A Dose-finding Study for Levodopa, Carbidopa and ODM-104 Test Formulations After Repeated Administration in Healthy Males
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Orion Corporation, Orion Pharma

ODM-104
Clinical study protocol 3112005
1 (1)
CLINICAL STUDY PROTOCOL
A DOSE-FINDING STUDY FOR LEVODOPA, CARBIDOPA AND ODM-104 TEST 
FORMULATIONS AFTER REPEATED ADMINISTRATION IN HEALTHY MALES
Study code:
3112005
Short study title:
COMDOS 1
Study design:
An open, randomised study with crossover design
Phase:
I
Standard:
GCP
EudraCT number:
2016-003779-23
Principal Investigator:
Denis Strugala, Dr. med.
Sponsor:
Orion Corporation Orion Pharma
Orionintie 1, FI-02200 Espoo, Finland
Date:
2 December 2016
Property of Orion Corporation
Confidential
This documentation and other submissions made to you by Orion Corporation contain confidential information 
which Orion Corporation considers a trade secret and exclusive property of Orion Corporation or its principals 
and which may not be disclosed to third parties nor used for purposes other than that for which it has been 
submitted without the express prior written consent of Orion Corporation, unless specifically provided for 
otherwise by law.
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ODM-104
Clinical study protocol 3112005
2 (2)
Sponsor approvals:
This document is electronically signed and the e-signatures appear on the last page: 
Clinical Study Director: 
Aila Holopainen, electronically signed by Tiina Koivisto
Development Leader: 
Juha Ellmen
Study Statistician:
Mikko Vahteristo
Pharmacokinetics Specialist:
Johanna Tuunainen
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ODM-104
Clinical study protocol 3112005
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................... 3
SYNOPSIS .................................................................................................................................... 6
ABBREVIATIONS AND DEFINITION OF TERMS............................................................................... 9
1.
INTRODUCTION ................................................................................................................ 11
1.1
Background................................................................................................................ 11
1.2
Rationale of the study ................................................................................................ 12
1.2.1
Rationale of the study design ................................................................................ 12
1.2.2
Rationale for selected doses.................................................................................. 12
1.3
Benefit-risk assessment.............................................................................................. 13
2.
STUDY OBJECTIVES.......................................................................................................... 13
2.1
Primary objective....................................................................................................... 13
2.2
Secondary objectives ................................................................................................. 14
3.
OVERALL STUDY DESIGN AND PLAN................................................................................. 14
3.1
Type of study ............................................................................................................. 14
3.2
Study design............................................................................................................... 14
4.
SELECTION OF STUDY POPULATION.................................................................................. 15
4.1
Number of subjects .................................................................................................... 15
4.2
Inclusion criteria ........................................................................................................ 15
4.3
Exclusion criteria ....................................................................................................... 16
4.4
Information collected on screening failures............................................................... 17
4.5
Removal of subjects from treatment or assessment................................................... 17
5.
STUDY TREATMENTS........................................................................................................ 18
5.1
Investigational medicinal products ............................................................................ 18
5.1.1
Test products ......................................................................................................... 18
5.1.1.1
ODM-104 capsules........................................................................................... 18
5.1.1.2
Levodopa 50 mg, 100 mg and 150 mg capsules (Levodopa 50 mg, 100 
mg and 150 mg A CAP) ................................................................................... 19
5.1.1.3
Carbidopa capsules........................................................................................... 19
5.2
Comparator product ................................................................................................... 19
5.2.1
Sinemet® 25 mg/100 mg tablet.............................................................................. 19
5.3
Selection and timing of doses .................................................................................... 19
5.4
Method of assigning study subjects to treatment groups........................................... 20
5.5
Blinding...................................................................................................................... 21
5.6
Emergency procedures............................................................................................... 21
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5.7
Prior and concomitant treatments .............................................................................. 21
5.8
Restrictions ................................................................................................................ 21
5.9
Treatment compliance and exposure ......................................................................... 22
5.10
Availability of investigational medicinal product after termination of study............ 22
6.
STUDY PROCEDURES AND ASSESSMENTS.......................................................................... 22
6.1
Study procedures........................................................................................................ 22
6.1.1
Procedures during the screening period ................................................................ 24
6.1.2
Procedures during the treatment periods............................................................... 25
6.1.2.1
Days -1 and 1.................................................................................................... 25
6.1.2.2
Days 2-5............................................................................................................ 25
6.1.2.3
Day 6 ................................................................................................................ 25
6.1.2.4
Day 7 ................................................................................................................ 26
6.1.2.5
Day 8 ................................................................................................................ 26
6.1.3
Procedures during the end-of-study visit .............................................................. 27
6.2
Pharmacokinetic assessments .................................................................................... 27
6.2.1
Blood sampling ..................................................................................................... 27
6.2.2
Determination of drug concentrations................................................................... 27
6.2.3
Calculation of pharmacokinetic variables............................................................. 28
6.3
Pharmacogenomic variables ...................................................................................... 29
6.4
Safety assessments..................................................................................................... 29
6.4.1
Adverse events ...................................................................................................... 29
6.4.1.1
Definitions ........................................................................................................ 29
6.4.1.2
Assessment of adverse events .......................................................................... 30
6.4.1.3
Reporting of serious adverse events by the investigator .................................. 31
6.4.1.4
Reporting of serious adverse events to competent authorities and ethics 
committees........................................................................................................ 32
6.4.2
Special situations................................................................................................... 32
6.4.3
Pregnancy during the study................................................................................... 32
6.4.4
Clinical safety assessments ................................................................................... 33
6.4.5
Laboratory safety assessments .............................................................................. 33
7.
DATA COLLECTION AND MANAGEMENT........................................................................... 36
8.
STATISTICAL METHODS.................................................................................................... 36
8.1
Statistical hypotheses................................................................................................. 36
8.2
Estimation of sample size .......................................................................................... 36
8.3
Analysis populations.................................................................................................. 37
8.4
Statistical analyses ..................................................................................................... 37
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ODM-104
Clinical study protocol 3112005
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8.4.1
Demographic and other baseline characteristics ................................................... 37
8.4.2
Treatment compliance and extent of exposure...................................................... 37
8.4.3
Pharmacokinetic analysis ...................................................................................... 37
8.4.4
Pharmacogenomic analysis ................................................................................... 38
8.4.5
Safety analysis....................................................................................................... 38
8.4.5.1
Analysis of adverse events ............................................................................... 38
8.4.5.2
Clinical safety analysis..................................................................................... 39
8.4.5.3
Laboratory safety analysis................................................................................ 39
8.4.5.4
Analysis of prior and concomitant treatments.................................................. 39
8.5
Interim analyses ......................................................................................................... 39
9.
DATA QUALITY ASSURANCE............................................................................................. 39
9.1
Training...................................................................................................................... 39
9.2
Case report forms....................................................................................................... 39
9.3
Monitoring, audits and inspections............................................................................ 40
9.4
Laboratories and other vendors.................................................................................. 40
10.
FURTHER REQUIREMENTS AND GENERAL INFORMATION.................................................. 40
10.1
Investigators and study administrative structure........................................................ 40
10.1.1
Investigators .......................................................................................................... 40
10.1.2
Data and safety monitoring board ......................................................................... 40
10.2
Insurance.................................................................................................................... 41
10.3
Retention of records................................................................................................... 41
10.4
Completion of the study............................................................................................. 41
10.5
Reports, publications and communication of results................................................. 41
11.
ETHICS............................................................................................................................. 41
11.1
Ethics committee........................................................................................................ 41
11.2
Ethical conduct of the study....................................................................................... 42
11.3
Subject information and informed consent................................................................ 42
11.4
Subject data protection............................................................................................... 42
12.
REFERENCE LIST .............................................................................................................. 43
13.
APPENDICES..................................................................................................................... 43
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ODM-104
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SYNOPSIS
Sponsor: Orion Corporation Orion Pharma
Finished product: Not applicable
Active pharmaceutical ingredients: ODM-104, levodopa, carbidopa
Study title: A dose-finding study for levodopa, carbidopa and ODM-104 test formulations after repeated 
administration in healthy males
Study code: 3112005
Investigator: The principal investigator is Denis Strugala, Dr. med.
Study centres: This study will be conducted in a single centre in Germany.
Development phase: I
Objectives:
Primary: The primary objective is to compare pharmacokinetics (PK) of 3 different strengths of levodopa after 
repeated administration in combination with carbidopa and ODM-104. ODM-104 and carbidopa dose effects will 
be studied with the 3 modified release (MR) levodopa strengths and compared with the standard levodopa 
formulation. Primary comparisons for each of the 4 treatment groups will be performed for levodopa PK between 
the treatments. The resulting PK data will be used to select the optimal combination of levodopa, carbidopa and 
ODM-104 for subsequent clinical studies.
Secondary: The secondary objectives are to determine the PK properties of 3-O-methyldopa (3-OMD), carbidopa 
and ODM-104 in plasma after repeated administration of the different combinations.
Methodology: This is a phase I, open, repeated dose, randomised PK study in healthy males. The study will 
consist of 4 parallel groups (Groups 1-4). All groups will have a crossover design with 4 treatment periods, each 
lasting for 8 days. The total duration of the study will be approximately 10-15 weeks for each subject. 
Number of subjects: The planned number of subjects is 56 (14 in each parallel group with crossover design).
Diagnosis and main criteria for inclusion: Written informed consent obtained, good general health ascertained 
by detailed medical history and physical examinations, males between 18-65 years of age, body mass index (BMI) 
between 19-30 kg/m2, weight at least 55 kg, regular intestinal transit (no recent history of recurrent constipation, 
diarrhoea or other intestinal problems, and no history of major gastrointestinal surgery).
Test products, dose and mode of administration:
Formulations for oral administration:

ODM-104 capsules in 50 mg and 100 mg strengths

Levodopa MR capsules in 50 mg, 100 mg and 150 mg strengths

Carbidopa capsules in 12.5 mg, 25 mg and 65 mg strengths
Doses:
Group 1

50 mg of MR levodopa + 12.5 mg of carbidopa

50 mg of MR levodopa + 65 mg of carbidopa

50 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104

50 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 2

100 mg of MR levodopa + 25 mg of carbidopa

100 mg of MR levodopa + 65 mg of carbidopa

100 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104

100 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 3

150 mg of MR levodopa + 37.5 mg of carbidopa

150 mg of MR levodopa + 65 mg of carbidopa

150 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104
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ODM-104
Clinical study protocol 3112005
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
150 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 4

100 mg of MR levodopa + 65 mg of carbidopa

100 mg of MR levodopa + 25 mg of carbidopa + 100 mg of ODM-104

100 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Comparator products, dose and mode of administration: 
Formulation: Sinemet 25 mg/100 mg immediate release (IR) tablets containing 100 mg of levodopa and 25 mg of 
carbidopa for oral administration.
Dose:
Group 4

100 mg of IR levodopa + 25 mg of carbidopa (Sinemet®)
Frequency/duration of treatment:
Carbidopa and ODM-104 (in treatment periods including ODM-104) will be taken 4 times a day, every 3.5 h, for 6 
days. On day 7, levodopa will be taken at the same time with carbidopa, with or without ODM-104, 4 times a day,
every 3.5 h.
Bioanalytical method: Concentrations of levodopa, carbidopa, 3-OMD and ODM-104 in plasma will be 
determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods.
Variables and methods of assessments:
The primary variable for the evaluation of PK of levodopa is the area under the concentration-time curve from 
time 0 to the 24 h PK sample (AUC0-24). Primary comparison will be made within levodopa dose level groups, 
between crossover treatment arms levodopa / 12.5, 25 or 37.5 mg of carbidopa and levodopa / 65 mg of carbidopa 
/ 100 mg of ODM-104. Other crossover comparisons will be performed and considered as secondary.
The secondary PK variable is the observed concentration at the end of each dosing interval (Cmin,tau), which is used 
to describe minimum concentration during the dosing intervals. The ratio of the maximum observed concentration 
(Cmax) in a dosing interval and the observed concentration at the end of the dosing interval, Cmax/Cmin,tau, which is 
used to describe levodopa fluctuation during the dosing intervals and other PK variables of levodopa, 3-OMD, 
carbidopa and ODM-104 will be evaluated as other variables.
Safety will be evaluated by recording heart rate, systolic and diastolic blood pressure, 12-lead electrocardiogram 
(ECG), physical examination findings, laboratory safety assessments and adverse events (AEs). Suicidality will be 
assessed with the Columbia-Suicide Severity Rating Scale (C-SSRS).
Statistical methods:
PK parameters will be analysed after logarithmic transformation and 90% confidence intervals (CIs) for the 
geometric means. The conclusions regarding possible differences between different study treatments will be based 
on both overall evaluation of levodopa concentration-time profiles and formal statistical analyses of PK 
parameters.
Primary pharmacokinetic evaluation
The primary PK variable will be summarised using descriptive statistics by treatment and analysed using a mixed 
linear model with 90% CI applicable for the crossover design. The statistical model will include treatment and 
period as fixed effects and subject as random effect. Sensitivity analysis adjusted for subject weight and age will 
be performed. The primary conclusions will be based on the per-protocol (PP) population. 
Secondary pharmacokinetic evaluation
Statistical evaluation of the secondary PK variable will be done using similar methods to the primary variable. 
Statistical model for Cmin,tau will include treatment, period, dosing interval and treatment by dosing interval 
interaction as fixed effects and subject by period interaction as random effect.
Other pharmacokinetic evaluations
PK variables for the evaluation of PK of levodopa, carbidopa, 3-OMD and ODM-104 will be summarised by 
treatment using descriptive statistics. Selected PK variables will be analysed using similar models and sensitivity 
analysis to the primary and secondary PK variables. Drug concentrations will be tabulated by time and treatment 
with descriptive statistics.
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ODM-104
Clinical study protocol 3112005
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Safety evaluation
AEs and serious adverse events (SAEs) will be summarised by treatment using subject and event counts. Clinical 
safety variables and their changes from baseline will be evaluated using descriptive statistics. 12-lead ECG 
abnormalities will be tabulated and the intra-subject differences between visits will be evaluated. Laboratory safety 
variables will be evaluated using descriptive statistics for the actual values and their changes from baseline. 
Physical examination and C-SSRS findings will be tabulated.
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ODM-104
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ABBREVIATIONS AND DEFINITION OF TERMS
3-ODM
3-O-methyldopa
AADC
Aromatic l-amino acid decarboxylase
AE
Adverse event 
AUC
Area under the concentration-time curve
BMI
Body mass index
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum concentration in plasma
Cmin
Minimum concentration in plasma
Cmin,tau
Observed concentration at the end of each dosing interval
COMT
Catechol-O-methyl transferase
eCRF
electronic case report form
CRO
Contract research organisation
C-SSRS
Columbia-Suicide Severity Rating Scale
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic data capture
GCP
Good clinical practice
GMP
Good manufacturing practice
HR
Heart rate
IC
Informed consent
IR
Immediate release
mITT
Modified intention-to-treat
MR
Modified release
PD
Parkinson’s disease
PG
Pharmacogenomic(s)
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Clinical study protocol 3112005
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PK
Pharmacokinetic(s)
PP
Per-protocol
PTF
Peak-trough fluctuation
SAE
Serious adverse event
λz
Terminal elimination rate constant
tmax
Time to reach maximum concentration in plasma
ULN
Upper limit of normal
Note on usage of terms:
Orion Corporation Orion Pharma is hereafter in this document called “Orion”.
The term ‘investigator’ in the text of the protocol refers to the principal investigator or co-
investigator. 
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1.
INTRODUCTION
1.1
Background
Levodopa, the dopamine precursor, still remains the most efficacious pharmacotherapeutic 
treatment for Parkinson’s disease (PD). The current concept of continuous dopaminergic 
stimulation suggests that a more stable plasma concentration of a given antiparkinsonian drug 
throughout the day will result in better daily treatment responses in terms of fewer motor 
fluctuations, lesser OFF-time (time when PD signs and symptoms return before the next dose 
of levodopa) and fewer motor complications such as dyskinesia (Nyholm D et al., 2004; 
Stocchi F et al., 2005).
The major pathway for the metabolism of levodopa is its decarboxylation to dopamine by 
aromatic l-amino acid decarboxylase (AADC). An inhibitor of AADC, such as carbidopa, is 
routinely co-administered with levodopa to improve its bioavailability. When AADC is 
inhibited, levodopa is increasingly metabolised to 3-O-methyldopa (3-OMD) by catechol-O-
methyl transferase (COMT). In man, the greatest activity of COMT is found in the liver,
kidney and gastrointestinal tract. Addition of a COMT inhibitor, such as entacapone, to 
levodopa/AADC inhibitor therapy, therefore, provides a further refinement in delivering 
levodopa into the brain. Increased plasma levodopa concentrations can be achieved by 
combining entacapone with levodopa/carbidopa therapy (Nutt JG et al., 1994; Paija O et al., 
2005), although daily variability in levodopa plasma levels during frequent dosing cannot be 
avoided (Kuoppamaki M et al., 2009). It also appears that after multiple daily doses of 
levodopa/carbidopa and entacapone, the plasma levodopa levels tend to increase towards the 
end of the day (Paija O et al., 2005).
ODM-104 is a new generation, mainly peripherally acting COMT inhibitor aimed at the 
treatment of PD in combination with levodopa and an AADC inhibitor. In experimental 
animals, ODM-104 has been shown to be metabolically more stable and its elimination longer 
than that of entacapone. It also provides longer-lasting COMT inhibition in peripheral tissues 
than entacapone. When co-administered with levodopa/carbidopa in rats, it increases the 
bioavailability of levodopa. In parkinsonian rat models, ODM-104 has been shown to be 
superior to entacapone in increasing levodopa-induced rotational behaviour (studies 11000118 
and 11000230). In healthy human subjects, single doses of ODM-104 have been shown to 
more potently inhibit COMT activity in erythrocytes than entacapone at similar doses, and to 
modify levodopa pharmacokinetics (PK) following repeated dosing. Single doses up to 800 mg 
and repeated doses up to 200 mg 4 times a day, combined with levodopa and carbidopa, for 
7 days have been well tolerated (study 3112001).
A modified release (MR) test formulation of levodopa will be further evaluated in this study. 
Compared with commercially available immediate release (IR) tablets of levodopa preparation 
(Sinemet®), more stable plasma levodopa profiles during repeated dosing were achieved with 
the MR levodopa formulation when administered 4 times a day with 65 mg of carbidopa and 
100 mg of ODM-104, while still maintaining adequate daily area under the time-concentration 
curve (AUC) of levodopa (study 3112002). In clinical practice, such a levodopa profile is 
expected to result in better symptom control throughout the day in PD patients with end-of-
dose motor fluctuations.
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This PK study in healthy subjects aims to confirm carbidopa and ODM-104 dose selection in 
the MR levodopa combination with different levodopa strengths for the foreseen clinical 
studies. Levodopa PK from the test combinations will be compared with a marketed 
levodopa/carbidopa product.
1.2
Rationale of the study
The rationale of this study is to justify the planned carbidopa and ODM-104 doses for the 
foreseen phase III program. The aim is to investigate levodopa PK during repeated daily 
dosing with a MR formulation of 50, 100 and 150 mg of levodopa combined with 2 carbidopa 
strengths (standard 1 to 4 carbidopa to levodopa ratio or fixed 65 mg) and 50 or 100 mg of 
ODM-104 in healthy male subjects. The combinations will also be compared with the currently 
used marketed levodopa carbidopa IR formulation (Sinemet). The rationale for comparing the 
above combination treatments is to confirm carbidopa and ODM-104 dose selection for 
regulatory purposes in the USA without formal phase II dose finding studies with clinical 
endpoints. Adding marketed levodopa/carbidopa formulation in the comparison was requested 
by the FDA and will be used as a comparator in phase III. 
PK variables such as AUC, maximum concentration (Cmax), time to reach maximum 
concentration (tmax) and minimum concentration (Cmin) will be determined. In addition, 
fluctuation of levodopa concentrations during the dosing intervals will be assessed. The 
primary focus will be on levodopa PK as the symptomatic effect of the combination in the 
treatment of PD is mediated through levodopa, and as carbidopa and ODM-104 do not have 
any therapeutic efficacy on their own.
Based on previous studies with levodopa, sex seems to have an effect on levodopa’s PK. In 
order to decrease variation and consequently to receive explicit results, only male subjects will 
be included into this study.
Test formulations instead of final formulations are used in this study to enable all relevant 
comparisons. For example, study treatment 100 mg of MR levodopa + 65 mg of carbidopa is 
not possible with final formulation where ODM-104 is also involved. A PK bridge between 
test formulations and final formulations will be proved with later studies.
1.2.1
Rationale of the study design
A crossover design was chosen for this study in order to reduce the impact of inter-individual 
variability on levodopa PK parameters. This design has been previously used successfully in 
similar PK studies. Open-label study drug administration is regarded appropriate, because the 
primary study variables are PK parameters derived from drug concentrations in plasma. 
Administration of carbidopa and COMT inhibitor for 6 days before levodopa administration 
will ensure clinically adequate AADC and COMT inhibition when assessing levodopa PK on 
day 7. There will be a wash-out period of at least 4 days between the study treatment 
administrations. The length of the wash-out period is considered sufficient for the elimination 
of levodopa, carbidopa and ODM-104.
1.2.2
Rationale for selected doses
The maximum doses of carbidopa (up to 65 mg) and ODM-104 (100 mg) chosen to be used in 
this study have been generally well tolerated in previous PK studies in healthy men (studies 
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3112001, 3112002 and 3112003). This has been the case also with repeated dosing of 100 mg 
of levodopa (4 times a day) with different carbidopa doses and COMT inhibitors. Inclusion 
criteria and screening assessments have been defined to exclude subjects that are thought to be 
at higher risk of different adverse effects due to the administered treatments. Levodopa 
concentrations in plasma after standard doses are proportional to body weight, and in order to 
avoid nausea, the minimum subject weight has been set to 55 kg.
1.3
Benefit-risk assessment
Healthy subjects in this study will not receive any direct health-related benefit from 
administration of levodopa, carbidopa and ODM-104. However, the study subjects will receive 
general information on their current health by laboratory tests, electrocardiograms (ECGs), 
physical examination including blood pressure (BP) and heart rate (HR) measurements.
Levodopa, carbidopa and ODM-104 have been generally well tolerated and safe in previous 
PK studies (studies 3112001, 3112002 and 3112003) and in an ongoing study (3112004) in 
patients with PD; however, they are known to cause different symptoms in some subjects. 
Headache, nausea, nasopharyngitis, flatulence, vomiting, increased blood creatine 
phosphokinase, constipation and dizziness were reported relatively frequently in previous PK 
studies with ODM-104. In addition, isolated cases of cardiac conduction abnormalities and 
mild increases in liver transaminases were reported. No serious adverse events (SAEs) have 
been reported in previous phase I studies on ODM-104. Based on these findings as well as the 
nonclinical data on ODM-104, the events of increase in liver tests, cardiac arrhythmias and 
gastrointestinal irritation are considered as important potential risks for ODM-104. These risks 
are subject to close monitoring during the clinical program.
Carbidopa single dose used in the test treatments is higher than those in many levodopa 
treatments on the market with 4 to 1 levodopa to carbidopa ratio. However, the dosing 
frequency is 4 times a day and the total daily dose of carbidopa will not exceed the daily dose 
of the approved levodopa products in this study. Higher carbidopa dose has been used in 
combination with levodopa and ODM-104 in the previous PK studies and in the ongoing study 
in patients. In the present study subjects remain in the research institute for the whole duration 
of the dosing period. Samples for laboratory tests and ECG monitoring are applied to exclude 
subjects with abnormalities from entering the study and after treatment initiation to be 
discontinued if specified abnormalities emerge. Signs of nausea, gastrointestinal and other 
symptoms will be followed clinically daily and if intolerable, treatment will be discontinued. 
Blood sampling may cause local pain and haematoma as well as fainting in isolated cases. In 
addition, ECG electrodes attached to the skin may cause irritation. 
In summary, the benefit-risk assessment remains positive for studying ODM-104 in 
combination with levodopa and carbidopa.
2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective is to compare PK of 3 different strengths of levodopa after repeated 
administration in combination with carbidopa and ODM-104.
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ODM-104 and carbidopa dose effects will be studied with the 3 MR levodopa strengths and 
compared with the standard levodopa formulation. Primary comparisons for each of the 
4 treatment groups will be performed for levodopa PK between the treatments. The resulting 
PK data will be used to select the optimal combination of levodopa, carbidopa and ODM-104 
for subsequent clinical studies.
2.2
Secondary objectives
The secondary objectives are to determine the PK properties of 3-OMD, carbidopa and ODM-
104 in plasma after repeated administration of the different combinations.
3.
OVERALL STUDY DESIGN AND PLAN
3.1
Type of study
This is a phase I, open, repeated dose, randomised PK study in healthy males. The study will 
be conducted at 1 centre. 
3.2
Study design
The study will consist of 4 parallel groups (Groups 1-4). All groups will have a crossover 
design with 4 treatment periods, each lasting for 8 days. The total duration of the study will be 
approximately 10-15 weeks for each study subject.
The study design is presented in Figure 1 and the study treatments for the 4 groups are 
presented in Table 1. 
Figure 1.
Study design
Carbidopa with or 
without ODM-104: 
days 1-7
Levodopa: day 7
Screening
Period 1
8
Wash-out 
≥ 4 days
Visits
Days
| = Ambulatory visit to the unit
|----| = Stay at the study centre
4-21 
days
≤ 21 days
|
|
Study treatments (depending on the parallel group and crossover design)

Carbidopa: 12.5, 25, 37.5 or 65 mg 4 times a day every 3.5 hours during days 1-7

ODM-104: 50 or 100 mg 4 times a day every 3.5 hours during days 1-7

MR levodopa: 50, 100 or 150 mg 4 times a day every 3.5 hours on day 7

IR levodopa: 100 mg 4 times a day every 3.5 hours on day 7
-1
Wash-out 
≥ 4 days
Carbidopa with or 
without ODM-104: 
days 1-7
Levodopa: day 7
Carbidopa with or 
without ODM-104: 
days 1-7
Levodopa: day 7
Wash-out 
≥ 4 days
Carbidopa with or 
without ODM-104: 
days 1-7
Levodopa: day 7
End-of-
study visit
-1
8
-1
8
|
-1
8
Period 2
Period 3
Period 4
|
|
|
------------------------
------------------------
------------------------
|
|
|
|
-----------------------
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Table 1.
Summary of study treatments
Group 1
A1
50 mg of MR levodopa + 12.5 mg of carbidopa
B1
50 mg of MR levodopa + 65 mg of carbidopa
C1
50 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104
D1
50 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 2
A2
100 mg of MR levodopa + 25 mg of carbidopa
B2
100 mg of MR levodopa + 65 mg of carbidopa
C2
100 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104
D2
100 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 3
A3
150 mg of MR levodopa + 37.5 mg of carbidopa
B3
150 mg of MR levodopa + 65 mg of carbidopa
C3
150 mg of MR levodopa + 65 mg of carbidopa + 50 mg of ODM-104
D3
150 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
Group 4
A4
100 mg of IR levodopa + 25 mg of carbidopa (Sinemet)
B4
100 mg of MR levodopa + 65 mg of carbidopa
C4
100 mg of MR levodopa + 25 mg of carbidopa + 100 mg of ODM-104
D4
100 mg of MR levodopa + 65 mg of carbidopa + 100 mg of ODM-104
4.
SELECTION OF STUDY POPULATION
4.1
Number of subjects
The planned number of subjects is 56 (14 in each parallel group with crossover design).
4.2
Inclusion criteria
Subjects must meet all of the following criteria to be included into the study:
1. Written informed consent (IC) obtained.
2. Good general health ascertained by detailed medical history and physical examinations.
3. Males between 18-65 years of age inclusive at screening.
4. Body mass index (BMI) between 19-30 kg/m2 (BMI = weight/height2) inclusive at 
screening.
5. Weight at least 55 kg inclusive at screening.
6. Regular intestinal transit (no recent history of recurrent constipation, diarrhoea, or other 
intestinal problems, and no history of major gastrointestinal surgery).
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7. Subject with a partner of childbearing potential agrees to use adequate contraception from 
the first dose of study treatment until 90 days after the last dose of study treatment. 
Adequate methods of contraception include: Hormonal contraceptives, barrier methods 
(condom, diaphragm, cervical cap, etc.) in combination with a spermicide, intrauterine 
device and sexual abstinence.
8. Subject agrees to not donate sperm from the first dose of study treatment until 90 days after 
the last dose of study treatment.
4.3
Exclusion criteria
Subjects will not be included into this study if they meet any of the following criteria:
1.
Evidence of clinically significant cardiovascular, renal, hepatic, haematological,
gastrointestinal, pulmonary, metabolic, endocrine, neurological or psychiatric disease or 
cancer (except local non-melanoma skin cancer) within the previous 2 years.
2.
Any condition requiring regular concomitant treatment (including vitamins and herbal
products) or likely to need any concomitant treatment during the study. As an exception, 
paracetamol for occasional pain is allowed. 
3.
Any clinically significant abnormal laboratory value or ECG (such as prolonged 
QTcF >450 ms or QRS >120 ms) that in the opinion of the investigator could interfere 
with the interpretation of study results or cause a health risk for the subject if he takes 
part in the study.
4.
Known hypersensitivity to the active substances or the excipients of the drugs.
5.
History of vasovagal collapses or vagal reactions with unexplained reason within the 
previous 2 years or a tendency for vasovagal reactions during blood sampling.
6.
HR < 50 bpm or > 90 bpm in the supine position after 5 min rest at the screening visit. 
7.
At the screening visit:

systolic BP < 100 mmHg or > 140 mmHg in the supine position after 5 min rest

diastolic BP < 50 mmHg or > 90 mmHg in the supine position after 5 min rest.
8.
Creatinine > 1.5 x upper limit of normal (ULN) and alanine aminotransferase or 
aspartate aminotransferase >1.25 x ULN at screening.
9.
History of anaphylactic/anaphylactoid reactions.
10. Strong tendency to motion sickness.
11. Recent or current (suspected) drug abuse.
12. Recent or current alcohol abuse; regular drinking of more than 21 units per week (1 unit 
= 4 cl spirits or equivalent).
13. Current use of nicotine-containing products more than 5 cigarettes (or equivalent)/day 
and/or inability to refrain from the use of nicotine-containing products for 48 h before
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the first dose in each period until collection of the 24 h PK sample in the morning of day 
8.
14. Use of caffeine-containing beverages more than 600 mg of caffeine/day and/or inability
to refrain from using caffeine-containing beverages 24 h before the first levodopa 
administration on the PK day (day 7) until collection of the 24 h PK sample in the 
morning of day 8.
15. Blood donation or loss of a significant amount of blood (> 500 ml) within 90 days before 
the first study treatment administration.
16. Participation in another investigational drug study or administration of another
investigational drug within 60 days before the first study treatment administration.
17. Veins unsuitable for repeated venipuncture or cannulation.
18. Predictable poor compliance or inability to communicate well with the study centre 
personnel.
19. Inability to participate in all treatment periods.
4.4
Information collected on screening failures
For subjects screened but not included in the study, the following electronic case report forms 
(eCRFs) will be completed: date of the screening visit, IC, demography (sex, year of birth, age 
and racial group), criteria causing the exclusion, decision of entry, adverse events (AEs)
related to study assessments and SAEs.
4.5
Removal of subjects from treatment or assessment
Study subjects are free to discontinue the study at any time without providing a reason. 
However, the investigator should try to identify the reason and document it on the eCRF. 
A subject must discontinue the study treatment if the investigator or the sponsor considers the 
discontinuation to be medically necessary or in the best interest of the subject.
A subject must discontinue the study treatment for example for the following reasons:

Personal reason

AE requiring discontinuation of the study treatment, as judged by the investigator:

Intolerable dopaminergic AEs such as prolonged moderate or severe vomiting with 
massive fluid loss and consequent circulatory disorders

Intolerable gastrointestinal AEs such as prolonged moderate or severe diarrhoea 
with massive fluid loss and consequent circulatory disorders

Abnormal 12-lead ECG finding of clinical relevance:
o
increase in QTc of >60 ms from baseline 
o
increase in QRS of >25% from baseline
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o
2nd or 3rd degree atrioventricular block
o
sustained (>30 s) cardiac arrhythmias (supraventricular or ventricular 
tachycardia, atrial fibrillation and/or flutter)
o
any symptomatic arrhythmia (except isolated extrasystoles)

Increase in alanine aminotransferase, aspartate aminotransferase or alkaline 
phosphatase to >3 x ULN

Other AE (e.g. fainting or profound weakness) requiring discontinuation of the 
study treatment

Lost to follow-up

Protocol deviation that could affect the outcome of the study, as judged by the 
investigator

Other reason (e.g. impossibility to obtain blood samples)
Irrespective of the reason for discontinuation, the subject should be invited to end-of-study 
assessments as soon as possible. As long as the subject consents, all relevant assessments, at 
least those of safety, should be performed, preferably according to the schedule for the end-of-
study assessments.
The study monitor should be notified about premature discontinuations within 24 h in the event 
of discontinuation due to an SAE (see section 6.4.1.3) or within 7 days in the event of 
discontinuation due to another reason.
The sponsor will decide if study subjects who prematurely discontinue will be replaced. 
Discontinued study subjects are not allowed to re-enter the study.
5.
STUDY TREATMENTS
Manufacturing, packaging, and labelling of the study treatments will comply with good 
manufacturing practice (GMP) regulations (Annex 13 of EU guide to GMP).
5.1
Investigational medicinal products
5.1.1
Test products
5.1.1.1
ODM-104 capsules
ODM-104 capsules in 50 mg and 100 mg strengths are provided in size 0 hard gelatine 
capsules for oral administration. The colour of the capsules is Swedish orange. ODM-104 
capsules are manufactured by Patheon UK Limited, the United Kingdom. 
The capsules are stored below 30°C
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5.1.1.2
Levodopa 50 mg, 100 mg and 150 mg capsules (Levodopa 50 mg, 100 mg and 150 mg 
A CAP)
Levodopa MR capsules in 50 mg, 100 mg and 150 mg strengths will be provided in size 0 hard 
gelatin capsules for oral administration. The colour of the capsules is white. Levodopa 
capsules are manufactured by Glatt GmbH, Germany.
The capsules are stored below 30°C.
5.1.1.3
Carbidopa capsules
Carbidopa capsules in 12.5 mg, 25 mg and 65 mg strengths will be provided for oral 
administration. Carbidopa 12.5 mg and 25 mg will be in size 3 hard gelatine white capsules
and carbidopa 65 mg will be in size 0 hard gelatine dark green capsules. Carbidopa capsules 
are manufactured by Orion Corporation, Finland. 
The capsules are stored below 30°C.
5.2
Comparator product
5.2.1
Sinemet® 25 mg/100 mg tablet
Sinemet 25 mg/100 mg IR tablets contain 100 mg of levodopa and 25 mg of carbidopa for oral 
administration. Sinemet 25 mg/100 mg tablets are manufactured by Merck, Sharp & Dohme 
B.V.
The tablets are stored below 30ºC.
5.3
Selection and timing of doses
Overall, MR levodopa strength will be 50, 100 or 150 mg, carbidopa strength will be 12.5, 25 
or 65 mg and ODM-104 strength will be 0, 50 mg or 100 mg. Sinemet contains 100 mg of IR 
levodopa and 25 mg of carbidopa.
The strength of levodopa, carbidopa and ODM-104 will depend on the parallel group (Groups 
1-4) the study subject has been assigned to. The doses during the 4 treatment periods are 
presented in Table 1 in section 3.2.
In all parallel groups, depending on the treatment period, carbidopa with or without ODM-104 
will be taken 4 times a day during the days 1-6. On day 7 (PK sampling day), carbidopa with 
or without ODM-104 will be taken at the same time with levodopa 4 times a day. The duration 
of treatment will be 7 days for carbidopa and ODM-104 and 1 day for levodopa. In one of the
periods in Group 4, Sinemet will be taken on day 7 without ODM-104 and on days 1-6, only 
carbidopa 25 mg will be administered.
The selected strengths and dosing regimens are based on previous PK studies in healthy 
subjects conducted during ODM-104 development program and other levodopa programs.
Carbidopa and ODM-104 (in treatment periods including ODM-104) will be taken 4 times a 
day – first dose, 3.5 h, 7 h and 10.5 h doses, for 6 days. The study treatments should be taken 
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at the same time every day to provide even concentrations of the active ingredients. The 
recommended study treatment intake times on days 1-6 are 8:00, 11:30, 15:00 and 18:30 h.
Subjects will arrive at the study centre in the evening before day 1 (day -1) and stay at the 
study centre until the 24 h PK blood sample has been drawn in the morning of day 8. Subjects 
will take all study treatments at the study centre. 
In the evening of day 6, subjects will start fasting for at least 10 h (from around 22:00 h on 
day 6) before the first morning dose (0 h) at approximately 8:00 h on day 7. Drinking of water
is permitted until 1 h before dosing.
The recommended study treatment intake times on day 7 are the same as those on the previous 
6 days: 8:00, 11:30, 15:00 and 18:30 h. Study treatments will be ingested with 200 ml of water. 
Study subjects should maintain an upright position (sitting or standing) for at least 1 h after the 
study treatment administration and as much as possible during the day until 24:00 h.
On day 7, 150 ml of water will be given 2 h after each dosing. If extra water is needed, the 
extra amount of consumed water and time of drinking will be recorded on the eCRF. A 
standard breakfast will be served 1 h, a standard lunch 4.5 h, a standard snack 8 h, a standard 
dinner 11.5 h and a light night snack 14 h after the first morning dose. If the standard meals are 
not eaten completely, this will be recorded on the eCRF. Meals should be eaten within 30 min.
Meals on days 1-6 will be served at about the same time as on day 7. However, drinking of 
water is not restricted and there is no 30 min time limit for eating a meal.
Subjects will remain housed in the unit until the morning of day 8, i.e. 24 h after the first dose 
of levodopa on the previous day.
5.4
Method of assigning study subjects to treatment groups
All subjects screened will be assigned a screening number. To ensure random allocation of the 
study treatment sequences, all subjects to be randomised into the study will receive the 
treatment sequence that corresponds to the next consecutive randomisation number in the 
study. At the study site, subjects will be assigned with next consecutive subject number before 
first treatment administration. The treatment sequence will be allocated to this subject number 
when his entry into the first treatment period of the study is confirmed using the dedicated 
eCRF. The subject is considered randomised at the time when eCRF provides the treatment 
sequence allocated to the subject. 
In case a discontinued subject will be replaced, the replacing subject will receive the same 
treatment sequence as the subject he is replacing. If replacement subjects will be enrolled, 
these will be randomised to go through all 4 treatment periods.
In practise, the first subject who made a registration for the study fulfilling all inclusion criteria 
and none of the exclusion criteria will be dosed first, the next subject will be dosed second and 
so on. However, precedence will be given to subjects who participate in a study at the site for 
the first time and for subjects who served as “stand by” during a preceding study.
Randomisation will be carried out on the day of the first treatment administration.
The study will be randomised consisting of 4 parallel groups (Groups 1-4). All groups will 
have a crossover design with 4 treatment periods, each lasting for 8 days.
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Randomisation will be performed across all the groups, i.e. the subject entering the study may 
be randomised to any of the treatment sequences presented in Table 2.
Table 2.
Example of the treatment sequences
Group
Sequence
Group
Sequence
1
B1 / C1 / A1 / D1
3
D3 / C3 / B3 / A3
A1 / B1 / D1 / C1
B3 / D3 / A3 / C3
D1 / A1 / C1 / B1
A3 / B3 / C3 / D3
C1 / D1 / B1 / A1
C3 / A3 / D3 / B3
2
C2 / B2 / D2 / A2
4
A4 / D4 / C4 / B4
D2 / C2 / A2 / B2
C4 / A4 / B4 / D4
A2 / D2 / B2 / C2
B4 / C4 / D4 / A4
B2 / A2 / C2 / D2
D4 / B4 / A4 / C4
See Table 1 for definitions of A1-D4
5.5
Blinding
This is an open-label study.
5.6
Emergency procedures
The investigator is responsible for ensuring adequate medical expertise and facilities to handle 
possible emergency situations during the study. Emergencies will be treated according to the 
decision of the physician in charge or the investigator when available.
5.7
Prior and concomitant treatments
Concomitant treatments including herbal products, vitamins and dietary supplements are not 
allowed during the study (within 2 weeks or 5 half-lives of the drug, whichever is longer, 
before the first study treatment administration until the end-of-study visit). Paracetamol may 
be taken for the treatment of occasional pain.
In case any concomitant treatment is required during the study, the study subject needs to 
discontinue the study due to a protocol deviation, if the investigator or sponsor considers that 
the concomitant treatment could affect the outcome of the study (see section 4.5). The decision 
will be based on the time the concomitant treatment was taken and the pharmacology and PK 
of the concomitant treatment. 
All concomitant treatments during the study, including the post-treatment period, must be 
recorded on the eCRF. No other investigational treatment is allowed to be used concomitantly 
with the study treatment. The study subject must not participate concurrently in any other 
clinical drug study or have been administered another investigational drug within 60 days 
before the first study treatment administration.
5.8
Restrictions
Intake of grapefruit, grapefruit juice, bitter orange and bitter orange juice are prohibited during 
the study (from the screening visit until the end of study visit).
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The use of coffee, black and green tea, energy drinks or any other caffeine-containing products 
is not allowed from 24 h before the first levodopa administration on the PK sampling day (day 
7) until the last PK blood sample is taken on the following day. Only moderate consumption of 
caffeine-containing products is allowed on other study days.
Subjects will be instructed to abstain from consuming alcohol and nicotine-containing products 
for at least 48 h prior to first dosing in each period and during in-house stay.
If the subject practises intensive physical exercise, it should remain on a stable level during the 
study. Intensive physical exercise is not allowed from 48 h before first dosing in each period 
and during in-house stay.
Blood donation and administration of another investigational study treatment are not allowed 
during the study. Sauna bath is prohibited during in-house stay until 24 h after the last PK 
blood sample is taken.
See section 6.4.5 for restrictions regarding fasting before safety laboratory tests and section 5.3
regarding fasting and timing of meals related to dosing of study treatments.
See section 5.7 for restrictions regarding concomitant treatments.
5.9
Treatment compliance and exposure
All study treatment intakes will be performed in accordance with the specifications of the 
investigator and under the supervision of study centre personnel. This includes checking the 
oral and buccal cavity.
Levodopa, carbidopa and ODM-104 concentrations in plasma will indicate that each subject 
has ingested the study treatments. Any deviation from the treatment regimen must be 
documented on the eCRF. 
The investigator or other study centre personnel is responsible for study drug accountability 
during the study. The investigator must maintain accurate records demonstrating the date and 
amount of drug received, to whom and by whom dispensed (drug dispensing list) and accounts 
of drugs accidentally or deliberately destroyed. At the end of the study, all original containers, 
whether empty or containing unused products, will be returned to the sponsor for disposal.
5.10 Availability of investigational medicinal product after termination of 
study
There is no option to continue study treatment once the study subject has completed or 
discontinued the study.
6.
STUDY PROCEDURES AND ASSESSMENTS
6.1
Study procedures
Table 3 lists all study procedures and indicates with an ‘x’ during which visit a particular 
procedure is performed.
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Table 3.
Schedule of study events
Protocol activities
Screening
Treatment period
End-of-
study
21 days 
before first 
dose
4-21 days 
from last 
dose
Day
-1
Day
1
Days
2-5
Day
6
Day
7
Day
8
IC1
Physical examination
X
X
Demography and substance use
X
Use of nicotine
X
X
Weight and BMI
X
X
Height 
X
Vital signs: BP and HR
X
X
X2
X3
X4
X
12-lead ECG
X
X
X2,5
X6
X7
X
Laboratory assessments

Haematology and clinical 
chemistry
X
X2,8
X8
X9

Urinalysis
X
X2
X
X

Serology 
X
Alcohol breath test
X
X
Urine drug abuse test
X
X
C-SSRS
X
X
Decision of entry
X
Study treatments, 4 times a day
Carbidopa
X
ODM-104
X10
Levodopa
X 
Blood samples for PK
X
X
Blood sample for PG
X11
Medical history and current 
medical conditions
Continuously
AEs
Continuously
Concomitant treatments
Continuously
1
IC for the main study before any screening activities; for the optional PG IC, see footnote 11
2
On day 1: 0-2 h before the first dose
Vital signs in supine position after 5 min rest:
3
On day 6: 1-2 h after the 7 h dose
4
On day 7: 0-2 h before the first dose and at 1-2 h after the 7 h dose
12-lead ECG in supine position after 5 min rest
5
On day 1: 0-2 h before the first dose - 3 recordings within 5 min, 1-2 min interval between the measurements
6
On day 6: 1-2 h after the 7 h dose
7
On day 7: 0-2 h before the first dose and 1-2 h after the 7 h dose
8
Selected laboratory tests before the first dose of the day
9
The same laboratory tests as at the screening visit except thyroid stimulating hormone and albumin
10
Only in treatment periods including ODM-104
11
PG (optional): The sample is taken once from subjects who have signed the PG IC
C-SSRS = Columbia-Suicide Severity Rating Scale; PG = pharmacogenomics
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6.1.1
Procedures during the screening period
Screening procedures will start after receiving approval from the ethics committee (EC) and 
competent authority (CA).
A prospective subject will receive both written and verbal information about the study and will 
have an opportunity to ask questions and sufficient time to decide whether or not to participate 
in the study. A signed and dated written IC for the main study will be obtained prior to any 
screening activities (see section 11.3). A separate pharmacogenomic (PG) IC will be obtained 
from subjects who agree to take part in the optional study-related exploratory PG study (see 
section 6.3).
The screening visit will take place within 21 days before the first study treatment 
administration. 
The following procedures will be performed at the screening visit:

Physical examination will be performed. 

Demographic data (sex, year of birth, age and racial group), substance use (use of nicotine, 
alcohol and caffeine, and drug abuse) and weight, height and BMI will be recorded.

Medical history, current medical conditions and concomitant treatments will be recorded.

AEs will be recorded. 

BP and HR will be recorded in the supine position after at least 5 min rest. 

12-lead ECG will be recorded in the supine position after at least 5 min rest.

Alcohol breath testing will be performed.

Blood samples for haematology, clinical chemistry and serology will be collected after 
fasting for at least 10 h; see section 6.4.5 for details.

Urine drug abuse testing will be performed.

Urinalysis will be performed.

Columbia-Suicide Severity Rating Scale (C-SSRS) will be performed.

Subjects will be instructed to call the study centre when they experience AE or need to take 
concomitant treatment after the screening visit until the end-of-study visit when they are 
not in-house. 
For practical reasons, the procedures outlined above may be performed on 2 separate 
occasions, for example, the physical examination may be performed a couple of days later than 
the other procedures.
A subject will be entered into the study if all of the inclusion criteria and none of the exclusion 
criteria are met and will be randomised to one of the treatment sequences before starting study 
treatments.
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6.1.2
Procedures during the treatment periods
6.1.2.1
Days -1 and 1 
Subjects will arrive at the study centre in the evening before day 1 (day -1) and stay at the 
study centre until the 24 h PK blood sample has been collected in the morning of day 8.
The following procedures will be performed on day -1:

Alcohol breath and urine drug abuse tests will be performed before the first study treatment 
administration. Use of nicotine-containing products within the previous week will be 
enquired. 

BP and HR will be recorded in the supine position after at least 5 min rest.

12-lead ECG will be recorded in the supine position after at least 5 min rest.
The following procedures will be performed on day 1:

BP and HR will be recorded in the supine position after at least 5 min rest 0-2 h before the 
first morning dose.

12-lead ECG will be recorded in the supine position after at least 5 min rest 0-2 h before 
the first dose. 3 recordings will be performed within 5 min (1-2 min interval between the 
measurements).

Blood samples for selected haematology and clinical chemistry tests will be collected
before the first dose; see section 6.4.5.

Urinalysis will be performed before the first dose.

Subjects will take carbidopa and ODM-104 (in study periods including ODM-104) as 
described in section 5.3. 

Meals will be served as described in section 5.3.

Current medical conditions and concomitant treatments will be recorded.

AEs will be recorded.
6.1.2.2
Days 2-5
The following procedures on days 2-5 will be performed:

Subjects will take carbidopa and ODM-104 (on study periods including ODM-104) similar 
to day 1 and as described in section 5.3. 

Meals will be served as described in section 5.3.

AEs, current medical conditions and concomitant treatments will be recorded.
6.1.2.3
Day 6
The following procedures on day 6 will be performed:
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
Subjects will take carbidopa and ODM-104 (on study periods including ODM-104) similar 
to day 1 and as described in section 5.3. 

HR and BP will be recorded in the supine position after at least 5 min rest 1-2 h after the 
7 h dose.

12-lead ECG will be recorded in the supine position after at least 5 min rest 1-2 h after the 
7 h dose.

Meals will be served as described in section 5.3.

Current medical conditions and concomitant treatments will be recorded.

AEs will be recorded.
6.1.2.4
Day 7
Subjects will fast from 22:00 h (10 h) on day 6 until breakfast on day 7, except that drinking of 
water is permitted up to 1 h before dose.

BP and HR will be recorded in the supine position after at least 5 min rest 0-2 h before the 
first dose and 1-2 h after the 7 h dose.

12-lead ECG will be recorded in the supine position after at least 5 min rest 0-2 h before 
the first dose and 1-2 h after the 7 h dose.

Blood samples for selected haematology and clinical chemistry tests will be collected 
before the first dose; see section 6.4.5 for details.

Urinalysis will be performed.

C-SSRS will be performed.

Subjects will take the first dose (levodopa, carbidopa and possible ODM-104) 
approximately at 8:00 h after the pre-dose PK blood sampling. All study treatments will be 
taken precisely at the planned time points, including time points coinciding with PK blood 
sampling; see section 5.3 for details.

Blood samples for PK assessments will be collected; see section 6.2.1 for details.

Meals will be served as described in section 5.3. 

AEs, current medical conditions and concomitant treatments will be recorded.
6.1.2.5
Day 8

Blood sample for 24-h PK assessments will be collected in the morning of day 8; see 
section 6.2.1 for details.

Subjects will be instructed to call the study centre when they experience any AE or need to 
take any concomitant treatment until the end-of-study visit when the subjects are not in-
house. 

Subjects can leave the study centre after the 24 h PK blood sample has been collected.
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6.1.3
Procedures during the end-of-study visit
The end-of-study visit will take place 4-21 days after the last study treatment dose. The 
following procedures will be performed at the end-of-study visit:

Physical examination will be performed. Weight will be measured and BMI recorded.

BP and HR will be recorded in the supine position after at least 5 min rest. 

12-lead ECG will be recorded in the supine position after at least 5 min rest.

Blood samples for haematology and clinical chemistry tests will be collected. The same 
haematology and clinical chemistry tests as at the screening visit except thyroid stimulating 
hormone and albumin will be determined; see section 6.4.5 for details.

Urinalysis will be performed.

AEs, current medical conditions and concomitant treatments will be recorded.
6.2
Pharmacokinetic assessments
6.2.1
Blood sampling
Peripheral venous blood samples will be drawn for the determination of concentrations of 
levodopa, carbidopa, 3-OMD and ODM-104 in plasma. For blood sampling, a forearm vein 
will be cannulated. Blood samples will be drawn before the drug administration (0 h) and at 
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 
13, 13.5, 14, 15, 16 and 24 h after the drug administration. At time points 3.5, 7 and 10.5 h, the 
study treatment will be administered and the blood sample drawn at a same time. However, 
exact timing of study treatment administration will be prioritised, e.g. in case of problems in 
blood sampling.
Before the start of the study, detailed instructions for collecting, handling, storing and shipping 
of the plasma samples will be provided to the study centre. Maximum volume of blood 
collected in the study is provided in the subject information.
6.2.2
Determination of drug concentrations
The concentrations of levodopa, carbidopa, 3-OMD and ODM-104 in plasma will be 
determined with validated LC-MS/MS methods. Metabolites of ODM-104 will be determined, 
if indicated necessary by the PK results of the study. Bioanalytical details and criteria for 
acceptance of the results will be described in the bioanalytical plans and reported in 
bioanalytical reports.
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6.2.3
Calculation of pharmacokinetic variables
Table 4 lists the PK parameters which will be derived from the concentration-time data of 
levodopa, carbidopa, 3-OMD and ODM-104.
Table 4.
PK parameters to be calculated for levodopa, carbidopa, 3-OMD and ODM-104
Parameter
Levodopa
Carbidopa
3-OMD
ODM-104
Cmax
X1
X1
X1
X1
Cmax,tau
X1
X
tmax
X
X
X
X
tmax,tau
X
X
Cmin,tau
X1
X
Cmin,tau,actual
X1
AUCtau
X1
X
AUC0-16
X1
AUC0-24
X1
X1
X1
X1
AUC∞
X
X
t½
X
X
λz
X
X
Cmax/Cmin,tau 
X1
Cmax/Cmin,tau,actual
X1
Cmax/C(16h)
X1
PTFtau
X1
PTF0-16h
X1
1 Statistical analysis will be performed
Cmax
The maximum observed concentration of the concentration-time curve
Cmax,tau
The maximum observed concentration for each dosing interval
tmax
The time to reach the maximum observed concentration
tmax,tau
The time to reach the maximum observed concentration for each dosing interval
Cmin,tau
The observed concentration at the end of each dosing interval i.e. concentration at 
3.5 h, 7 h, 10.5 h and 14 h
Cmin,tau,actual
The observed minimum plasma concentration after each dose before the concentration 
starts to rise due to the following dose. For the 4th dosing interval, the plasma 
concentration at time 16 h will be used as the minimum plasma concentration.
AUCtau
The area under the concentration-time curve calculated with linear trapezoidal rule for 
each dosing interval
AUC0-16
The area under the concentration-time curve calculated with linear trapezoidal rule 
from time 0 to the 16 h PK sample
AUC0-24
The area under the concentration-time curve calculated with linear trapezoidal rule 
from time 0 to the 24 h PK sample
AUC∞
The area under the concentration-time curve from time 0 to infinity, AUC∞ will be 
determined by adding area under the concentration-time curve from time 0 to the last 
sample with a quantifiable concentration (AUCt) to the extrapolated area that will be 
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determined by dividing the last quantifiable concentration by z
t½
The terminal elimination half-life that is calculated with the equation ln 2 / z
z
The terminal elimination rate constant from the log-linear portion of the concentration-
time curve after the last (10.5 h) dose
Cmax/Cmin,tau
Ratio of the maximum observed concentration in each dosing interval and the observed 
concentration at the end of each dosing interval
Cmax/Cmin,tau,actual Ratio of the maximum observed concentration in each dosing interval and the observed 
minimum plasma concentration after each dose before the concentration starts to rise 
due to the following dose. For the 4th dosing interval the plasma concentration at time 
16 h was used as the minimum plasma concentration
Cmax/C(16h)
Ratio of the maximum observed concentration from time 0 to 16 h and the observed 
concentration at time 16 h
PTFtau
Peak-trough fluctuation for each dosing interval, calculated by (Cmax,tau-Cmin,tau) 
x100/Cav,tau, where the average concentration, Cav,tau = AUCtau/duration of dose interval
PTF0-16
Peak-trough fluctuation, calculated by (Cmax-Cmin) x100/Cav, where the average 
concentration, Cav = AUC0-16/16 h
The PK parameters will be calculated with non-compartmental methods using PhoenixTM
WinNonlin® Build 6.3.0.395 or a later software version (Certara L.P., USA). The actual time 
of sampling will be used in the calculation of PK parameters. Possible outlying concentrations 
excluded from the PK analysis will be reported and justified in the study report.
6.3
Pharmacogenomic variables
A blood sample for DNA extraction will be collected once between the day 1 of the first study 
period and the end-of-study visit from those subjects who agree to take part in the optional 
study-related exploratory PG study. A separate IC is required from the subject participating in 
this PG study. DNA from these subjects will be stored in the sponsor’s sample repository until 
analysis.
The objective of exploratory DNA analysis is to investigate possible factors that may give 
supportive information related to the absorption, distribution, metabolism, excretion, 
pharmacodynamics and safety of ODM-104, its metabolites or other drug treatments given in 
this study.
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study.
6.4
Safety assessments
6.4.1
Adverse events
6.4.1.1
Definitions
An AE is any untoward medical occurrence in a study subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE 
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can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product, whether or not related to the investigational medicinal product. The 
definition also covers medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.
Thus, an AE may be an appearance or worsening of any undesirable sign or symptom, any 
worsening of the current medical conditions or onset of a new disease, compared with the 
previous observations or a clinically significant adverse change in a laboratory variable or 
other diagnostic finding (e.g. ECG).
An SAE is any untoward medical occurrences that at any dose

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability/incapacity 

is a congenital anomaly/birth defect, or

is an important medical event jeopardizing the patient or requiring intervention to 
prevent serious outcome (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; development of drug dependency or 
drug abuse; overdose or interaction)
Other significant AEs are AEs (other than those meeting the definition of serious) that are of 
clinical importance and lead to:

a diagnostic or therapeutic intervention

discontinuation of the investigational medicinal product

reduction of its dose

significant additional concomitant treatment, or

marked haematological and other laboratory abnormalities
6.4.1.2
Assessment of adverse events
All AEs must be elicited, documented and reported by the investigator to the sponsor from the 
time that a study subject signs the IC form until the end-of-study visit, i.e. 4-21 days after the 
last dose of study treatment.
SAEs and other significant AEs should be followed up until resolved or until the event is 
considered a chronic or stable outcome, or both.
AE may be notified to the investigator by the study subject or observed by the investigator 
clinically, or be an adverse change in laboratory assessment results. The investigator will 
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evaluate the subject’s AEs at each visit by asking a standard question such as “Since you were 
last asked, have you felt unwell or different from the usual in any way?”
The investigator will assess and record the causality and severity of the AEs. Causality should 
be assessed in relation to the investigational medicinal product (see criteria for causality and 
severity below).
Causality criteria:
Related: The temporal relationship of the AE/SAE onset to the administration of the 
investigational medicinal product makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a sufficient explanation for 
the AE/SAE.
Not related: The temporal relationship of the AE/SAE onset to the administration of the 
investigational medicinal product makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient explanation for the 
AE/SAE.
Severity criteria:
Mild: Discomfort noticed, but it does not affect normal activity.
Moderate: Discomfort sufficient to reduce or affect normal daily activity.
Severe: Incapacitating with inability to work or perform normal daily activity.
From the time that a study subject candidate signs the IC form, newly appearing diagnosed 
diseases will be recorded on the AE eCRF.
Investigators must report all AEs to the sponsor on a specific AE eCRF irrespective of their 
assessment of the causal relationship of the investigational medicinal product to the event.
SAEs are by definition AEs and should be elicited in the same way, and also reported on the 
AE eCRF.
6.4.1.3
Reporting of serious adverse events by the investigator
The investigator must report all SAEs within 24 h of becoming aware of an SAE. SAEs must 
be reported within 24 h regardless of the time that may have elapsed since the time the event 
occurred and regardless of the causal relationship of investigational medicinal product to the 
event.
All SAEs should be reported on an electronic SAE form, which should be completed by the 
investigator or other relevant study centre personnel and signed by the investigator. Optionally, 
if the investigator is not able to complete the SAE form electronically, the paper version of the 
SAE form can be completed and sent by e-mail or faxed to Orion Drug Safety. The SAE 
reporting contact information can be found on the SAE form and will be filed in the 
investigator’s study file.
If the initial report is reported by phone or e-mail to the study monitor or other contract 
research organisation (CRO) personnel and the study centre personnel are unable to fill in the 
SAE form within 24 h, a paper SAE form will be initiated by the person receiving the report. 
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The investigator must report the SAE on the SAE eCRF as soon as possible. In addition, SAEs 
should be reported on the AE eCRF.
The minimum criteria for SAE reporting are: the event or outcome meets the SAE definition, 
the event happens to an identifiable study subject, and the event is reported by an identifiable 
and qualified reporter (usually an investigator or other qualified study centre personnel)
A follow-up report to an SAE should be prepared if any relevant change in the condition of the 
study subject occurs after the initial report. The follow-up report should be documented as an 
update to the initial report.
SAEs that occur after the end-of-study visit (4-21 days after the last dose of study treatment),
should be reported on the SAE form, if the investigator feels that there is a reasonable 
possibility for the event to have been caused by the study subject’s participation in the study. 
6.4.1.4
Reporting of serious adverse events to competent authorities and ethics committees
The sponsor is responsible for expediting all suspected unexpected serious adverse reactions 
(SUSARs) as well as other safety issues requiring expedited reporting to the relevant 
authorities within applicable timelines.
Notification of the ECs about all relevant events (SUSARs, other relevant safety information) 
will be performed by the CRO as a delegate of the sponsor.
The expectedness evaluation is required for regulatory reporting and it is performed by the 
sponsor. The expectedness in this study is evaluated against the Reference safety information 
section in the current ODM-104 Investigator’s brochure (days 1-7, groups 1-4) and the 
Sinemet UK Summary of Product Characteristics (SmPC) (day 7, group 4).
6.4.2
Special situations
The special situations with study treatment are defined as: 

medication error

overdose

abuse

misuse

interaction
These special situations with study treatment are reported on the Special situations with study 
treatment eCRF even if there is no accompanying AE. All clinical manifestations in relation to 
these special situations will be reported as AEs or SAEs at the same time using the 
corresponding section of the eCRF.
6.4.3
Pregnancy during the study
Whenever it becomes known that a female partner of a subject becomes pregnant during the 
exposure to study treatments, the outcome of the pregnancy, delivery, postpartum recovery and 
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the clinical condition of the offspring during the neonatal period should be reported, subject to
the partner’s consent. A pregnancy follow-up form will be provided to the investigator for 
completion after the sponsor has received the initial report.
Any case of pregnancy during a clinical study should be reported by the investigator in the 
same way as an SAE.
6.4.4
Clinical safety assessments
HR, PB and 12-lead ECG will be recorded in the supine position after at least 5 min rest. The 
time points at which HR, BP and 12-lead ECG are recorded ECG are presented in Table 3.
12-lead ECG will be recorded 3 times within 5 min (1-2 min interval between the 
measurements) on day 1 pre-dose. The mean of 3 separate 12-lead ECG recordings will be 
considered as a baseline.
All 12-lead ECG data collected will be stored. Decision on whether or not to analyse all data 
will be made during or after the study. If additional ECG analysis will be performed, the 
results may be reported in a separate report.
A physical examination will be performed by the investigator at screening and end-of-study.
6.4.5
Laboratory safety assessments
The following laboratory tests will be taken at the screening visit after at least 10 h of fasting:
Haematology:

Haemoglobin

Haematocrit

Erythrocytes

Thrombocytes

Mean corpuscular volume

Mean corpuscular haemoglobin

Mean corpuscular haemoglobin concentration

Leucocytes

Differential count (lymphocytes, monocytes, eosinophils, neutrophils, basophils)
Clinical chemistry:

Albumin

Creatinine

Alkaline phosphatase

Alanine aminotransferase
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
Aspartate aminotransferase

Creatine kinase

Gamma-glutamyl transferase

Glucose

Magnesium 

Sodium

Potassium

Calcium (albumin corrected)

C-reactive protein

Thyroid stimulating hormone

Total bilirubin
Urinalysis: 

Stick-test: pH, leucocytes1, nitrites1, protein, blood1, glucose (1 in case of findings, a 
microscopy examination of urine sediment will be performed)
Serology:

Human immunodeficiency virus antigen/antibody

Hepatitis C virus antibodies

Hepatitis B-surface antigen
Selected laboratory tests
The following selected laboratory tests will be performed on days 1 and 7 in each treatment 
period, before the first dose:
Haematology: 

Haemoglobin

Haematocrit

Erythrocytes

Thrombocytes

Mean corpuscular volume

Mean corpuscular haemoglobin

Mean corpuscular haemoglobin concentration

Leucocytes
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
Differential count (lymphocytes, monocytes, eosinophils, neutrophils, basophils)
Clinical chemistry:

Creatine kinase

Creatinine

Alkaline phosphatase

Aspartate aminotransferase

Gamma-glutamyl transpeptidase

Alanine aminotransferase

Total bilirubin

Sodium

Potassium

Magnesium

C-reactive protein
Urinalysis 

Stick-test: pH, leucocytes1, nitrites1, protein, blood1, glucose (1in case of findings, a 
microscopy examination of urine sediment will be performed)
End-of-study laboratory tests
The same laboratory tests as at the screening visit, except determination of thyroid stimulating 
hormone and albumin, serology tests, urine test for drug abuse and alcohol breath test will be 
performed.
Alcohol and drug abuse tests during the study
An alcohol breath test will be performed at the screening visit and on admission in each 
treatment period.
A urine drug abuse test will be performed at the screening visit and on admission in each 
treatment period. 
The reference ranges of the local laboratories will be recorded on the eCRFs by the sponsor. 
The investigator’s assessment of clinical relevance will be documented on the eCRFs.
In case there are clinically relevant findings, control assessments may be performed according 
to the judgement of the investigator.
Instructions for the collection, handling, storage and transportation of samples will be provided 
before the start of the study.
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7.
DATA COLLECTION AND MANAGEMENT
The investigators and study centre personnel will prepare and maintain accurate source data for 
each study subject about clinical findings specified in the protocol. Source data include e.g. 
subject records and laboratory results. The data from source documents will be recorded into 
an electronic data capture (EDC) system, Medidata Rave (Medidata Inc), using eCRFs at the 
study centre. Externally produced data, if any, will be uploaded directly into the EDC system 
or transferred to the sponsor at agreed time intervals. All data on the eCRFs must be verifiable 
in the source data unless eCRF data are declared as source data.
Investigators and other relevant study centre personnel will be trained to use the eCRFs. After 
completion of training, they are provided with user names and authorised access to enter and 
correct data on the eCRFs.
Electronic queries about missing, misleading, incomplete or illogical data will appear in the 
EDC system. An audit trail within the system will track all changes/corrections made. The 
investigator has to confirm the content of the eCRF with an electronic signature.
Individual data fields in the EDC system may be locked on an ongoing basis during the study. 
The fields may be unlocked if further updates are needed. When all data have been entered and 
all queries resolved, the whole database will be locked. Only authorised and well-documented 
updates to the study data are possible after the database lock. 
Further details regarding data collection and management are presented in the data 
management plan.
8.
STATISTICAL METHODS
8.1
Statistical hypotheses
The primary variable for the evaluation of PK of levodopa is AUC0-24. Primary comparison 
will be made within levodopa dose level groups, between crossover treatment arms levodopa / 
12.5, 25 or 37.5 mg of carbidopa and levodopa / 65 mg of carbidopa / 100 mg of ODM-104. 
Other crossover comparisons will be performed and considered as secondary. Parallel group 
comparisons may be performed. The conclusions on possible differences between treatments 
will be based on both overall evaluation of levodopa concentration-time profiles and formal 
statistical analyses of PK parameters.
H0: AUC0-24, levodopa/carbidopa/ODM-104 = AUC0-24, levodopa/carbidopa
H0: AUC0-24, levodopa/carbidopa/ODM-104 ≠ AUC0-24, levodopa/carbidopa
8.2
Estimation of sample size
The sample size estimation is based on earlier ODM-104 phase I study 3112003. Sample size 
is estimated using the AUC0-24. Based on the results from 12 subjects that completed treatment 
periods with levodopa 100 mg / carbidopa 25 mg / entacapone 200 mg and MR levodopa 
100 mg / carbidopa 65 mg / ODM-104 100 mg. The latter treatment arm with ODM-104 and 
65 mg of carbidopa increased exposure by 22% (AUC0-24 14022.2 vs. 17092.6). Within subject 
variability is estimated to be 0.1386 (√MSE in logarithmic scale). It is assumed that MR 
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levodopa 100 mg / carbidopa 65 mg / ODM-104 100 mg will increase exposure by 40% 
compared to MR levodopa 100 mg / carbidopa 25 mg. 
When the sample size in each sequence is 3 (with a total sample size of 12), a crossover design 
will have 80% power to detect a difference in means of 0.336 assuming that the within subject 
variation is 0.139 using a crossover Analysis of variance (ANOVA) with a 0.1 two-sided 
significance level. To allow drop outs 14 subjects per group and 56 subjects in total will be 
randomised into this study with 4-treatment, 4-period William’s crossover design. This will 
provide adequate power for the primary comparison. 
Replacement subjects may be enrolled (see section 4.5).
8.3
Analysis populations
The datasets derived from individual study subjects will be classified into following 3 classes 
prior to database lock and before carrying out any statistical analyses:

Modified intention-to-treat (mITT) population: all randomised subjects who have 
received at least 1 dose of study treatment.

Per-protocol (PP) population: Subjects who have completed the study according to the 
protocol without major protocol deviations.

Safety population is the same as the mITT population.
8.4
Statistical analyses
Statistical analyses are described in more detail in the statistical analysis plan.
8.4.1
Demographic and other baseline characteristics
All relevant demographic and baseline characteristics will be summarised using descriptive 
statistics. The number and reasons for discontinuations will be listed and tabulated by 
treatment groups.
8.4.2
Treatment compliance and extent of exposure
The number of exposed subjects, the number of administered study treatments and the duration 
of study treatment exposure will be tabulated with descriptive statistics.
8.4.3
Pharmacokinetic analysis
The primary variable for the evaluation of PK of levodopa is AUC0-24 to describe the total 
levodopa exposure. The secondary PK variable is Cmin,tau, which is used to describe minimum 
concentration during the dosing intervals. The ratio of the Cmax in a dosing interval and the 
observed concentration at the end of the dosing interval, Cmax/Cmin,tau, which is used to describe 
levodopa fluctuation during the dosing intervals and other PK variables of levodopa, 3-OMD, 
carbidopa and ODM-104 will be evaluated as other variables.
PK parameters will be analysed after logarithmic transformation and 90% confidence intervals
(CIs) for the geometric means will be calculated.
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The conclusions regarding possible differences between different study treatments will be 
based on both overall evaluation of levodopa concentration-time profiles and formal statistical 
analyses of PK parameters.
Primary pharmacokinetic evaluation
The primary PK variable will be summarised using descriptive statistics by treatment and 
analysed using a mixed linear model with 90% CI applicable for the crossover design. The 
statistical model will include treatment and period as fixed effects and subject as random 
effect. Sensitivity analysis adjusted for subject weight and age will be performed.
Levodopa fluctuation ratios (Cmax/Cmin,tau, Cmax/C(16 h), PTFtau and PTF0-16), and AUC0-24, Cmax
and Cmin,tau will be the main PK variables of interest.
The primary conclusions will be based on the PP population. 
Secondary pharmacokinetic evaluation
Statistical evaluation for secondary PK variable will be done using similar methods as for 
primary variable. Statistical model for Cmin,tau will include treatment, period, dosing interval, 
and treatment by dosing interval interaction as fixed effect and subject by period interaction as 
random effect.
Other pharmacokinetic evaluations
The other PK variables for the evaluation of PK of levodopa, carbidopa, 3-OMD and ODM-
104 are presented in Table 4. All PK variables will be summarised by treatment using 
descriptive statistics. Selected PK variables will be analysed using similar models and 
sensitivity analysis to the primary and secondary PK variables. Drug concentrations will be 
tabulated by time and treatment with descriptive statistics.
8.4.4
Pharmacogenomic analysis
In the context of this study, genetic polymorphisms may be analysed in relation to significant 
variation or specific scientific questions in PK or safety variables of levodopa, carbidopa or 
ODM-104. If such analysis is decided to be performed, a substudy will be designed and the
results will be reported in a separate report.
8.4.5
Safety analysis
An authorised person will code AEs, medical history and concomitant diseases using standard 
coding dictionaries.
8.4.5.1
Analysis of adverse events
AEs will be classified by system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and proportion of subjects 
reporting each AE and the number of events will be presented in a frequency table. The 
following AE data will be summarised: overview of AEs, severity of AEs and causality to the 
study treatment. SAEs, AEs leading to premature discontinuation of study treatment and other 
significant AEs will be evaluated case by case.
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AEs occurring before and after the initiation of study treatment will be reported separately.
8.4.5.2
Clinical safety analysis
Vital signs (systolic and diastolic BP and HR) at each visit and change from baseline 
(screening value) in each vital sign will be summarised using descriptive statistics. 12-lead
ECG parameters at each time point and change from baseline (screening value) will be 
summarised using descriptive statistics. Physical examination and C-SSRS findings will be 
tabulated.
8.4.5.3
Laboratory safety analysis
Laboratory values and changes from baseline (screening value) in laboratory values will be 
summarised using descriptive statistics. The number and proportion of subjects with laboratory 
values outside the normal range will be summarised by visit for each laboratory analyte.
8.4.5.4
Analysis of prior and concomitant treatments
Prior and concomitant treatments will be coded using the anatomical therapeutic chemical 
(ATC) classification system. The number and percentage of subjects using concomitant 
treatments will be summarised by a pharmacological subgroup and chemical substance.
8.5
Interim analyses
No interim analysis is planned for this study.
9.
DATA QUALITY ASSURANCE
9.1
Training
An initiation meeting will be arranged for the investigators and other relevant study centre 
personnel. This meeting will include a review of the protocol, eCRF completion and study 
procedures.
The investigators will ensure that appropriate training relevant to the study is given to the 
medical, nursing and other personnel involved in the study. The investigators will also ensure 
that any information relevant to the conduct of the study is forwarded to other relevant study 
centre personnel.
9.2
Case report forms
Electronic queries about missing, misleading, incomplete or illogical data will appear in the 
EDC system. An audit trail within the system will track all changes/corrections made. The 
investigator has to confirm the content of the eCRF with an electronic signature.
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9.3
Monitoring, audits and inspections
The study monitor will visit the study centre regularly as agreed by the investigator and the 
sponsor. The study monitor will ensure that the study complies with good clinical practice 
(GCP) and applicable regulatory requirements and that the protocol is followed in all aspects, 
including the randomisation procedure, accurate recording of results, reporting of AEs, drug 
accountability and record keeping. Furthermore, it will be verified that the clinical facilities 
remain appropriate, and that the eCRFs correspond with source data. Further details regarding 
monitoring are presented in the monitoring manual.
The study may be audited by independent representative(s) of the sponsor or inspected by the 
CAs. For these purposes, the study monitor, auditors and inspectors will be allowed direct 
access to source data of the study subjects, original laboratory data etc., as far as they are 
related to the study.
It is essential that the investigator and other relevant members of the study centre team are 
available during the monitoring visits, audits and inspections, and that they devote sufficient
time to these processes.
9.4
Laboratories and other vendors
All blood and urine samples will be worked up and analysed in the CRO’s clinical laboratory. 
ECGs will be recorded and analysed in the clinic of the CRO.
Details regarding laboratory safety assessments and ECG analyses are presented in separate 
instructions. Quality certificates are required from all safety laboratories.
Bioanalytics will be performed using validated methods.
10. FURTHER REQUIREMENTS AND GENERAL INFORMATION
10.1 Investigators and study administrative structure
10.1.1
Investigators
Should the principal investigator transfer one of his/her responsibilities to other members of 
the study centre team, he/she must have this documented.
In the event of changes in key study centre team members, the responsible investigator must 
ensure that the successor is fully informed and capable of following the procedures.
A curriculum vitae in English must be obtained from all investigators who sign the protocol, 
and from other relevant persons.
10.1.2
Data and safety monitoring board
No data and safety monitoring board will be established for this study.
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10.2 Insurance
The sponsor will provide clinical trial liability insurance for study subjects according to local 
regulations.
10.3 Retention of records
The investigator agrees to keep the following documentation in the investigator’s study file: 
study subject records, including a subject screening log, a subject identification list, all original 
signed IC forms, a copy of eCRFs and records of drug dispensing.
The study files will be stored in the respective archives for 15 years, after which the sponsor 
will be contacted and the possibility of future archiving will be mutually agreed upon.
10.4 Completion of the study
The study is estimated to start in February 2017 (first subject first visit) and end when the last 
subject’s last visit takes place.
Upon completion of the study, all unresolved issues will be clarified and remaining study 
treatments and other study materials will be collected.
The sponsor reserves the right to prematurely terminate the study for valid scientific or 
administrative reasons. After such a decision, the investigator must contact all participating 
study subjects within 7 days, and invite them for an end-of-study visit. All eCRFs must be 
completed up to the end-of-study visit.
10.5 Reports, publications and communication of results
Orion wishes to collaborate with the investigator to publish the results as timely as possible, 
without compromising accuracy or industrial property rights. The preparation, submission and 
authorship for publications containing the study results shall be in accordance with a process 
determined by mutual written agreement among the sponsor and participating institutions, and 
in accordance with international criteria for authorship; see International Committee of 
Medical Journal Editors recommendations, available at http://www.icmje.org.
Orion remains the exclusive owner of the study data defined by the protocol.
This study will be registered in one of the acceptable registries before the enrolment of the first 
subject.
11. ETHICS
11.1 Ethics committee
The study protocol, subject information sheet, IC form, and all other necessary documents will 
be submitted to an independent EC for review according to local regulations.
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A favourable opinion will be obtained from the EC for the study, as well as any amendment(s),
and communication of study-related safety issues as requested by the EC. The investigator 
should file all correspondence with the EC in the investigator’s study file. Relevant copies of 
this correspondence should be forwarded to the sponsor. 
11.2 Ethical conduct of the study
The study will be conducted in accordance with the Declaration of Helsinki guiding physicians 
in biomedical research involving human subjects.
The study shall not be initiated before favourable opinion from the EC and approval from the 
CA has been obtained for the protocol.
The study will be conducted in compliance with the protocol, GCP (ICH/135/95) and 
applicable regulatory requirements. A substantial amendment shall not be implemented until 
the protocol amendment has received a favourable opinion from the EC and approval from the 
CA. Only in case of the need to eliminate an immediate hazard(s) to study subjects, the 
investigator may implement deviation from the protocol without prior favourable opinion from 
the EC and approval from the CA for the protocol amendment.
11.3 Subject information and informed consent
The investigator will ensure that each subject is fully informed about the objectives and 
procedures of the study. The investigator will also explain any possible risks with participating 
in the study and answer all questions regarding the study. The subject will be given sufficient 
time to make a decision regarding participation in the study.
Subjects will be informed of their right to discontinue the study at any time without their 
medical care or legal rights being affected. Subjects will also be informed that representatives 
of the sponsor or CA may inspect relevant parts of their medical records and study data.
The investigator will obtain a signed and dated consent from each subject before any study 
related procedures are performed. One original of the signed and dated IC will be given to the 
subject. A second original will be retained in the investigator’s study file. The investigator 
should confirm the receipt of every IC by entering the date of the consent both on the subject’s 
eCRF and also on the subject screening log and identification list.
11.4 Subject data protection
Information collected during the course of the study will be stored in a database and used in 
the further development of study treatments and thereafter for as long as the information is 
relevant to patient care. The use includes the transfer of data to CAs in the European Union, 
the United States or other countries for the purpose of obtaining and maintaining marketing 
authorisations. All information is handled confidentially and according to local laws and 
regulations.
The study subjects can be identified in the eCRFs only by study subject number, sex, year of 
birth, age and racial group.
The confidentiality of PG data will be protected according to local laws and regulations.
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12. REFERENCE LIST
Kuoppamaki M et al. (2009) Comparison of pharmacokinetic profile of levodopa throughout 
the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when 
administered four or five times daily. Eur J Clin Pharmacol 65(5):443-55.
Nutt JG et al. (1994) Effect of peripheral catechol-O-methyltransferase inhibition on the 
pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. 
Neurology 44(5):913-9.
Nyholm D et al. (2004) Levodopa infusion therapy in Parkinson disease: state of the art in 
2004. Clin Neuropharmacol 27(5):245-56.
Paija O et al. (2005) Entacapone increases levodopa exposure and reduces plasma levodopa 
variability when used with Sinemet CR. Clin Neuropharmacol 28(3):115-9.
Stocchi F et al. (2005) Intermittent vs continuous levodopa administration in patients with 
advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 
62(6):905-10.
13. APPENDICES
Appendix 1.
Investigator signature
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Signature page 
eSigned 
 
Signature page 
 
 
Written by: 
 
 
Date dd.mm.yyyy (UTC) 
Justification 
Electronically signed by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vahteristo Mikko (mikvah)
Koivisto Tiina a (tiikoi)
Ellmen Juha (juhael)
02.12.2016 13:31:27
Tuunainen Johanna (johmak)
02.12.2016 13:33:52
02.12.2016 14:27:24
02.12.2016 15:19:56
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