponsor and timelines ................35
5.2.6.2.3 Pregnancy ..................................................................35
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................36
5.3.1
Assessment of pharmacokinetics .........................................................36
5.3.2
Methods of sample collection...............................................................36


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5.3.2.1
Blood sampling for pharmacokinetic analysis of pramipexole36
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................37
5.4
ASSESSMENT OF BIOMARKERS................................................................37
5.5
BIOBANKING ...................................................................................................37
5.6
OTHER ASSESSMENTS .................................................................................37
5.6.1
Pharmacogenomic evaluation..............................................................37
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................37
6.
INVESTIGATIONAL PLAN.................................................................. 38
6.1
VISIT SCHEDULE............................................................................................38
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................38
6.2.1
Screening period....................................................................................38
6.2.2
Treatment periods.................................................................................38
6.2.3
Follow-up period and trial completion ...............................................39
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 40
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................40
7.2
PLANNED ANALYSES....................................................................................40
7.2.1
General considerations.........................................................................40
7.2.1.1
Analysis sets.............................................................................40
7.2.1.2
Pharmacokinetics.....................................................................41
7.2.2
Primary endpoint analyses...................................................................41
7.2.3
Secondary endpoint analyses ...............................................................43
7.2.5
Safety analyses.......................................................................................43
7.2.6
Interim analyses ....................................................................................44
7.3
HANDLING OF MISSING DATA ..................................................................44
7.3.1
Safety......................................................................................................44
7.3.2
Pharmacokinetics..................................................................................44
7.4
RANDOMISATION ..........................................................................................44
7.5
DETERMINATION OF SAMPLE SIZE ........................................................44
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 46
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................46
8.2
DATA QUALITY ASSURANCE .....................................................................47
8.3
RECORDS..........................................................................................................47


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8.3.1
Source documents .................................................................................47
8.3.2
Direct access to source data and documents.......................................48
8.3.3
Storage period of records.....................................................................49
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................49
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......49
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................49
8.6
TRIAL MILESTONES .....................................................................................50
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................50
9.
REFERENCES......................................................................................... 52
9.1
PUBLISHED REFERENCES...........................................................................52
9.2
UNPUBLISHED REFERENCES.....................................................................52
10. APPENDICES .......................................................................................... 54
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 55
11.1
GLOBAL AMENDMENT 1 .............................................................................55


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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study (synonym for End of Trial)
F
Absolute bioavailability factor
FAS
Full Analysis Set
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HR
Heart rate
IB
Investigator’s brochure


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IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RLS
Restless Legs Syndrome
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
T
Test product or treatment
TMF
Trial master file
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan


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1.
INTRODUCTION
Pramipexole (Sifrol®) is a dopamine receptor agonist. The pramipexole immediate release 
(IR) tablets are an approved medicine for the treatment of signs and symptoms of Parkinson`s 
disease (either as monotherapy or in combination with levodopa) since 1997, and for the 
treatment of primary Restless Legs Syndrome since 2006 [U04-1242-08]. Boehringer 
Ingelheim intends to outsource the production of Sifrol® tablets to 
 
 This trial shall establish the bioequivalence of Sifrol® tablets manufactured by 
BI (reference) and by 
 (test).
1.1
MEDICAL BACKGROUND
Parkinson’s disease is a neurodegenerative disorder manifested by abnormally slow 
movements (bradykinesia), diminished motor activity (hypokinesia), muscle rigidity, resting
tremor, flexed posture, and the loss of postural reflexes. As the disease progresses, patients 
may develop clinical features partially augmented by levodopa (the usually prescribed 
therapy), such as motor complications (e.g. wearing off phenomenon and dyskinesia). 
Dopamine agonists are currently being used either in monotherapy for the treatment of 
Parkinson’s disease in the early stage of the disease (as part of the levodopa sparing strategy 
to delay as much as possible the occurrence of levodopa-related motor fluctuations) or in the 
later phase of the disease to lessen motor complications caused by levodopa. The beneficial 
effects of dopamine agonists used as adjuvant therapy in patients experiencing response 
fluctuations or diminished response to levodopa are well documented [U04-1242-08]. The 
recommended dosing scheme in Parkinson’s disease is a weekly up-titration from 0.25 mg to 
a maximum of 1.5 mg (t.i.d. dosing) resulting in a total daily exposure from 0.375 mg to a 
maximum of 4.5 mg (all doses refer to the salt). Abrupt discontinuation of pramipexole can 
lead to the development of a neuroleptic malignant syndrome. Therefore, pramipexole should 
be tapered off after the subject has received a dose of at least 0.75 mg [R24-1508, R24-1562].
Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs 
while at rest with a worsening of symptoms at night, which significantly impacts patient`s 
quality of life. RLS may be primary (idiopathic) or secondary pregnancy or various systemic 
disorders, especially iron deficiency, and chronic renal insufficiency. Although the patho-
genesis of RLS remains unclear a central dopaminergic dysfunction is likely to be involved. 
Therapeutic options include iron-replacement (if body-iron stores are reduced) or prescription 
of gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole and 
rotigotine  [P21-04108].
The recommended dosing scheme for the indication RLS (restless legs syndrome) is a weekly
up-titration over the following once daily doses: 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg (all 
doses refer to the salt) [R24-1508, R24-1562].


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1.2
DRUG PROFILE
Pramipexole is a non-ergot dopamine receptor agonist, i.e. it is structurally different from the 
ergot-derived drugs (e.g. bromocriptine, pergolide). It is a full agonist and has a high receptor 
selectivity for the D2 subfamily of dopamine receptors. [U04-1242-08]
1.2.1
Clinical pharmacokinetics (PK) of pramipexole
Pramipexole is rapidly and completely absorbed following oral administration. The absolute 
bioavailability is greater than 90% and the maximum plasma concentrations occur between 
01:00 and 03:00 hours. Food intake reduces the rate of absorption but not the overall extent 
of absorption. Pramipexole shows linear kinetics and relatively small inter-patient variability 
of plasma levels [R24-1508, R24-1562].
Pramipexole is metabolised in man only to a small extent. Renal excretion of unchanged 
pramipexole is the major route of elimination and accounts for about 80% of dose. 
Approximately 90% of a 14C labelled dose is excreted through the kidneys while less than 2% 
is found in the faeces. The elimination half-life (t½ [h]) varies from 08:00 hours in the young 
to 12:00 hours in the elderly [U92-0018].
For a more detailed description of the pramipexole PK profile, please refer to the current 
SmPC [R24-1562].
1.2.2
Safety and tolerability of pramipexole
Safety and tolerability in patients
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients 
on pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently 
reported for both groups. 63% of patients on pramipexole and 52% of patients on placebo 
reported at least one adverse drug reaction.
The most frequently (≥ 5%) reported adverse events in patients suffering from Morbus 
Parkinson were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, 
constipation, hallucination, headache, and fatigue.
The most frequently (≥ 5%) reported adverse events in patients suffering from RLS were 
nausea, headache, dizziness, and fatigue [R24-1508, R24-1562].


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For further description of the pramipexole safety profile, please refer to the current SmPC
[R24-1562].
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of pramipexole is 2 days. This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Sifrol® is an approved medicinal product currently used in the treatment of Parkinson`s 
disease and Restless Legs Syndrome. To assure further market supply the manufacturing of 
Sifrol® tablets will be outsourced to 
. This trial 
targets to establish bioequivalence between Sifrol® tablets produced at the current
(Ingelheim) and alternative (Ennigerloh) manufacturing site.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance to assure further market supply with 
Sifrol® providing an effective treatment to patients suffering from Parkinson’s disease and 
Restless Legs Syndrome. 
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: pramipexole
Cardiovascular effects 
including orthostatic 
dysregulation
Among the most frequently 
(≥ 5%) reported known side 
effects of dopamine receptor 
agonists (see 1.2.2)
Subjects are confined to bed until 
4 h p.a. covering the time of 
maximum serum concentration. 
Vital signs will be monitored.
AEs related to gastro-
intestinal tract and to the 
central nervous system
Known side effects of 
dopamine receptor agonists 
(see 1.2.2)
Reported AEs can be managed 
within the setting of a phase I trial. 


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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Trial procedures
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site.
The total volume of blood withdrawn per subject during the entire trial will not exceed 150 
ml (the volume of a normal blood donation is 500 mL). No health-related risk to healthy 
subjects is expected from withdrawal of this volume of blood.
1.4.3
Benefit risk assessment
Sifrol® is an approved medicine for more than 25 years. The nature of the target and the 
mechanism of action of pramipexole is well understood, its safety and tolerability are well 
characterised in patients as well as in healthy subjects.
In the current trial the lowest available clinical dose of Sifrol® is administered as a single 
dose on 2 occasions to healthy subjects, which is below the maximum daily dose used in the 
treatment of patients with Parkinson’s disease or Restless Legs Syndrome. The trial will be 
performed to assure the further market supply with Sifrol®. It is therefore considered that the 
benefit of Sifrol® administration in this trial outweighs the potential risks for participating 
subjects.


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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 this trial is to establish the bioequivalence of Sifrol® tablets produced 
at the current (Ingelheim; Reference, R) and alternative (Ennigerloh; Test, T) manufacturing 
site following oral administration.
2.1.2
Primary endpoint
The following pharmacokinetic parameters will be determined for pramipexole:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for pramipexole:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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2.2.2.2
Safety and tolerability
Safety and tolerability of pramipexole will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a randomised, open-label, two-way crossover trial in healthy 
male and female subjects in order to compare the test treatment (T) to the reference treatment 
(R). The treatments will be one Sifrol® 0.088 mg tablet (manufactured in Ennigerloh) as test 
treatment (T) and one Sifrol® 0.088 mg tablet (manufactured in Ingelheim) as reference 
treatment (R). Both treatments are administered to subjects in the fasting state. The subjects 
will be randomly allocated to the 2 treatment sequences (T-R or R-T). For details, refer to 
Section 4.1.
There will be a washout period of at least 3 days between the treatments.
Figure 3.1:1 trial design scheme
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For bioequivalence trials, the crossover design is preferred because of its efficiency: since 
each subject serves as his/her own control, the comparison between formulations is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 28 healthy male and female subjects will enter the trial. They will be 
recruited from the volunteers' pool of the trial site.
3 days
R
T
T
R
Treatment period
1
2
Treatment
sequence
A
B


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A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Either male subject, or female subject who meet any of the following criteria for a highly 
effective contraception from at least 15 days before the first administration of trial 
medication until 30 days after trial completion:
- Use of combined (estrogen and progestogen containing) hormonal contraception that 
prevents ovulation (oral, intravaginal or transdermal), plus condom
- Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
- Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
- Sexually abstinent
- A vasectomised sexual partner who received medical assessment of the surgical success 
(documented absence of sperm) and provided that partner is the sole sexual partner of 
the trial participant
- Surgically sterilised (including hysterectomy)
- Postmenopausal, defined as no menses for 1 year without an alternative medical cause
(in questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:


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1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. 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
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site


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21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
22. For female subjects: Lactation, pregnancy, or plans to become pregnant during the trial or 
within 30 days after trial completion
23. For female subjects: Positive pregnancy test
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3), the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy,
surgery, adverse events (AEs), or diseases)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.


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If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reason 2 is met, the trial must be discontinued immediately):
1. Deviation from GCP, or the CTP impairing the appropriate conduct of the trial
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
3. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity in one treatment period, or if at least one drug-related serious 
adverse event is reported
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacologist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable subjects anticipated to complete the trial. A replacement subject will be assigned a 
unique trial subject number, and will be assigned to the same treatment sequence as the 
subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Sifrol® tablets that are currently available on the market are produced in Ingelheim (reference 
treatment). In the future Sifrol® tablets will be manufactured by 
 
 (test treatment).  
Each tablet contains 0.125 mg pramipexole dihydrochloride monohydrate (salt form) 
corresponding to 0.088 mg pramipexole (base) [R24-1562]. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product (manufactured in Ennigerloh) are given below:
Name:
Sifrol® Tabletten
Substance:
Pramipexole
Pharmaceutical formulation: IR tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
0.088 mg
Posology:
1-0-0
Mode of administration:
Oral
The characteristics of the reference product (manufactured in Ingelheim) are given below:
Name:
Sifrol® Tabletten 
Substance:
Pramipexole
Pharmaceutical formulation: IR tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
0.088 mg
Posology:
1-0-0
Mode of administration:
Oral
4.1.2
Selection of doses in the trial
The dose selected for this trial is the starting dose used for up-titration in the clinic 
[R24-1562].
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial site in advance.


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Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
scheme will be allocated to the subjects by drawing lots. Subjects are then assigned to a 
treatment sequence according to the randomisation scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. 
The randomisation procedure is described in Section 7.4
4.1.4
Drug assignment and administration of doses for each subject
This is a 2-way crossover trial. All subjects will receive the 2 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
Pramipexole
Tablet
(Ennigerloh)
0.088 mg
1 tablet, single dose
0.088 mg
R (Reference)
Pramipexole
Tablet
(Ingelheim)
0.088 mg
1 tablet, single dose
0.088 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to subjects who are in a standing position. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication.
Subjects will be kept under close medical surveillance until 24 h after drug administration. To 
avoid orthostatic dysregulation subjects are confined to bed for 4 hours after pramipexole 
dosing. 
The treatments will be separated by a wash-out phase of at least 3 days.
4.1.5
Blinding and procedures for unblinding
This is an open trial and will be handled open throughout.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.


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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
For details of packing and the description of the label, refer to the ISF.
The labels will be prepared according to Regulation (EU) No 536/2014, Annex 6 omitting 
certain particulars with the following justifications:
-
The investigator name was omitted from the label because it is included on the Trial 
Identification Card, which will be issued to each trial participant.
-
The "keep out of reach of children" statement was omitted from the label because the 
product will remain at the clinical site.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EU Trial number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 


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products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives or ovary 
hormone replacement. All concomitant or rescue therapies will be recorded (including time 
of intake on trial days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3500 mL.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each trial period is collected.
Alcoholic beverages are not permitted from 2 days before the first administration of trial 
medication until after the last PK sample of each trial period is collected. 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or
chocolate) are not allowed during in-house confinement.
Smoking is not allowed during in-house confinement.


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Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, 
 at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis (if 
erythrocytes, leukocytes, nitrite or protein are abnormal in urine), respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.;
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.;
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time (Quick)
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant) 
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine Leucocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 4 (end of trial examination)


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
) will be performed prior to each treatment period, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Surestep Multiline test and Cleartest® Diagnostik HCG test, respectively, or 
comparable test systems. In case of positive drug screen, a confirmatory test may be done at 
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory results. Clinically relevant 
abnormal findings as judged by the Investigator are to be reported as adverse events (please 
refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 


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5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
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 considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 


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
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.
5.2.6.1.2
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 prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment 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
A suspected unexpected serious adverse reaction (SUSAR) is an untoward and unintended 
response to a study drug. A SUSAR should be considered as unexpected if the nature, 
seriousness, severity, or outcome of the reaction is not consistent with the reference safety 
information of the investigational drug (e.g. the investigator's brochure, or the corresponding 
defined local label such as the summary of product characteristics).
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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 eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.


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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (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 
Section 5.2.6.2.2.
No AESIs have been defined for this trial.
5.2.6.1.5
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
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, 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 reduced)
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)


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
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

There is an 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
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.


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5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, SUSARs, AESIs, and non-serious AEs which are 
relevant for the reported SAE, SUSAR or AESI, on the BI SAE form to the sponsor’s unique 
entry point within 24 hours of becoming aware of the event (the only exception to this rule 
are SAEs and AESIs in phase I trials in healthy volunteers, when subjects discontinue from 
the trial due to screening failures prior to administration of any trial medication), the country 
specific reporting process will be provided in the ISF. The same timeline applies if follow-up 
information becomes available. On specific occasions, the Investigator could inform the 
sponsor upfront via telephone. This does not replace the requirement to complete and send
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. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject 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.
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 Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI 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
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of pramipexole
For quantification of pramipexole concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from plasma sample production from collection of whole blood samples should be 
completed within 60 min of blood sample collection. The resulting plasma samples should be 
transferred into the freezer within 60 min from plasma sample generation, with interim 
storage of blood samples and plasma aliquots at room temperature. The time each aliquot was 
placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at approximately -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.


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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs and standard laboratory values, that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an orally administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs and AE/CT questioning will be ± 60 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling and vital signs
recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening, pregnancy 
test), ECG, vital signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods. At least 3 days will separate 
drug administrations in the first and second treatment period.
In the evening of Day -1 of each treatment period, trial participants will be admitted to the 
trial site and kept under close medical surveillance for at least 24 h following drug 
administration in the morning of Day 1. The subjects will then be allowed to leave the trial 
site after formal assessment and confirmation of their fitness in the morning of Day 2. Further 
PK samplings on Day 2 and 3 will be performed in an ambulatory fashion.


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For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, pregnancy test in females, recording of ECG and vital 
signs, and physical examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
Although there are multiple primary endpoints, an alpha adjustment is not needed because it 
is required that all primary endpoints meet the equivalence criterion as described below 
simultaneously. Therefore, a one-sided alpha of 5% will be used for testing.
The assessment of bioequivalence will be based upon two-sided 90% confidence intervals 
(CIs) for the ratio of the geometric means (test/reference) for the primary endpoints using an 
acceptance range of 80.00 - to 125.00%. This method is equivalent to the two-sided t-test 
procedure, each at the 5% significance level.
The following hypotheses are tested:
Null hypothesis H0 (Inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and 
R

are the means of the log-transformed endpoint for the test and reference 
treatments, respectively, and δ is the bioequivalence limit that defines the acceptance range 
on the logarithmic scale. Alternative hypothesis Ha (Equivalence):
δ
μ
μ
δ
R
T




In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (test/reference) for endpoints on the original scale.
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for 
R
T



in the acceptance range (-δ, δ).
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.


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Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for pramipexole will be 
calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the  Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 


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effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Bioequivalence is considered established if the 90% confidence intervals of the geometric 
means for the primary endpoints are contained in the pre-defined acceptance range, see 
Section 7.1.
Further exploratory analyses
The statistical model as stated above will be repeated for the primary endpoints but with all 
sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach, the endpoints will be analysed descriptively.


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7.2.3
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP (see 
Section 1.2.3) will be assigned to the respective treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before database 
lock will be reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs and other significant AEs (according 
to ICH E3) will be listed separately. 
Relevant ECG findings will be reported as AEs.
Previous and concomitant therapies will be presented per treatment without consideration of 
treatment periods.


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Laboratory data will be compared to their reference ranges. Clinically relevant values outside 
the reference range will be highlighted in the listings. 
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
For vital signs, baseline is defined per period as the last measurement prior to trial drug 
administration.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences (R-T, T-R) in a 1:1 ratio.
The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 28 subjects in the trial with the aim of at least 24 PK evaluable 
subjects, because this sample size is considered sufficient to achieve the aims of this trial. 
The sample size was determined using assumptions on the intra-individual variability of the 
primary endpoints based on trial 248.560 (U06-1598-01) investigating pharmacology of 
0.375 mg pramipexole for various tablet formulations in healthy male volunteers. For Cmax
and various AUCs up to 30 hours post drug administration, the intra-individual geometric 
coefficient of variation (gCV) ranged from 12.5 – 13.6%. Hence, the assumed intra-
individual gCVs in this trial are for Cmax and AUC0-tz about 15%. 


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Due to the high correlation between the primary endpoints, only Cmax will be considered for 
power calculations. Using a sample size of 24 subjects (12 per sequence group), the power to 
reject both one-sided null hypotheses for one parameter each at the 5% level of significance 
in favour of bioequivalence is displayed in Table 7.5: 1, under various assumptions for the 
T/R gMean ratio. To account for the uncertainty of the assumed gCV, a range of gCVs 
around 15% is also presented.
Table 7.5: 1
Power for concluding bioequivalence (acceptance range 80-125%) 
based on a geometric coefficient of variation around 15% and for 
different expected ratios of geometric means (test/reference) in a 2x2 
crossover trial (N=24)
gCV [%]
gMean ratio (T/R) [%]*
92.5
95
100
105
107.5
12
99.2
99.9
99.9
99.9
99.5
15
94.7
98.7
99.9
98.9
96.0
20
79.2
89.6
96.7
90.3
81.8
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
From the above table, a sample size of 24 PK evaluable subjects will yield approximately 
90% power to conclude bioequivalence for an assumed gCV of 20% if the ratio is not more 
than 5% different from the ratio of 100% which reflects no difference in exposure. In 
addition, this sample size still provides approximately 80% power in case the ratio is not 
more than 7.5% different from 100% and the gCV is 20%.
Accounting for a drop-out rate of approximately 15%, a total of N = 24 + 4 = 28 subjects are 
planned to be entered into the trial.
The calculations were performed as described by Diletti et al. [R94-1445] using the function 
power.TOST() of the R package PowerTOST Version 1.5-4 in R Version 4.1.2.


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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 Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects 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. As a general rule, no trial results should be 
published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject 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 subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
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 risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
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 subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
Electronic Study Documentation System:
In the 
 Boehringer Ingelheim's Phase I unit, a validated 
electronic study documentation system (ClinBaseTM or successor Trial Complete Early Phase, 
TCEP) is used for processing information and controlling data collected in clinical trials. In 
addition to its function as a procedure control system, the study documentation system serves 
as databases. Instead of being entered into CRFs, selected data are directly entered into the 
system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ 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 subject 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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 


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and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: gender, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject 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 subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM or TCEP (that is, without prior written or electronic 
record) are considered to be source data. The place where data are entered first will be 
defined in a trial specific Source Data Agreement. The data in ClinBaseTM or TCEP are 
available for inspection at any time.
8.3.2
Direct access to source data and documents
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 Clinical Research Associate, 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.


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8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
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.
Reporting suspected unexpected serious adverse reactions (SUSARs) to the EMA will be done via E2B 
transmission of Individual Case Safety Reports (ICSRs) to the Eudravigilance CT Module.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
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 and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data


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
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial and is defined as the date when the 
first trial participant (subject) in the whole trial signs informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
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.
The sponsor will notify the IEC/competent authority in each participating EU member state 
about all required trial milestones according to the respective laws. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
 under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial 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 local Clinical Trial Mangers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the 
 


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Safety laboratory tests will be performed by the local laboratory of the trial site (
 
Analyses of pramipexole concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by 
 
 according to BI SOPs.
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
P21-04108
Grossard TR, Trotti LM, Videnovic A, Louis EKS. Restless legs syndrome: 
contemporary diagnosis and treatment. Neurotherapeutics; 2021; 18(1); 
140-155
R24-1508
Fachinfo Sifrol® Tabletten Januar 2024
R24-1562
Fachinfo Sifrol® Tabletten März 2024
R94-1445
Diletti E, Hauschke D, Steinijans VW. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin 
Pharmacol Ther Toxicol; 1992; 30(Suppl 1); S51-S58.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
U04-1242-08
 Investigator's brochure Pramipexole extended-release (ER) 
tablets Parkinson's disease. 11.05.2012
U05-2046
 A multiple dose seven-way 
cross-over formulation-finding study comparing the oral bioavailability of 
seven prototype slow-release formulations with 0.75 mg pramipexole (four 
days each) to immediate-release tablets at steady state in healthy male ...
248.529. 28.11.2005
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. 248.560. 25.04.2007
U08-1652-01
 A double-
blind, randomised, placebo-controlled study with two sequential two-way
cross-over parts to demonstrate that the influence of pramipexole up to 4.5 
mg daily on the QT interval of the ECG in healthy male and female 
volunteers is comparable with placebo, with a positive control (two-way 
cross-over moxifloxacin versus placebo). 248.545. 25.06.2008
U89-0039
A Single Increase Dose Tolerance Study in 
Healthy Volunteer after Oral Administration. 836.001. 10.11.1988
U91-0026
 
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) 836.005. 28.09.1990


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U92-0018
. SND 
919 CL 2 Y: Investigations on the pharmacokinetics and metabolism of 
SND 919 CL 2 Y after administration of single radioactive doses of 0.100 
mg intravenously and 0.300 mg orally in 6 volunteers. 7215-94-014. 30
September 1991.
U95-0470
 A study in healthy 
volunteers to compare the bioavailability of pramipexole after thrice daily 
repeated per oral administration of either the formulation used in the main 
clinical studies or the final formulation intended for marketing (at strengths 
of 0.125 and 1.5 mg). 248.116. 24.08.1995


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
29 April 2024
EudraCT number
EU number
2024-510764-23-00
BI Trial number
0248-0689
BI Investigational Medicinal 
Product(s)
Sifrol®, pramipexole
Title of protocol
Bioequivalence of two Sifrol® tablets following 
oral administration in healthy subjects (an open-
label, randomised, single-dose, two-way crossover 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1) 1.1, 1.2.1, 1.2.2, 4.1, 4.1.2
2) 5.2.6.1.2
3) 5.2.6.2.2
4) 8.4
Description of change
1) New SmPCs (Jan 2024 and Mar 2024) 
added
2) SUSAR definition added
3) Reporting of SUSARs to sponsor added
4) Reporting of SUSARs to Eudravigilance 
database added
Rationale for change
1) Regulatory request (RFI part I)
2) Regulatory request (RFI part I)
3) Regulatory request (RFI part I)
4) Regulatory request (RFI part I)


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43506074
2.0
clinical-trial-protocol-version-02
Bioequivalence of two Sifrol® tablets following oral administration in healthy
subjects (an open-label, randomised, single-dose, two-way crossover trial)
Approval-Clinical Trial Leader
29 Apr 2024 14:31 CEST
Approval-Clinical Program 
29 Apr 2024 14:33 CEST
Author-Trial Statistician
29 Apr 2024 14:44 CEST
Verification-Paper Signature
Completion
29 Apr 2024 17:11 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43506074
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SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c44584904-01
BI Trial No.:
0248-0689
Title:
Bioequivalence of two Sifrol® tablets following oral 
administration in healthy subjects (an open-label, randomised, 
single-dose, two-way crossover trial) 
Investigational
Product(s):
Sifrol®, pramipexole
Responsible trial 
statistician(s):
Date of statistical 
analysis plan:
23 AUG 2024
Version:
1.0
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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....................................................13
6.3
INTERCURRENT EVENTS .............................................................................13
6.4
SUBJECT SETS ANALYSED...........................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY OBJECTIVE ANALYSIS..............................................................18
7.4.1
Main analysis.......................................................................................................19
7.5
SECONDARY OBJECTIVE ANALYSIS........................................................20
7.5.1
Key secondary objective analysis.......................................................................20
7.5.2
Secondary objective analysis..............................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22


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7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
7.9
OTHER ANALYSIS...........................................................................................23
7.9.1
Biomarker analyses.............................................................................................23
7.9.2
PK / PD analyses .................................................................................................23
7.9.3
Physical examination ..........................................................................................23
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............24
11.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 1
Treatments and labels used in the analysis.......................................................11
Table 2
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs and concomitant therapies...................12
Table 3
Subject sets analysed ........................................................................................14
Table 4
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the last quantifiable data point
BP
Blood pressure
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma 
CSD
Company Standard Displays
CV
Arithmetic coefficient of variation
gCV
Geometric coefficient of variation
gMean
Geometric mean
Max
Maximum
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
Q1
1st quartile
Q3
3rd quartile
R
Reference treatment
RAGe
Report Appendix Generator system
SD
Standard deviation
T
Test treatment


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Term
Definition / description
TS
Treated set


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3. INTRODUCTION
As per ICH E9 (9.1), 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.
Study data as collected in the electronic case report form (eCRF) will be stored in a trial 
database within the RAVE electronic data capture (EDC) system. All study data (including 
external data) will then be uploaded to the Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 8.1.1 or higher, 
 or SAS Version 9.4 (or later 
version).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP:
The following pharmacokinetic parameters will be determined for pramipexole:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
Section 2.1.3 of the CTP:
The following pharmacokinetic parameter will be determined for pramipexole:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Adverse events (including clinically relevant findings from the physical examination)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered and selection of doses, refer to 
CTP Sections 3 and 4. 
This trial is designed as an open-label, randomized, single-dose, two-treatment, two-sequence, 
two-period crossover design in 28 healthy male and female subjects with a wash-out phase of 
at least 3 days between the single dose administrations of the two different Sifrol® tablets in 
the two periods.
For details of dosage and formulation, see Table 1 below.
Table 1
Treatments and labels used in the analysis 
Treatment
Short label
R
Sifrol® Tabletten (manufactured in Ingelheim), IR tablet, 0.088 mg 
pramipexole (base), single dose in the morning of Day 1
Pra-Ing (R)
T
Sifrol® Tabletten (manufactured in 
 
), IR tablet, 0.088 mg pramipexole (base), single dose in the 
morning of Day 1
Pra-Enn (T)
Subjects are randomly allocated to one of the two treatment sequences ‘R-T’ or ‘T-R’.
Section 1.2.3 of the CTP:
The Residual Effect Period (REP) of pramipexole is 2 days. This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.
Based on this, the following study phases, analysing treatment and actual treatment will be 
defined for the analysis of PK endpoints, adverse events (AEs), and other safety endpoints:


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Table 2
Analysis phases for statistical analysis of AEs, and actual treatment 
for analysis of laboratory data, vital signs and concomitant therapies
Study 
analysis 
phase
Treatment 
Period
Treatment 
short label
Start
End
Screening
Screening
Date/time of informed 
consent 
Date/time of administration 
of pramipexole in treatment 
period 1
On 
treatment
Period 1, 2
Pra-Ing, 
Pra-Enn
Date/time of administration 
of pramipexole (T or R) in 
the applicable treatment 
period
Date/time of next 
administration of 
pramipexole (T or R) in the 
applicable treatment period
OR 
Date/time of previous 
pramipexole administration 
plus 2 days
— whichever is earlier
Follow-up
FU
2 days (48 h) after date/time 
of previous administration 
of pramipexole (T or R)
If applicable: date/time of 
next administration of 
pramipexole (T or R) 
OTHERWISE
Date/time of EoS 
examination
Section 7.2.5 of the CTP:
Note that AEs occurring after the last per protocol contact but entered before database lock 
will be reported to Pharmacovigilance only and will not be captured in the trial database.
The following AE displays will be provided in the CTR:
In Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays, the on treatment phase will be analysed (labelled with the short label for
treatment at onset as in Table 2). The screening and follow-up phases will not be included in 
this analysis.
A total over all on-treatment phases (‘Total on-treatment’) will be provided in addition for 
Section 15.3.
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening period, as 
well as the follow-up phases will additionally be included.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g., deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol deviation (iPD).
For definition of iPDs, and for the process of identification of these, refer to the Boehringer 
Ingelheim (BI) SOP ‘Identify and Manage Important Protocol Deviations (iPD)’ (9.2)
IPD categories are provided in the DV domain sheet, iPDs will be identified no later than in 
the Report Planning Meeting, and the iPD categories will be updated as needed.
If any iPDs are identified, they are to be summarised into categories by study period and will 
be captured in the iPD specification file (DV domain) (9.3) and in the decision log (9.4). Both 
documents will be stored within the trial master file (TMF) in electronic document 
management system (EDMS).
The iPDs will be summarised by treatment and listed in the CTR.
6.3
INTERCURRENT EVENTS
This section is not applicable.
6.4
SUBJECT SETS ANALYSED
Section 7.2.1.1 of the CTP:
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.


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Table 3
Subject sets analysed
Subject set
Class of analysis
TS
PKS
Primary and secondary endpoints
X
Further PK endpoints
X
Safety assessments 
X
Treatment exposure
X
iPDs
X
Disposition 
X
Demographics & baseline conditions
X
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP:
Section 7.3.1 of the CTP: It is not planned to impute missing values for safety parameters.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see ‘Handling of 
Missing and Incomplete AE Dates’) (9.5).
Section 7.3.2 of the CTP:
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
Missing data and outliers of PK data are handled according to BI standards (see ‘Standards 
and processes for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ 
(9.6) and ‘Noncompartmental PK/PD Analyses of Clinical Studies’ (9.7)).
6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value for vital signs analysis is defined as the last measurement before first 
pramipexole drug administration in each treatment period. This means, the baseline for the 
reference treatment period ‘Pra-Ing’ (R) and the test treatment period ‘Pra-Enn’ (T) is usually 


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the measurement at V2/V3 (as applicable) planned time -1:00 (Day 1) for the analysis of vital 
signs. Laboratory assessments are only planned at screening and at end of study examination, 
so the measurements at screening will be used for baseline.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g., for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and will be 
presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4) will be performed by 
 and will be presented in Section 15.5 of the CTR and in Appendix 
16.1.13.3.
Descriptive data analysis of PK endpoints and concentrations will be performed by 
 
 and will be 
presented in Section 15.6 of the CTR and in Appendix 16.1.13.5.
The format of the listings and tables will follow the BI standards (see ‘Standards for 
Reporting of Clinical Trials and Project Summaries’ (9.8)) with the exception of those 
generated for PK-calculations following BI standards for PK/PD analysis (9.9).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit and time point. The listings will be included in Appendix 16.2 of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For plasma concentrations and PK parameters, the following descriptive statistics will 
additionally be calculated (if applicable or needed):
Nobs
number of observations
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be calculated 
using the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR.


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Tabulations of frequencies for categorical data will include all possible categories available in 
the CRF and will display the number of observations in a category, as well as the percentage 
(%). Percentages will be given in integer numbers due to the small sample size of < 100. 
Percentages will be based on all subjects in the respective subject set whether they have non-
missing values or not. The category ‘missing’ will be displayed only if there are actually 
missing values.
Units of variables should be given in the titles or column/row descriptors in brackets (e.g., 
‘(mg)’).
Exclusion of PK parameters
The ADS ‘ADPP’ (PK parameters) contains column variables APEX and APEXCO 
indicating inclusion/exclusion (APEX) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEX is equal to ‘Included’.
Exclusion of PK concentrations
The ADS ‘ADPC’ (PK concentrations per time-point or per time-interval) contains column 
variables ACEX and ACEXCO indicating inclusion/exclusion (ACEX) of a concentration and 
an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the analysis 
flag comment ACEXCO. For example, if ACEXCO is set to 

‘ALL CALC’, the value will be excluded for all types of analyses based on 
concentrations. 

‘DESC STATS’ the value will be excluded from descriptive evaluations per planned 
time point/time interval. 

‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’ the value 
can be used for further analyses based on actual times. Excluded concentration itself will be
listed in the CTR associated with an appropriate flag. Further details are given in 
‘Noncompartmental PK/PD Analyses of Clinical Studies’ (9.7) and ‘Description of Analytical 
Transfer Files, PK/PD Data files and ADA files’ (9.10).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR, based on the TS.
The data will be summarised by treatment sequence group and in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR, based on the TS.
Concomitant diseases and non-drug therapies will be coded according most recent version of 
the coding system of the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Concomitant medications will be coded according to the most recent version of the World 
Health Organization Drug Dictionary (WHO DD). The coding version number will be 
displayed as a footnote in the respective output.
In the remainder of this document, ‘therapy’ will be used for non-drug therapies and 
concomitant medications.
Section 7.2.5 of the CTP:
Previous and concomitant therapies will be presented per treatment without consideration of 
treatment periods.
A therapy will be considered concomitant to a treatment, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
The diagnoses and therapies will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies will be marked with a ‘No’ in the respective column.
The relevance of the concomitant therapies to the evaluation of PK data will be decided no 
later than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint, but judged by observed 
analyte concentrations (cf. Section 5.4).
Treatment exposure to pramipexole is defined as the number of doses and total dose of 
pramipexole per subject and treatment.
Any deviations from complete drug intake will be addressed in the RPM and described in the 
CTR.
7.4
PRIMARY OBJECTIVE ANALYSIS
Independent of the main objectives stated in the CTP, this section describes further details of 
the primary endpoint analyses outlined in the CTP.


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7.4.1
Main analysis 
Section 7.2.2 of the CTP:
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within sequences, 
period and treatment. The effect ‘subjects within sequences’ will be considered as random, 
whereas the other effects will be considered as fixed. The model is described by the following 
equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary
endpoints […] and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Section 7.1 of the CTP:
The assessment of bioequivalence will be based upon two-sided 90% confidence intervals 
(CIs) for the ratio of the geometric means (test/reference) for the primary endpoints using an 


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acceptance range of 80.00 – to 125.00%. This method is equivalent to the two-sided t-test 
procedure, each at the 5% significance level.
The following hypotheses are tested: 
Null hypothesis H0 (Inequivalence):  − ≤−   − ≥
where  and  are the means of the log-transformed endpoint for the test and reference 
treatments, respectively, and δ is the bioequivalence limit that defines the acceptance range 
on the logarithmic scale. 
Alternative hypothesis Ha (Equivalence):
− <  − < 
In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), this 
translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric means 
(test/reference) for endpoints on the original scale.
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the
90% confidence interval for  − in the acceptance range (-δ, δ).
The implementation for this analysis will be accomplished by using the CSD macros based on 
the PKS. The SAS code given in the additional section 10.1.1 can be used.
7.5
SECONDARY OBJECTIVE ANALYSIS
Independent of the main objectives stated in the CTP, this section describes further details of 
the secondary endpoint analyses.
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.


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7.5.2
Secondary objective analysis
Section 7.2.3 of the CTP:
The secondary endpoint […] will be calculated according to the relevant BI internal 
procedures and will be assessed statistically using the same methods as described for the 
primary endpoints.
7.7
EXTENT OF EXPOSURE
Descriptive statistics of number of doses of pramipexole, as well as total dose, are planned for 
this section of the CTR, based on the TS. The date and time of drug administration will be 
listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated subjects who failed to complete the study (dropouts or
withdrawals) will be reported as far as their data are available. 
Section 7.2.5 of the CTP:
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting.
7.8.1 Adverse Events
AEs will be coded using MedDRA. The coding version number will be displayed as a 
footnote in the respective output.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 


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standards as presented in ‘Analysis and Presentation of AE data from clinical trials – display 
templates’ (9.11) and ‘Analysis and Presentation of AE data from clinical trials’ (9.12) will be 
applied.
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on-treatment’ or ‘follow-up’ phases as defined in 
Section 6.1.
An overall summary of adverse events will be presented. 
Section 5.2.6.1.4 of the CTP: No AESIs have been defined for this trial.
According to ICH E3 (9.13), in addition to deaths and serious adverse events, ‘other 
significant’ AEs need to be listed in the CTR. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g., discontinuation or dose reduced or 
interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 
serious AEs, for subjects with investigator-defined drug-related AEs, for subjects with 
investigator-defined drug-related serious adverse events, for subjects with AESIs and for 
subjects with AEs leading to discontinuation. In addition, the frequency of subjects with AEs 
will be summarised by worst intensity, treatment, primary system organ class (SOC) and 
preferred term (PT). The system organ classes will be sorted by default alphabetically, PTs 
will be sorted by descending frequency (within SOC).
In addition, for disclosure of AE data on ClinicalTrials.gov, frequencies of subjects with non-
serious AEs that had an incidence of > 5% (in preferred terms) for at least one treatment will 
be summarised by treatment, primary SOC and PT. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs and the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
7.8.2
Laboratory data
Laboratory assessments are only planned at screening and end of study examination, after the 
REP period, i.e., no on-treatment analyses are feasible. Instead, laboratory data will only be 
listed per planned timepoint. The corresponding CTR section 15 will include a reference to 
the listing in section 16 stating that no on-treatment measurements are available. Laboratory 
data will be analysed qualitatively via comparison of laboratory data to their reference ranges. 
Values outside the reference range will be flagged in the data listings (cf. Section 7.2.5 of the 
CTP).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such (checked at the RPM at the latest).


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7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the change from baseline (see Section 
6.7) will be provided. The results will be reported by treatment, as defined in Table 2. In 
addition, the time profiles of median and (min, max) will be displayed graphically by 
treatment.
Descriptive statistics of vital signs including change from baseline will be calculated by
planned time point based on the first value of the subject at that planned time point (or 
assigned to that planned time point). For baseline values, the last measurement before drug 
administration will be used.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study 
treatment) if judged clinically relevant by the investigator, and will be analysed as such.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under ‘Relevant Medical History / Baseline 
Conditions’ (prior to first administration of study treatment) or will be reported as AEs (after 
first administration of study treatment), and will be analysed as such. No separate listing or 
analysis of continuous ECG monitoring will be prepared.
7.9
OTHER ANALYSIS
7.9.1 Biomarker analyses
No biomarker analysis is planned.
7.9.2 PK / PD analyses
No PK/PD analysis is planned.
7.9.3 Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarised as 
such.
No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
Not applicable due to open label fashion of the trial as described in the CTP Section 4.1.5.
The treatment information will be loaded into the trial database at trial initiation.


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11. HISTORY TABLE
Table 4
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
23-AUG-24
None
This is the final TSAP.