A Double-Blind, Placebo-Controlled, Randomized, 18-Month Phase 2a Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Oral UCB0599 in Study Participants With Early Parkinson's Disease
Phase: PHASE2
Conditions: Early-stage Parkinson's Disease
Sponsor: UCB Biopharma SRL

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A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, 
18-MONTH PHASE 2A STUDY TO EVALUATE THE EFFICACY, 
SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF 
ORAL UCB0599 IN STUDY PARTICIPANTS WITH EARLY 
PARKINSON’S DISEASE 
PROTOCOL PD0053 AMENDMENT 6 
PHASE 2A 
SHORT TITLE: 
A double-blind, placebo-controlled, randomized, Phase 2a study with oral UCB0599 in study 
participants with early Parkinson’s disease 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
Eudra CT Number: 
2020-003265-19 
IND Number: 
141003 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
Document History 
Document 
Date 
Type of amendment 
Amendment 6 
21 Mar 2024 
Nonsubstantial 
Amendment 5 
30 Jun 2023 
Substantial 
Amendment 4 
24 Feb 2022 
Substantial 
Amendment 3 
04 Oct 2021 
Substantial 
Amendment 2.2 UK 
04 Jun 2021 
Nonsubstantial 
Amendment 2.1 France 
04 Jun 2021 
Nonsubstantial 
Amendment 2 
21 May 2021 
Nonsubstantial 
Amendment 1.7 Germany  10 Aug 2021 
Substantiala 
Amendment 1.6 Germany  17 May 2021 
Nonsubstantial 
Amendment 1.5 Germany 
01 Apr 2021 
Nonsubstantial 
Amendment 1.4 UK 
25 Feb 2021 
Not applicable 
Amendment 1.3 Germany 
22 Feb 2021 
Not applicable 
Amendment 1.2 France 
17 Feb 2021 
Not applicable 
Amendment 1.1 Canada 
15 Feb 2021 
Not applicable 
Amendment 1 
29 Oct 2020 
Not applicable 
Original Protocol 
13 Oct 2020 
Not applicable 
a Amendment 1.7 Germany was initially submitted as a nonsubstantial amendment. 
 
Amendment 6 (21 Mar 2024) 
PD0053 Protocol Amendment 6 was completed to provide clarification around blinding, the 
timing of the Month 12 data analysis, and to remove analyses that are no longer needed. In 
addition, the list of secondary and exploratory efficacy endpoints was updated. The following 
changes were implemented: 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Throughout the protocol, references to 
PD0055 were updated to clarify that 
this is a dose-blinded (not an 
open-label) extension study.  
Correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Objectives and Endpoints 
and 
Section 3 OBJECTIVES AND 
ENDPOINTS 
A new Secondary Efficacy Endpoint 
for the primary efficacy objective was 
added and replaces the former 
exploratory endpoint ‘MDS-UPDRS 
selected items’ (as described below): 
• 
MDS-UPDRS Part III ePD 
subscore on selected items 
(timeframe: Baseline to 18 
months) 
To add a new secondary 
efficacy endpoint based on 
the MDS-UPDRS Part III 
subscale. 
 
A new Secondary Efficacy Endpoint 
was added for the primary efficacy 
objective: 
• 
Emerging symptoms as measured 
by MDS-UPDRS Part II 
(timeframe: Baseline to 
18 months) 
To add a new secondary 
efficacy endpoint 
consisting of an additional 
analysis of the 
MDS-UPDRS Part II data 
already collected in the 
study. 
 
The following Secondary Efficacy 
Endpoint for the primary efficacy 
objective was revised (bolded text 
added): 
• 
Time to worsening of the disease 
as measured by MDS-UPDRS 
Part III (timeframe: Baseline to 
18 months) 
To further specify the 
endpoint. 
 
The following Exploratory Efficacy 
Endpoint for the primary efficacy 
objective was revised (see 
strikethrough text): 
• 
Time to worsening in MDS-
UPDRS Part I and Part II 
subscales 
To further specify the 
endpoint (Part II subscale is 
removed as it is now part of 
new secondary emerging 
symptoms endpoint). 
 
The following Exploratory Efficacy 
Endpoint for the primary efficacy 
objective was removed and is now 
covered by the new secondary 
endpoint ‘MDS-UPDRS Part III ePD 
subscore (selection of items)’: 
• 
MDS UPDRS selected items 
To modify an exploratory 
efficacy endpoint: this 
endpoint is now part of the 
secondary endpoints. 
 
A new Exploratory Efficacy 
Endpoint was added for the primary 
efficacy objective: 
• 
Composite endpoint (based on 
MDS-UPDRS and/or Early PD 
PROs)   
To add an exploratory 
efficacy endpoint 
composed of endpoints 
already included in the 
study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Objectives and Endpoints 
The Exploratory Efficacy Endpoint 
‘CSF ASYN oligomers/seeding 
capacity’ was added for the secondary 
efficacy objective. 
To align with Section 3 
(implementing a change 
from Amendment 4 that 
was missed in 
Amendment 5). 
Section 1.3 Schedule of 
Activities 
Footnote ‘b’ was removed from V9.  
Footnote ‘b’ was added to V16. 
Correction. To align with 
the visits that can be done 
from the participant’s 
home. 
Section 5.2 Exclusion criteria 
In exclusion criterion #31b (1) 
(previously #31a [1]), bupropion was 
added back. 
Correction. Bupropion had 
inadvertently been removed 
in Amendment 4. 
Section 6.3 Measures to 
minimize bias: randomization 
and blinding 
In the fifth paragraph, the following 
bullet was added to further clarify who 
may have access to the randomization 
code: 
• 
Unblinded pharmacometrics staff 
and statistical programmers, 
independent from the study team, 
who have access to the 12-month 
data for the preparation of the 
exposure-response analysis 
To add access to the 
randomization code to 
independent experts for 
exposure-response model 
development, which has no 
impact on the ongoing 
study monitoring and 
conduct. 
Section 6.5.2 Prohibited 
concomitant treatments 
(medications and therapies) 
Bupropion was added to the list of 
medications that are not allowed 
during the 50 days before DaT-SPECT 
imaging. 
To complete the list of 
drugs that may affect the 
DaT-SPECT scan. 
Section 8.1.1.1 MDS-UPDRS 
The introductory sentence for the 
MDS-UPDRS was revised to clarify 
that the 4 parts are referred to as 
“subscales.” 
To clarify terminology. 
Section 9.3 Planned 
efficacy/outcome analyses 
Table 9-1 was updated to reflect the 
updates to secondary and exploratory 
efficacy endpoints. 
 
To align with updates to the 
list of exploratory efficacy 
endpoints in objectives and 
endpoints table. 
 
Text below Table 9-1 was updated to 
clarify that the efficacy data analysis 
will take place once all participants 
have completed their 18-month Visit. 
To clarify the timepoint of 
the efficacy analysis. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3 Planned 
efficacy/outcome analyses 
Text around sensitivity analyses was 
removed at the end of the section. 
To remove sensitivity 
analyses that are no longer 
relevant due to the large 
proportion of participants 
having initiated ST during 
the study, and/or due to the 
data being unblinded at end 
of study only and not at 
Month 12. 
Section 9.3.1.1.1 Primary 
Efficacy Estimand: MDS-
UPDRS Parts I-III sum score 
at 12 months (“De Jure” 
Estimand) 
and 
Section 9.3.1.2.3 Secondary 
Efficacy Estimand: MDS-
UPDRS Part I/Part II/Part III 
subscales at 18 months (“De 
Jure” Estimand) 
Under ICEs and handling strategies, 
‘while-on-treatment’ was updated to 
‘hypothetical’. 
 
Updated to use 
‘hypothetical’ in place of 
‘while-on-treatment’ 
throughout (no change to 
actual handling of data, 
post-ICE data will still be 
set to missing). 
Section 9.3.1.1.1.1 
Supplementary Efficacy 
Estimand to MDS-UPDRS 
Parts I-III sum score at 12 
months (“De Facto” Estimand) 
Under Estimator, text was updated to 
refer to Section 9.3.1.2.1.1 (LMEM 
estimator based on Baseline to Month 
18 data). 
Separate 12-month analyses 
will not be performed. 
Estimates at Month 12 will 
be generated from the 
analyses over 18 months. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.1.1.1 Primary 
Efficacy Estimand: MDS-
UPDRS Parts I-III sum score 
at 12 months (“De Jure” 
Estimand) 
and 
Section 9.3.1.1.2 Key 
Secondary Efficacy Estimand: 
MDS-UPDRS Part III subscale 
at 12 months (“De Jure” 
Estimand) 
and 
Section 9.3.1.1.4 Secondary 
Efficacy Estimands: MDS-
UPDRS Part I/II subscales at 
12 months (“De Jure” 
Estimands) 
and  
Section 9.3.1.2.1 Key 
Secondary Efficacy Estimand: 
MDS-UPDRS Parts I-III sum 
score at 18 months (“De Jure” 
Estimand) 
and 
Section 9.3.1.2.5 (previously 
9.3.1.2.4) Secondary Efficacy 
Estimand: MoCA over 18 
months 
Subheading and text for Sensitivity 
analyses was removed. 
Sensitivity analyses for 
these estimands are no 
longer relevant. 
 
Section 9.3.1.1.3 Key 
Secondary Efficacy Estimand: 
Worsening on MDS-UPDRS 
Part III subscale at 12 months 
(“De Jure” Estimand) 
Section was removed. 
To remove a time-to-event 
analysis which has become 
redundant as unblinding 
will only occur at end of 
study. 
Section 9.3.1.1.3 Key 
Secondary Efficacy Estimand: 
MDS-UPDRS Part III subscale 
and Part III early-stage PD 
subscore at 12 months 
New section was added. 
To align with updates to the 
list of exploratory efficacy 
endpoints in objectives and 
endpoints table. 
Section 9.3.1.1.4 Secondary 
Efficacy Estimands: MDS-
UPDRS Part I/II subscales at 
12 months (“De Jure” 
Estimands) 
Text under ICEs and handling 
strategies and Population-level 
summary was updated. 
Correction to handle 
MDS-UPDRS Part I and 
Part II in the same way for 
the secondary estimand, 
and handle both regardless 
of ST in the supplementary 
estimand. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.1.1.4 Secondary 
Efficacy Estimands: MDS-
UPDRS Part I/II subscales at 
12 months (“De Jure” 
Estimands) 
Under Estimator, text was replaced to 
be a reference to Section 9.3.1.2.3 
(LMEM estimator based on Baseline 
to Month 18 data). 
Separate 12-month analyses 
will not be performed. 
Estimates at Month 12 will 
be generated from the 
analyses over 18 months. 
Section 9.3.1.1.4.1 
Supplementary Efficacy 
Estimand to MDS-UPDRS 
Part I/II subscales at 12 
months (“De Facto” Estimand) 
Under Estimator, estimates, and 
sensitivity analyses, text was replaced 
to be a reference to Section 9.3.1.2.1.1 
(LMEM estimator based on Baseline 
to Month 18 data). 
Separate 12-month analyses 
will not be performed. 
Estimates at Month 12 will 
be generated from the 
analyses over 18 months. 
Section 9.3.1.1.5 Exploratory 
Efficacy Endpoints at 12 
months 
and 
Section 9.3.1.2.6 (previously 
9.3.1.2.5) Exploratory Efficacy 
Endpoints at 18 months 
The first Exploratory Efficacy 
Endpoint in the list was updated (see 
strikethrough text): 
• 
Time to worsening in MDS-
UPDRS Part I and Part II 
subscales 
 
The second Exploratory Efficacy 
Endpoint in the list was removed: 
• 
MDS UPDRS selected items 
 
A new Exploratory Efficacy Endpoint 
was added below the Mobility PRO: 
• 
Composite endpoint (based on 
MDS-UPDRS and/or Early PD 
PROs) 
To align with updates in 
objectives and endpoints 
table. 
Section 9.3.1.2.3 Secondary 
Efficacy Estimand: MDS-
UPDRS Part I/Part II/Part III 
subscales at 18 months (“De 
Jure” Estimand) 
Under Sensitivity analyses, text was 
updated. 
To remove sensitivity 
analyses that are no longer 
relevant. 
Section 9.3.1.2.3.1 Key 
Secondary Efficacy Estimand: 
MDS-UPDRS Part III subscale 
and Part III ePD subscore at 18 
months 
New section was added. 
To align with updates to the 
list of exploratory efficacy 
endpoints in objectives and 
endpoints table. 
Section 9.3.1.2.3.2 (previously 
9.3.1.2.3.1) Supplementary 
Efficacy Estimand: MDS-
UPDRS Part II/Part III 
subscales at 18 months (“De 
Facto” Estimand) 
Under Estimator, estimates, and 
sensitivity analyses, a reference to the 
SAP for further exploratory analyses 
was removed. 
To remove sensitivity 
analyses that are no longer 
relevant. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.1.2.4 Secondary 
Efficacy Estimand: MDS-
UPDRS Part II emerging 
symptoms over 18 months 
New section was added. 
To align with updates to the 
list of exploratory efficacy 
endpoints in objectives and 
endpoints table. 
Section 9.3.2.1 Secondary 
Efficacy Estimand: DaT-
SPECT mean Striatum SBR at 
Month 12 and Month 18 
Throughout, references to “18 months” 
have been replaced by “Month 12 and 
Month 18” for clarity. 
 
The text under Sensitivity analyses 
was updated. 
To clarify that separate 
12-month analyses will not 
be performed. Estimates at 
Month 12 will be generated 
from the analyses over 
18 months. 
Section 9.3.2.1.1 
Supplementary Efficacy 
Estimand: DaT-SPECT mean 
Striatum SBR at 18 months 
Section was removed. 
To remove a supplementary 
analysis that is no longer 
relevant. 
Section 9.3.2.2 Other 
Secondary Efficacy Estimand: 
DaT-SPECT mean Striatum 
SBR at 12 months 
Section was removed. 
Section no longer applies as 
no separate 12-month 
analyses will be done. 
Estimates at Month 12 will 
be generated from the main 
analyses over 18 months. 
Section 9.3.2.2 (previously 
9.3.2.3) Exploratory Efficacy 
Endpoints at Month 12 and 
Month 18 
In the section title, “at 12 and 18 
months” was changed to “Month 12 
and Month 18.” 
Minor editorial change. 
Section 9.3.3.1 Secondary 
Efficacy Estimand: Time to ST 
initiation over 18 months 
The section heading was corrected: 
“Time to ST intake at initiation over 
18 months” 
The subheading Supplementary 
analyses and reference to the SAP was 
removed. 
To remove supplementary 
analyses that are no longer 
relevant. 
Section 9.3.3.2 Secondary 
Efficacy Estimand: Intake of 
ST at 18 months 
and 
Section 9.3.3.3 Other 
Secondary Efficacy Estimand: 
Intake of ST at 12 months 
The following sentence was removed 
under Sensitivity analyses: 
The main model will be adjusted for 
Baseline predictors of early initiation 
of ST. 
To remove sensitivity 
analyses that are no longer 
relevant. 
Section 9.3.4 Subgroup 
analyses 
Text was updated to clarify that 
analyses by subgroup will be 
performed as part of exploratory 
analyses. 
To remove analyses that are 
no longer planned as part of 
the main analysis. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.5 Handling of ICEs, 
protocol deviations, and 
resulting missing data 
The second bullet for the ‘while-on-
treatment’ strategy was removed. 
The third bullet for the ‘hypothetical’ 
strategy was revised. 
The overview of handling strategies 
for MDS-UPDRS ICEs and study 
termination was updated (Table 9-2 
and associated text). 
To remove the ‘while-on-
treatment’ strategy and 
align with updates to 
efficacy endpoints 
throughout the protocol. 
Section 9.5.1 ICEs potentially 
affecting the interpretation of 
measurements 
Under MDS-UPDRS, the description 
of how the post-ICE data will be 
censored was updated. 
Under DaT-SPECT, the description of 
the supplementary analysis was 
removed. 
Under Treatment 
discontinuation/nonadherence, ‘while-
on-treatment’ strategy was replaced 
with ‘hypothetical’ strategy. 
To remove the DaT-SPECT 
supplementary analysis 
which was no longer 
relevant and to align with 
other changes made 
throughout the protocol, eg, 
to reflect change in 
wording of handling 
strategy from ‘while on 
treatment’ to ‘hypothetical’. 
Section 9.5.3 Other protocol 
deviations 
In the fourth paragraph, ‘while-on-
treatment’ strategy was replaced with 
‘hypothetical’ strategy. 
The eighth paragraph on the ‘while-on-
treatment’ strategy was removed. 
To replace the ‘while-on-
treatment’ strategy with 
‘hypothetical’ strategy 
throughout and align with 
other changes made 
throughout the protocol. 
Section 9.6 Planned analysis at 
12 months and data monitoring 
The first paragraph was revised to 
clarify that the analyses of Month 12 
data will be carried out at study end. 
A paragraph was added to describe that 
a limited team of independent 
pharmacometricians and statistical 
programmers with access to the 12-
month data will be unblinded to 
prepare for the exposure-response 
analysis.  
To clarify that no primary 
analysis at Month 12 will 
be done, and to describe the 
unblinding of an 
independent expert group to 
develop the exposure-
response model which has 
no impact on the study 
monitoring or conduct. 
 
Section 10.6 Appendix 6: 
Liver safety – suggested 
actions and follow-up 
assessments 
In Table 10-1 (Phase 2 Liver 
Chemistry Stopping Criteria and 
Follow-up Assessments), GGT was 
added as an optional follow-up 
assessment. 
To better characterize the 
important potential 
UCB0599 risk of 
transaminases elevation in 
case of potential 
drug-induced liver injury. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 11 REFERENCES 
The following reference was added: 
Tosin et al, 2022.  
The following references were 
removed: Mehrotra et al, 2017; 
Parashos et al, 2009; Simuni et al, 
2016. 
To add a new reference and 
to remove references that 
are no longer cited. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not 
been summarized. 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies) 
 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ............................................................................................... 18 
1.1 
Synopsis ....................................................................................................................... 18 
1.2 
Schema ......................................................................................................................... 22 
1.3 
Schedule of Activities .................................................................................................. 23 
2 
INTRODUCTION ........................................................................................................... 31 
2.1 
Study Rationale ............................................................................................................ 31 
2.2 
Background .................................................................................................................. 31 
2.3 
Benefit/Risk assessment............................................................................................... 33 
2.3.1 
Coronavirus Disease-2019 benefit/risk assessment ............................................. 33 
2.3.1.1 
COVID-19 risk mitigation measures ......................................................... 34 
2.3.1.2 
COVID-19 benefit/risk conclusion ........................................................... 35 
2.3.2 
Wearable sensor regulatory classification ........................................................... 35 
2.3.3 
Wearable sensor benefit/risk assessment ............................................................. 35 
2.3.3.1 
Potential benefits ....................................................................................... 35 
2.3.3.2 
Potential risks of the wearable sensor ....................................................... 35 
2.3.3.3 
Wearable sensor benefit/risk conclusion ................................................... 37 
2.3.4 
Overall benefit/risk conclusion ............................................................................ 37 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 37 
4 
STUDY DESIGN ............................................................................................................. 40 
4.1 
Overall design .............................................................................................................. 40 
4.1.1 
Decentralized model ............................................................................................ 40 
4.1.2 
Study conduct due to COVID-19 ........................................................................ 41 
4.2 
Scientific rationale for study design ............................................................................ 42 
4.3 
Justification for dose .................................................................................................... 44 
4.3.1 
Safety-based dose levels ...................................................................................... 44 
4.3.2 
Pharmacology-based dose levels ......................................................................... 45 
4.4 
End of study definition................................................................................................. 46 
5 
STUDY POPULATION .................................................................................................. 46 
5.1 
Inclusion criteria .......................................................................................................... 46 
5.2 
Exclusion criteria ......................................................................................................... 48 
5.3 
Lifestyle restrictions..................................................................................................... 53 
5.3.1 
Meals and dietary restrictions .............................................................................. 53 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 53 
5.3.3 
Activity ................................................................................................................ 53 
5.4 
Screen failures .............................................................................................................. 53 
6 
STUDY TREATMENTS/INVESTIGATIONAL DEVICE ............................................ 54 
6.1 
Treatments administered .............................................................................................. 55 
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6.2 
Preparation, handling, storage, and accountability requirements ................................ 55 
6.2.1 
Drug accountability ............................................................................................. 56 
6.3 
Measures to minimize bias: randomization and blinding ............................................ 56 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 58 
6.3.1.1 
Maintenance of study treatment blind ....................................................... 58 
6.3.1.2 
Breaking the treatment blind in an emergency situation ........................... 58 
6.4 
Treatment compliance .................................................................................................. 58 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 58 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 58 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 58 
6.5.3 
Rescue medication ............................................................................................... 59 
6.6 
Dose modification ........................................................................................................ 60 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 60 
6.8 
Treatment after the end of the study ............................................................................ 60 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 61 
7.1 
Discontinuation of study medication ........................................................................... 61 
7.1.1 
Hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) ............... 61 
7.1.2 
Liver Chemistry Stopping Criteria ...................................................................... 61 
7.1.3 
QTc Stopping Criteria .......................................................................................... 62 
7.1.4 
Temporary Discontinuation ................................................................................. 63 
7.1.5 
Rechallenge .......................................................................................................... 63 
7.2 
Participant Discontinuation/Withdrawal from the study ............................................. 63 
7.3 
Lost to follow up .......................................................................................................... 64 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 65 
8.1 
Efficacy assessments .................................................................................................... 66 
8.1.1 
Clinical assessments ............................................................................................ 66 
8.1.1.1 
MDS-UPDRS ............................................................................................ 66 
8.1.1.2 
Modified Hoehn and Yahr staging ............................................................ 67 
8.1.1.3 
Dopamine Transporter Imaging with Single Photon Emission Computed 
Tomography .............................................................................................. 67 
8.1.1.4 
ST intake .................................................................................................... 68 
8.1.1.5 
Montreal Cognitive Assessment ................................................................ 68 
8.1.1.6 
Clinical Global Impression of Improvement ............................................. 68 
8.1.1.7 
Clinical Global Impression of Severity ..................................................... 69 
8.1.1.8 
Movement Disorder Society Non-motor symptom scale .......................... 69 
8.1.1.9 
Schwab and England Activities of Daily Living Scale ............................. 69 
8.1.1.10 
Starkstein Apathy Scale ............................................................................. 69 
8.1.2 
Patient-reported outcomes ................................................................................... 69 
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8.1.2.1 
Fatigue PRO .............................................................................................. 70 
8.1.2.2 
Early PD Function Slowness PRO ............................................................ 70 
8.1.2.3 
Early PD Mobility PRO ............................................................................ 71 
8.1.2.4 
PGIS .......................................................................................................... 71 
8.1.2.5 
PGIC .......................................................................................................... 71 
8.1.2.6 
HADS ........................................................................................................ 71 
8.1.2.7 
EQ-5D-5L .................................................................................................. 71 
8.1.3 
Wearable sensor ................................................................................................... 71 
8.2 
Safety assessments ....................................................................................................... 73 
8.2.1 
Physical examination ........................................................................................... 73 
8.2.2 
Neurological examination .................................................................................... 74 
8.2.3 
Vital signs ............................................................................................................ 74 
8.2.4 
Electrocardiograms .............................................................................................. 74 
8.2.5 
Clinical safety laboratory assessments ................................................................ 75 
8.2.6 
Suicidal risk monitoring ...................................................................................... 75 
8.2.7 
MRI assessments ................................................................................................. 76 
8.2.8 
Wearable sensor data ........................................................................................... 76 
8.3 
Adverse events and serious adverse events ................................................................. 76 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 77 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 77 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 77 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 78 
8.3.5 
Pregnancy ............................................................................................................ 78 
8.3.6 
Adverse events of special interest ........................................................................ 78 
8.3.6.1 
Hypersensitivity reaction monitoring and management ............................ 79 
8.3.6.2 
Renal function safety monitoring and management .................................. 82 
8.3.7 
Anticipated serious adverse events ...................................................................... 82 
8.3.8 
Wearable sensor – adverse events (adverse sensor effects, unanticipated adverse 
sensor effects, SAEs, serious adverse drug events, and unanticipated serious 
adverse drug events) and sensor deficiencies ...................................................... 82 
8.4 
Safety signal detection ................................................................................................. 83 
8.5 
Treatment of overdose ................................................................................................. 83 
8.6 
Pharmacokinetics ......................................................................................................... 84 
8.7 
Genetics........................................................................................................................ 84 
8.8 
Pharmacodynamics ...................................................................................................... 84 
8.9 
Biomarkers ................................................................................................................... 84 
8.10 
Medical resource utilization and health economics ..................................................... 85 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 85 
9.1 
Definition of analysis sets ............................................................................................ 85 
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9.2 
General statistical considerations ................................................................................. 86 
9.3 
Planned efficacy/outcome analyses ............................................................................. 86 
9.3.1 
Analysis of the Primary Efficacy Objective: “Clinical symptoms at 12 and 18 
months” ................................................................................................................ 90 
9.3.1.1 
Analysis of “Clinical symptoms at 12 months” ........................................ 90 
9.3.1.2 
Analysis of “Clinical symptoms at 18 months” ........................................ 95 
9.3.2 
Analysis of the Secondary Efficacy Objective: “Neurodegeneration at 12 and 18 
months” .............................................................................................................. 101 
9.3.2.1 
Secondary Efficacy Estimand: DaT-SPECT mean Striatum SBR at Month 
12 and Month 18 ...................................................................................... 102 
9.3.2.2 
Exploratory Efficacy Endpoints at Month 12 and Month 18 .................. 103 
9.3.3 
Analysis of the Secondary Efficacy Objective: “Intake of ST at 12 and 18 
months” .............................................................................................................. 103 
9.3.3.1 
Secondary Efficacy Estimand: Time to ST initiation over 18 months .... 103 
9.3.3.2 
Secondary Efficacy Estimand: Intake of ST at 18 months ...................... 104 
9.3.3.3 
Other Secondary Efficacy Estimand: Intake of ST at 12 months ............ 105 
9.3.3.4 
Exploratory Efficacy Endpoint at 18 months .......................................... 106 
9.3.4 
Subgroup analyses ............................................................................................. 106 
9.3.5 
Center effects ..................................................................................................... 106 
9.4 
Planned safety and PK analyses ................................................................................. 106 
9.4.1 
Safety analyses ................................................................................................... 106 
9.4.2 
PK analyses ........................................................................................................ 106 
9.5 
Handling of ICEs, protocol deviations, and resulting missing data ........................... 107 
9.5.1 
ICEs potentially affecting the interpretation of measurements ......................... 110 
9.5.2 
ICEs potentially affecting the existence of measurements ................................ 111 
9.5.3 
Other protocol deviations .................................................................................. 112 
9.6 
Planned analysis at 12 months and data monitoring .................................................. 112 
9.7 
Determination of sample size ..................................................................................... 113 
9.7.1 
Primary efficacy estimand ................................................................................. 113 
9.7.2 
Power for key secondary efficacy estimand (MDS-UPDRS Part III) ............... 115 
9.7.3 
Power for secondary efficacy estimand (DaT-SPECT mean Striatum SBR) .... 115 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS. 116 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ....................... 116 
10.1.1 
Regulatory and ethical considerations ............................................................... 116 
10.1.2 
Financial disclosure ........................................................................................... 116 
10.1.3 
Informed consent process .................................................................................. 117 
10.1.4 
Data protection ................................................................................................... 118 
10.1.5 
Committees structure ......................................................................................... 118 
10.1.6 
Data quality assurance ....................................................................................... 118 
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10.1.6.1 
Case Report form completion .................................................................. 119 
10.1.6.2 
Apps ......................................................................................................... 119 
10.1.7 
Source documents .............................................................................................. 119 
10.1.8 
Study and site closure ........................................................................................ 119 
10.1.9 
Publication Policy .............................................................................................. 120 
10.2 
Appendix 2: Clinical Laboratory Tests ...................................................................... 121 
10.3 
Appendix 3: AEs – definitions and procedures for recording, evaluating, follow-up, 
and reporting .............................................................................................................. 123 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 129 
10.5 
Appendix 5: Genetics ................................................................................................. 133 
10.6 
Appendix 6: Liver safety – suggested actions and follow-up assessments ............... 134 
10.7 
Appendix 7: Wearable sensor AEs, adverse sensor effects, SAEs, and sensor 
deficiencies: definition and procedures for recording, evaluating, follow-up, and 
reporting ..................................................................................................................... 137 
10.8 
Appendix 8: Rapid Alert Procedures ......................................................................... 139 
10.9 
Appendix 9: Country-specific requirements .............................................................. 140 
10.9.1 
Specific requirements for Germany ................................................................... 140 
10.9.2 
Specific requirements for France ....................................................................... 140 
10.10 Appendix 10: Abbreviations and Trademarks ........................................................... 142 
10.11 Appendix 11: Protocol Amendment History ............................................................. 145 
10.11.1 
Amendment 5 (30 Jun 2023) ............................................................................. 145 
10.11.2 
Amendment 4 (24 Feb 2022) ............................................................................. 146 
10.11.3 
Amendment 3 (04 Oct 2021) ............................................................................. 151 
10.11.4 
Amendment 2 (21 May 2021) ............................................................................ 162 
10.11.5 
Amendment 1 (29 Oct 2020) ............................................................................. 162 
10.12 Appendix 12: In-clinic VME Investigator rating scale .............................................. 164 
11 REFERENCES .............................................................................................................. 168 
SPONSOR DECLARATION ................................................................................................ 171 
 
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LIST OF TABLES 
Table 4-1: 
Cmax and AUC and unbound (Cmax[u] and AUC[u]) UCB0599 exposures 
calculated on measured plasma protein binding in monkey or human 
plasma samples ................................................................................................ 45 
Table 4-2: 
UCB0599 exposure at pharmacological dose .................................................. 46 
Table 8-1: 
Anticipated serious adverse events for Parkinson’s disease population .......... 82 
Table 9-1: 
Overview of planned efficacy analyses ........................................................... 86 
Table 9-2: 
Overview of handling strategies for MDS-UPDRS ICEs and study 
termination ..................................................................................................... 108 
Table 10-1: 
Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments ..... 134 
 
LIST OF FIGURES 
Figure 7-1: 
Phase 2 liver chemistry stopping criteria and increased monitoring 
algorithm .......................................................................................................... 62 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title:  
A double-blind, placebo-controlled, randomized, 18-month Phase 2a study to evaluate the 
efficacy, safety, tolerability, and pharmacokinetics of oral UCB0599 in study participants with 
early Parkinson’s disease 
Short Title: 
A double-blind, placebo-controlled, randomized, Phase 2a study with oral UCB0599 in study 
participants with early Parkinson’s disease 
Rationale: 
UCB0599 is an orally available inhibitor of alpha-synuclein (ASYN) misfolding and 
downstream aggregation. Aggregated forms of ASYN are the hallmark fibrillar protein deposits 
in Parkinson’s disease (PD) and other synucleinopathies, and evidence suggests that it is the 
misfolded forms of ASYN that propagate through the central nervous system (CNS) during 
disease progression. These accumulations of ASYN-containing neuronal inclusions form Lewy 
bodies and Lewy neurites. 
Nonclinical and in vivo pharmacology studies have provided scientific evidence suggesting that 
UCB0599 may slow disease progression in PD, which remains the main unmet medical need in 
this condition. A first-in-human (FIH) study using UCB0599, UP0030, was conducted in healthy 
elderly participants. UP0030 provided the safety, tolerability, and pharmacokinetic (PK) 
information for single dose exposures up to 450mg and multiple dose exposures of 180mg/day 
for up to 21 days in healthy elderly participants (defined as ≥55 to ≤75 years of age). The first 
study in the target population, UP0077, provided safety, tolerability, and PK information for 
multiple dose exposures of 180mg/day and 360mg/day for 28 days in study participants with PD. 
UP0077 also provided information for the design of the current proof-of-concept (POC) study in 
study participants with early-stage PD. PD0053 is designed to provide proof of concept for the 
efficacy of the synuclein misfolding inhibitor UCB0599 in reducing disease progression in study 
participants with early-stage PD and to instruct later stage development. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy Objective 
To demonstrate the superiority of 
UCB0599 over placebo with 
regard to clinical symptoms of 
disease progression over 12 and 
18 months in participants 
diagnosed with early-stage PD 
Primary Efficacy Endpoint 
• MDS-UPDRS Parts I-III sum score 
(timeframe: Baseline to 18 months) 
Secondary Efficacy Endpoints 
• MDS-UPDRS Part III subscale (timeframe: Baseline 
to 18 months) 
• MDS-UPDRS Part III ePD subscore on selected items 
(timeframe: Baseline to 18 months) 
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Objectives 
Endpoints 
• MDS-UPDRS Part II subscale (timeframe: Baseline to 
18 months) 
• MDS-UPDRS Part I subscale (timeframe: Baseline to 
18 months) 
• Emerging symptoms as measured by MDS-UPDRS 
Part II (timeframe: Baseline to 18 months) 
• Time to worsening of the disease as measured by 
MDS-UPDRS Part III (timeframe: Baseline to 
18 months) 
• MoCA (timeframe: Baseline to 18 months) 
Exploratory Efficacy Endpoints 
• Time to worsening in MDS-UPDRS Part I subscale 
• Modified Hoehn and Yahr staging 
• CGII 
• CGIS 
• Fatigue-PRO 
• Early PD Function Slowness PRO 
• Early PD Mobility PRO 
• Composite endpoint (based on MDS-UPDRS and/or 
Early PD PROs)  
• PGIS, overall and fatigue-specific 
• PGIC, overall and fatigue-specific 
• SE-ADL 
• HADS 
• MDS-NMS 
• Starkstein Apathy Scale 
• EQ-5D-5L 
• Wearable sensor 
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Objectives 
Endpoints 
Secondary Efficacy Objectives 
To demonstrate the superiority of 
UCB0599 over placebo with 
regard to neurodegeneration of 
dopaminergic neurons over 12 
and 18 months in participants 
diagnosed with early-stage PD 
Secondary Efficacy Endpoints 
• Change from Baseline (Screening) in DaT-SPECT 
mean Striatum SBR (timeframe: Screening to 
18 months) 
Exploratory Efficacy Endpoints 
• DaT-SPECT mean SBR in striatal subregions 
• CSF total ASYN 
• CSF ASYN oligomers/seeding capacity 
To assess the effect of UCB0599 
vs placebo with regard to intake 
of ST over 18 months in 
participants diagnosed with 
early-stage PD 
Secondary Efficacy Endpoints 
• Time to start of ST (timeframe: Baseline to 
18 months) 
• ST intake (timeframe: Baseline to 18 months) 
Exploratory Efficacy Endpoints 
• Levodopa cumulative daily dose 
Primary Safety Objective 
To assess the safety and 
tolerability of UCB0599 in 
participants diagnosed with 
early-stage PD 
Secondary Safety Endpoints 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to participant withdrawal 
Other Safety Endpoints 
• Change from Baseline in clinical laboratory values 
(chemistry, hematology, and urinalysis) 
• Change from Baseline in vital signs 
• Change from Baseline in physical examination 
• Change from Baseline in neurological examination 
findings 
• C-SSRS findings 
• ECG findings 
Exploratory PK Objective 
To assess the PK of UCB0599 
and its N-oxide metabolite in 
participants diagnosed with 
early-stage PD 
Exploratory PK Endpoint 
• UCB0599 and N-oxide metabolite plasma and CSF 
concentrations 
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ASYN=alpha-synuclein; CGII=Clinical Global Impression of Improvement; CGIS=Clinical Global Impression of 
Severity; CSF=cerebrospinal fluid; C-SSRS=Columbia-Suicide Severity Rating Scale; DaT-SPECT=Dopamine 
Transporter Imaging with Single Photon Emission Computerized Tomography; ECG=electrocardiogram; 
ePD=early-stage PD; EQ-5D-5L=EuroQol-5-dimension-5-level; HADS=Hospital Anxiety and Depression Scale; 
MDS-NMS=Movement Disorder Society-Non-motor Scale; MDS-UPDRS=Movement Disorder Society-Unified 
Parkinson’s Disease Rating Scale; MoCA=Montreal Cognitive Assessment; PD=Parkinson’s disease; 
PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of Severity; PK=pharmacokinetic; 
PRO=Patient-Reported Outcome; SAE=serious adverse event; SBR=specific binding ratio; SE-ADL=Schwab and 
England Activities of Daily Living; ST=symptomatic treatment; TEAE=treatment-emergent adverse event 
Overall Design 
PD0053 is a randomized, double-blind, placebo-controlled, 18-month Phase 2a study to evaluate 
the efficacy, safety, tolerability, and PK of orally administered UCB0599 in study participants 
with early-stage PD who are not treated with symptomatic medications targeting motor 
symptoms of PD at the time of inclusion. The primary objective of the study is to demonstrate 
the superiority of UCB0599 over placebo with regard to clinical symptoms of disease 
progression over 12 and 18 months in this patient population. The difference between UCB0599 
and placebo will be evaluated for both the low and high doses of UCB0599 (180mg/day and 
360mg/day). The comparison of the high dose of UCB0599 with placebo will be considered as 
the primary evaluation. Oral UCB0599 capsules or matching placebo capsules will be 
administered twice per day (BID), approximately 12 hours apart.  
PD0053 includes a Screening Period (including, where available, a wearable sensor 
familiarization period for those participants who consent to its use), an 18-month Treatment 
Period (including, where available, a wearable sensor familiarization period for those 
participants who consent to its use after the Screening Period), and a Safety Follow-up (SFU) 
Period. Study participants who complete the Treatment Period will have the option to transition 
into a dose-blinded extension study, PD0055. In this case, participants will not enter the SFU 
Period of PD0053. 
The outcomes of this study will inform the design and dose selection for confirmatory studies, 
and help to further validate novel endpoints and technologies and support strategic development 
program decisions. 
Number of Participants 
Approximately 645 participants will be screened to achieve 450 participants randomly assigned 
to study medication and 429 evaluable participants, for an estimated total of 143 evaluable 
participants per treatment group. 
Treatment Groups and Duration 
PD0053 includes a Screening Period of 3 to 6 weeks, an 18-month Treatment Period, and an 
SFU Period of 1 month, for a total duration of approximately 21 months. PD0053 starts with 
participants randomized 1:1 to either UCB0599 360mg/day or placebo. Participants will be 
randomized to either UCB0599 360mg/day (180mg BID), UCB0599 180mg/day (90mg BID), or 
placebo when the IMP for low dose UCB0599 180mg/day (90mg BID) will be available to 
supply sites so that the final allocation ratio is 1:1:1.  
 
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1.2 
Schema 
 
BID=twice per day; D=day; DMC=Data Monitoring Committee; M=month; pts=participants; SFU=Safety Follow-up; V=Visit 
Note: All visits are in-clinic visits in France.  
Note: Visit 8a will be conducted as an unscheduled visit. 
 
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k In case of early termination of study medication, the DaT-SPECT will occur at EOT (End of Treatment), provided that the previous DaT-SPECT occurred 
more than 6 months prior to the EOT. There will be no DaT-SPECT assessment at M12 in Germany (for German-specific requirements, please refer to 
Section10.9, Appendix 9). 
l Participants have the opportunity to opt out of CSF sampling; however, the aim is to collect samples from at least 50 participants/arm. For those participants 
undergoing CSF sampling at Visit 2, sampling at M12 is mandatory, while sampling at EOT is optional. The CSF sampling should all occur at the same time of 
the day and should be timed with blood sampling. These samples should be collected only after all other assessments of the visit have been performed. 
m All ECG recordings will be performed in triplicate with no more than 2 minutes separating recordings, and the study participant should be resting in the supine 
position for at least 10 minutes before recording. 
n The visits at Days 0, 10, 30, 60, 120, 240, 360, 480, and 540 require blood sampling for the purpose of UCB0599 concentration determination. In case the visit 
is scheduled for up to 11:00 in the morning, study participants will be asked to take their study medication during the site visit after the first blood sample is 
collected, measuring trough drug concentration. Importantly, 2 blood samples must be collected: one immediately prior to study medication intake (maximum 
of 15 minutes) and 1 sample between 1 to 6 hours after study medication intake. Clinical staff is encouraged to take the blood samples for PK analysis at the 
scheduled time window; however, deviations from the scheduled sample times are not considered protocol deviations. The exact time and date of the blood 
draw as well as study medication intake must be recorded using an unambiguous format such as DD MON YYYY and HH:MM using a 24-hour clock. Ideally, 
sampling should be conducted on the same day of each week at approximately the same time after study medication. 
o In case the visit is scheduled before 11:00am, study participants will be asked to take their study medication during the site visit after the blood sample is 
collected. Blood samples will be drawn at the same time of the sampling for clinical laboratory tests. The time and date of collection will be recorded in the 
eCRF. 
p  Pregnancy test only for women of child-bearing potential (for France-specific requirements, please refer to, Section 10.9 Appendix 9). 
q The Visit 3 pregnancy test must be performed before the study participant receives study medication. 
r Monitored by Sponsor/clinical site but not captured in the EDC. 
s Participants consenting to its use will receive the wearable sensor for 2 to 3 weeks for familiarization at home to address potential technical issues and to collect 
stable Baseline data. The frequency of the Virtual Motor Exam will be changed thereafter to weekly on the wearable sensor by the Investigator at the next visit. 
Please refer to Section 8.1.3 for further guidance on the wearable sensor. These data will be entered into the EDC system. 
t To be performed after MDS-UPDRS Part III (applicable only to the participants wearing the sensor). 
u Randomization should only occur after all results from Visit 1 and Visit 2 are available and assessed.  
v First day of UCB0599 administration will be the evening of the BL Visit (Day 0); last administration will be in the morning of the EOT Visit (Day 540). 
w Visit 8a will be conducted as an unscheduled visit. 
 
 
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2 
INTRODUCTION 
2.1 
Study Rationale 
UCB0599 is an orally available inhibitor of ASYN misfolding and downstream aggregation. 
Aggregated forms of ASYN are the hallmark fibrillar protein deposits in Parkinson’s 
disease (PD) and other synucleinopathies, and evidence suggests that it is the misfolded forms of 
ASYN that propagate through the CNS during disease progression. These accumulations of 
ASYN-containing neuronal inclusions form Lewy bodies and Lewy neurites. 
Nonclinical and in vivo pharmacology studies have provided scientific evidence suggesting that 
UCB0599 may slow disease progression in PD, which remains the main unmet medical need in 
this condition. A FIH study using UCB0599, UP0030, was conducted in healthy elderly 
participants. UP0030 provided the safety, tolerability, and PK information for single dose 
exposures up to 450mg and multiple dose exposures of 180mg/day for up to 21 days in healthy 
elderly participants (defined as ≥55 to ≤75 years of age). The first study in the target population, 
UP0077, provided safety, tolerability, and PK information for multiple dose exposures of 
180mg/day and 360mg/day for 28 days in study participants with PD. UP0077 also provided 
information for the design of the current POC study in study participants with early-stage PD. 
PD0053 is designed to provide proof of concept for the efficacy of the synuclein misfolding 
inhibitor UCB0599 in reducing disease progression in study participants with early PD and to 
instruct later stage development. 
2.2 
Background 
Parkinson’s disease is a progressive neurodegenerative disorder that presents with a spectrum of 
motor and non-motor signs and symptoms. The mean age at onset is 60 years. The incidence of 
PD is approximately 20/100,000 persons per year; however, it is much higher in the population 
aged 65 years or older (>100/100,000 persons per year) (Twelves et al, 2003). Similarly, the 
prevalence of PD increases with age. It is estimated to be 1.4% in the population aged 55 years 
or older and 4.3% in the population aged 85 years and older (de Rijk et al, 1995). 
The clinical diagnosis of PD relies on the presence of the cardinal motor signs: bradykinesia, 
rigidity, tremor, and postural instability. However, non-motor symptoms such as loss of smell, 
depression, constipation, and rapid eye movement sleep behavior disorder can occur several 
years before the onset of motor symptoms. 
Early PD is characterized by mild, manageable motor symptoms that may not require 
symptomatic treatment (ST), or that show a good response to levodopa, which represents the 
standard of care. Other commonly used standard of care medications include dopamine agonists, 
monoamine oxidase B inhibitors, and catechol-O-methyl transferase inhibitors. As PD 
progresses, the motor and non-motor symptoms become more bothersome, and patients may start 
experiencing motor complications. After 2 to 5 years of treatment with levodopa, 30% to 50% of 
patients develop motor fluctuations. Advanced PD is characterized by marked motor disability 
with loss of independent ambulation. After ≥10 years since onset, most patients suffer from 
difficult-to-treat motor symptoms (eg, falls, freezing of gait, dysarthria, and dysphagia) and from 
non-motor symptoms for which treatment options are limited (eg, dementia, psychosis, 
depression, autonomic dysfunction, and pain). Patients are often bedridden after 10 to 14 years 
(Poewe, 2006). To this day, slowing disease progression remains the main unmet medical need 
in PD. 
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Parkinson’s disease is pathologically characterized by the loss of dopaminergic neurons in the 
substantia nigra, associated with ASYN pathology (neuronal cytosolic inclusions called Lewy 
bodies which consist of misfolded, pathological aggregates of ASYN). Although the majority of 
PD cases are sporadic, a small proportion are caused by mutations in PD-related genes, including 
copy number variations and point mutations of the ASYN-coding gene (SNCA) (Siddiqui et 
al, 2016). The gene copy number variations are of particular interest, as they indicate that an 
increased frequency of the wild-type ASYN is sufficient to cause PD. This is further reinforced 
by the observations in families with SNCA copy number variations where the pathogenic effect 
depends on the gene dosage (Devine et al, 2011). Furthermore, single nucleotide polymorphisms 
in SNCA that have been associated with PD in genome-wide association studies have been shown 
to increase ASYN expression, highlighting the relevance of genetic variation in SNCA in 
sporadic PD (Soldner et al, 2016; Nalls et al, 2014). The 140-amino acid ASYN protein is highly 
expressed in the brain but is also found in the cerebrospinal fluid (CSF) and periphery (ie, red 
blood cells and plasma). As an intrinsically disordered protein, ASYN exists in a soluble 
monomeric form in the cytoplasm and in the extracellular compartment. When it adopts a 
partially ordered, extended helical structure, ASYN also has a natural affinity for membranes, 
such as synaptic vesicles. Under certain conditions, ASYN can convert into oligomeric, 
beta-sheet rich structures where such aggregation is driven through the central region of the 
molecule, rich in hydrophobic residues (residues 61 to 95) known as the nonamyloid beta 
component region. These oligomeric structures are believed to be the toxic species responsible 
for the spread of pathology from neuron to neuron (Chen et al, 2015). Treatments that prevent 
misfolding and aggregation of ASYN may slow the neurodegeneration in PD, resulting in slower 
progression of motor symptoms, thus providing a therapeutic benefit to patients with PD. 
UCB0599 is an orally available inhibitor of ASYN misfolding and downstream ASYN 
aggregation. Nonclinical pharmacology studies have provided evidence that UCB0599 inhibits 
ASYN misfolding in the presence of lipid membranes. In vivo pharmacology studies 
demonstrated that UCB0599 reduced total brain ASYN levels as well as proteinase K-resistant 
(ie, aggregated) ASYN in a transgenic mouse model overexpressing SNCA. Moreover, it reduced 
glial fibrillary acidic protein, a marker of neuroinflammation, and normalized dopamine 
transporter loss observed in this model, which are both considered a functional consequence of 
ASYN aggregation. These data suggest UCB0599 may slow neurodegeneration in PD, resulting 
in slower disease progression, thus providing a therapeutic benefit to patients with PD. To date, 
slowing PD disease progression remains the main unmet medical need in PD. 
UCB0599 has not been approved by any health authorities worldwide as of the date of this 
document. UCB has conducted five Phase 1 clinical studies to support the development of 
UCB0599: 1 study, conducted with the UCB1332 racemate and a single microdose of the 
UCB0599 R-enantiomer (UP0023), and 4 studies with UCB0599 administration at clinically 
relevant doses (UP0030, TM0017, UP0077, and UP0078). 
In the UCB0599 Phase 1 clinical development program, UP0023, UP0030, TM0017, and 
UP0077 demonstrated that UCB0599 has good PK properties (dose-exposure linearity, rapid 
absorption, t½ of approximately 11 to 13 hours, and no time-dependent PK behavior observed) 
and an acceptable safety and tolerability profile for further clinical development. UP0078 
demonstrated that food had a minimal effect on the PK profile for UCB0599. Coadministration 
of the strong cytochrome P450 3A4 (CYP3A4) inhibitor, itraconazole, had a significant effect on 
UCB0599 disposition, demonstrating a strong drug-drug interaction effect. Further information 
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regarding UP0023, UP0030, TM0017, UP0077, and UP0078 is provided in the Investigator’s 
Brochure (IB). UP0030, UP0077, and UP0078 provide the primary UCB0599 clinical safety and 
clinical pharmacology data to date. 
2.3 
Benefit/Risk assessment 
To date, there are no approved ‘neuroprotective’ and/or ‘disease-modifying’ treatments to stop or 
slow disease progression of PD, which remains a large unmet medical need. 
UCB0599 acts at an early-stage of ASYN aggregation by inhibiting the initial nucleation event 
or seed formation by inhibiting misfolding; therefore, it may halt the progression of PD vs only 
treating the symptoms. The outcome of this study will support the development of a medication 
that may provide a potential benefit for patients with PD. 
Drug hypersensitivity is an important identified risk. Other potential risks include: hepatotoxicity 
(based on clinical data) and cardiac effects. Renal laboratory abnormalities are also kept under 
close safety monitoring. 
In Phase 1 development of UCB0599, 5 studies (UP0030, TM0017, UP0023, UP0077, and 
UP0078) demonstrated that UCB0599 has acceptable safety, PK, and tolerability profiles for 
further clinical development. Overall, the majority of treatment-emergent adverse events 
(TEAEs) were mild or moderate in intensity and resolved. In UP0030, 2 events of 
hypersensitivity were reported. An additional 2 events of hypersensitivity occurred in study 
participants who received UCB0599 in UP0077. A causal relationship between the reported 
events of drug hypersensitivity and UCB0599 is considered plausible. The hypersensitivity 
reactions are further described in the IB. 
There have been no reports of anaphylaxis in the UCB0599 clinical program. 
As a result of these clinical data, drug hypersensitivity is now considered an important identified 
risk by the Sponsor and, therefore, further measures of risk monitoring and minimization are 
included. Sites will be informed and trained appropriately about the risk of a hypersensitivity 
reaction (such as rash, angioedema, or anaphylaxis) and the actions that need to be taken in case 
of hypersensitivity reaction. The participant will be informed by the Investigator during the 
consent procedure about the risk of a hypersensitivity reaction (such as rash, angioedema, or 
anaphylaxis) and other important potential risks for UCB0599. Risk mitigation measures include 
using a standard approach of (1) obtaining a detailed history of the hypersensitivity reaction and 
its evolution, (2) response with appropriate treatment, if needed, (3) a detailed physical 
examination, regular monitoring of vital signs, and (4) the addition of a guidance for the 
evaluation of suspected hypersensitivity reactions (please refer to Section 8.3.6.1) and reporting 
of the suspected hypersensitivity reaction as an adverse event of special interest (AESI). 
To monitor the potential risk of hepatotoxicity, monthly routine liver function tests are mandated 
during the first 6 months of treatment for study participants who receive multiple doses of study 
medication (see Schedule of Activities, Section 1.3). In addition, any cases meeting Hy´s law 
criteria must be reported as an AESI. Sites will be informed and trained appropriately. 
2.3.1 
Coronavirus Disease-2019 benefit/risk assessment 
UCB0599 is not known to exert an effect on the immune or respiratory systems, and its 
mechanism of action is not linked to immune or respiratory system agonism or inhibition. 
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To date, no increased risk of infection or respiratory problems has been identified in association 
with clinical UCB0599 administration. No such risks have been identified through regular 
review of published literature. PD0053 will include study participants with early-stage PD from 
40 up to and including 75 years of age (the mean age of onset of PD is 60 years of age). A 
similar population was exposed to UCB0599 in the Phase 1 clinical program. 
Although there is some evidence that severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2) might affect the CNS, there is no reason to assume on the basis of the 
mechanism of action that UCB0599 will have any substantial effect to worsen a Coronavirus 
Disease-2019 (COVID-19) disease or increase the risk of CNS and other complications in case a 
study participant with PD acquires SARS-CoV-2. There is no evidence that ASYN plays a role 
in immunological pathways of the CNS. Furthermore, there is no reason to assume that 
UCB0599 may enhance the infection risk or the disease manifestation. 
Therefore, UCB0599 is not expected to pose an additional risk of complications or poor 
prognosis of COVID-19. 
Considering the mechanism of action, the inclusion and exclusion criteria, and other risk 
mitigation, the risk from COVID-19 vaccination to study participants in PD0053 is not expected 
to be significantly different from the general population of individuals with PD. The benefit-risk 
profile of UCB0599 in PD0053 in the context of COVID-19 vaccination remains positive.  
Consequently, there are no restrictions on COVID-19 vaccination during PD0053 (ie, study 
participants should be free to receive COVID-19 vaccination as per local or national 
guidance/regulations). 
2.3.1.1 
COVID-19 risk mitigation measures 
• Current national laws and local recommendations for the prevention and control of the 
pandemic will be strictly adhered to. 
• This study will commence enrollment only when the Sponsor and contract research 
organization (CRO) both deem it is safe to do so. UCB is conducting ongoing assessments to 
approve which countries are suitable to conduct studies based on pandemic infection rates, 
country-level governmental status, Health Authority requirements, patient safety, study 
medication supply, CRO and site staff availability, local site level restrictions or guidance, 
and laboratory services. Individual sites in approved countries will be activated based upon a 
site-level review conducted by the study team. This review will confirm that these sites can 
conduct the study as per protocol and allow on-site monitoring or make remote 
monitoring feasible. 
• Participants will be closely monitored for and encouraged to report any signs and symptoms 
of COVID-19. The Investigator will consider the individual benefit/risk of the study 
participant upon identification of any signs and symptoms of COVID-19 infection 
(eg, continuation of dosing, site visits). 
• COVID-19 testing by optional laboratory assessment will be conducted based on availability 
and other practical considerations (eg, test capacity and turnaround time) of approved tests 
and at the Investigator’s discretion. The Investigator will consider the individual benefit/risk 
of the study participant in case of a positive COVID-19 test. 
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• The possibility of virus transmission will be controlled as much as possible by: 
− Advising participants to adhere to local requirements for reduction of exposure to the 
public while ambulatory. 
− Advising participants to adhere to clinical site requirements for reduction of exposure 
while at the site or interacting with site staff. This advice will be included in the informed 
consent form (ICF). 
• To reduce the risk of exposure during the study, consideration will be given to replace more 
site visits with telemedicine and home visits when feasible (eg, when only blood tests, 
physical examinations, and the collection of adverse events (AEs) are planned). 
• COVID-19 testing for clinical staff will be conducted if required by local guidelines. 
2.3.1.2 
COVID-19 benefit/risk conclusion 
Considering the mechanism of action of UCB0599, the inclusion and exclusion criteria, and the 
measures to mitigate risks described in this protocol, the risk to study participants in PD0053, 
both in terms of exposure to SARS-CoV-2 and morbidity from COVID-19, is not expected to be 
significantly different from the general population of individuals with PD. 
2.3.2 
Wearable sensor regulatory classification 
In the EU and Canada, the wearable sensor is an investigational product exclusively for research 
use in this clinical trial. It is manufactured by Verily Life Science LLC, and is not intended to be 
used to make any diagnosis or treatment decisions or for any individual benefit of the participant 
during the course of the PD0053 study.  
In the US, the wearable sensor is considered to be exempt from Investigational Device 
Exemption regulations as the data from the wearable sensor is not shared with the study 
participant or study investigator. Further, this classification assumes that the data generated by 
the wearable sensor is used for exploratory/research hypothesis generating purposes only and not 
used during patient clinical management. Moreover, the wearable sensor does not pose 
significant health risks to study participants (please refer to Section 2.3.3.2 for further details).  
2.3.3 
Wearable sensor benefit/risk assessment 
2.3.3.1 
Potential benefits 
The wearable sensor may make an evaluation of digital measurements for aspects of motor 
function, sleep, and neurovegetative parameters in real life possible, without requiring study 
participants to visit a clinical site. The wearable sensor in PD0053 is a noninvasive watch that 
will not guide diagnosis or therapy. 
2.3.3.2 
Potential risks of the wearable sensor 
Sensor electrodes on the wearable sensor are made with stainless steel to minimize potential skin 
reaction. Some parts of the sensor have a small amount of nickel which could irritate the skin due 
to nickel or metal jewelry allergy. Participants with known severe allergies to nickel or metal 
jewelry should not wear the wearable sensor. 
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The electronic case report form (eCRF) requires the Investigator to indicate whether there is a 
likely causal relationship between the wearable sensor and an AE. 
The types of risks the study participants will encounter from wearing the wearable sensor are 
similar to those of wearing commercially available smart watches. These may include: 
• Pruritus 
• Dry skin 
• Mild redness 
• Mild rash 
• Swelling at the site of the sensor 
These risks are considered anticipated sensor-related AEs that will also be collected as part of the 
PD0053 clinical study. 
The wearable sensor may generate electromagnetic interference because of static magnetic fields, 
radio frequency emissions, and applied voltages, and the sensor’s charging dock contains small 
magnets that could potentially affect implantable medical electronic devices such as cardiac 
pacemakers, implantable defibrillators, and medical pumps. The wearable sensor (while not worn 
on the wrist), the charging dock, and the wearable sensor hub should be kept at least 6 inches 
from any implantable device. Study participants with any implantable medical device are 
excluded from wearing the wearable sensor. This information is also relevant for people living in 
the same place as the study participant. People living in the same place should follow the 
wearable sensors instructions for use and should contact their healthcare provider if they have 
concerns regarding their implanted device during the study. 
The wearable sensor display is made of glass and may break under significant impact or falls. 
If participants experience discomfort, they should be instructed to stop wearing the wearable 
sensor and contact the study team. Any skin irritation should be allowed to clear up before 
returning the sensor (at the discretion of the Investigator) to the same wrist. 
Participants should be instructed to clean the wearable sensor bands often to remove any 
perspiration that may build up on the bands. Minimizing moisture on the bands may reduce the 
potential for skin complications such as irritation or rash. 
The wearable sensor is not waterproof. Participants should not soak or submerge the wearable 
sensor to avoid dysfunction. 
2.3.3.2.1 
Potential Wearable Sensor Hub risks 
The Wearable Sensor Hub is a connectivity bridge that allows compatible wearable sensor 
devices to upload user data to the Sensor Suite. The Wearable Sensor Hub does not control or 
alter the functions or parameters of the connected wearable sensor. The participant risks arising 
from potential breaches in data privacy and cybersecurity during data transfer from the wearable 
sensor to the Wearable Sensor Hub and then to the Verily Cloud Server have been mitigated 
through a Privacy Impact Analysis and Web Application Security (Penetration) testing. 
The Wearable Sensor Hub has been tested and found to comply with the limits for a Class B 
digital sensor, pursuant to Part 15 of the Federal Communications Commission Rules. For people 
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with a cardiac pacemaker, implantable defibrillator, medical pump, or other implantable medical 
electronic device who live in the same place as a study participant, it is important to be aware 
that the Wearable Sensor Hub may use wireless signals like Bluetooth, Wi-Fi, and cellular 
connections that could potentially affect their implantable medical electronic device. Participants 
with any implantable medical device are excluded from using the wearable sensor. 
The Wearable Sensor Hub is not waterproof. To avoid dysfunction, participants should not soak 
or submerge the Wearable Sensor Hub. 
The Wearable Sensor Hub may overheat at high temperatures. Participants should keep the 
Wearable Sensor Hub out of direct heat and in a well-ventilated environment. 
2.3.3.3 
Wearable sensor benefit/risk conclusion 
Based on the information available to UCB and given the unmet medical need, potential for 
benefit, risks, and risk mitigation measures, the benefit-risk for inclusion of the wearable sensor 
in PD0053 is considered positive. Considering the risk mitigation measures in place, the 
wearable sensor does not pose significant risks to study participants. Risks are similar to those of 
commercially available smart watches. The overall residual risk is acceptable for the sensor’s 
intended use in investigational clinical studies. 
2.3.4 
Overall benefit/risk conclusion 
The Sponsor will immediately notify the Investigator and Regulatory Agencies if any important 
clinically relevant information becomes available during the study. 
Given the current evidence, based on the scientific rationale, nonclinical data, and limited human 
data, the important unmet medical need in patients with PD, and the appropriate risk 
communication, monitoring, and minimization measures to be implemented, the Sponsor 
considers the benefit-risk profile for UCB0599 to be acceptable for further clinical development. 
More detailed information about the known and expected benefits and risks and expected 
adverse events of UCB0599 may be found in the IB and ICF. 
3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Efficacy Objective 
To demonstrate the superiority of 
UCB0599 over placebo with 
regard to clinical symptoms of 
disease progression over 12 and 
18 months in participants 
diagnosed with early-stage PD 
Primary Efficacy Endpoint 
• MDS-UPDRS Parts I-III sum score 
(timeframe: Baseline to 18 months) 
Secondary Efficacy Endpoints 
• MDS-UPDRS Part III subscale (timeframe: Baseline 
to 18 months) 
• MDS-UPDRS Part III ePD subscore on selected items 
(timeframe: Baseline to 18 months) 
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Objectives 
Endpoints 
• MDS-UPDRS Part II subscale (timeframe: Baseline to 
18 months) 
• MDS-UPDRS Part I subscale (timeframe: Baseline to 
18 months) 
• Emerging symptoms as measured by MDS-UPDRS 
Part II (timeframe: Baseline to 18 months) 
• Time to worsening of the disease as measured by 
MDS-UPDRS Part III (timeframe: Baseline to 
18 months) 
• MoCA (timeframe: Baseline to 18 months) 
Exploratory Efficacy Endpoints 
• Time to worsening in MDS-UPDRS Part I subscale 
• Modified Hoehn and Yahr staging 
• CGII 
• CGIS 
• Fatigue-PRO 
• Early PD Function Slowness PRO 
• Early PD Mobility PRO 
• Composite endpoint (based on MDS-UPDRS and/or 
Early PD PROs) 
• PGIS, overall and fatigue-specific 
• PGIC, overall and fatigue-specific 
• SE-ADL 
• HADS 
• MDS-NMS 
• Starkstein Apathy Scale 
• EQ-5D-5L  
• Wearable sensor 
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Objectives 
Endpoints 
Secondary Efficacy Objectives 
To demonstrate the superiority of 
UCB0599 over placebo with 
regard to neurodegeneration of 
dopaminergic neurons over 12 
and 18 months in participants 
diagnosed with early-stage PD 
Secondary Efficacy Endpoints 
• Change from Baseline (Screening) in DaT-SPECT 
mean Striatum SBR (timeframe: Screening to 
18 months) 
Exploratory Efficacy Endpoints 
• DaT-SPECT mean SBR in striatal subregions 
• CSF total ASYN 
• CSF ASYN oligomers/seeding capacity 
To assess the effect of UCB0599 
vs placebo with regard to intake 
of ST over 18 months in 
participants diagnosed with 
early-stage PD 
Secondary Efficacy Endpoints 
• Time to start of ST (timeframe: Baseline to 18 
months) 
• ST intake (timeframe: Baseline to 18 months) 
Exploratory Efficacy Endpoints 
• Levodopa cumulative daily dose 
Primary Safety Objective 
To assess the safety and 
tolerability of UCB0599 in 
participants diagnosed with 
early-stage PD 
Secondary Safety Endpoints 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to participant withdrawal 
Other Safety Endpoints 
• Change from Baseline in clinical laboratory values 
(chemistry, hematology, and urinalysis) 
• Change from Baseline in vital signs 
• Change from Baseline in physical examination 
• Change from Baseline in neurological examination 
findings 
• C-SSRS findings 
• ECG findings 
Exploratory PK Objective 
To assess the PK of UCB0599 
and its N-oxide metabolite in 
participants diagnosed with 
early-stage PD 
Exploratory PK Endpoint 
• UCB0599 and N-oxide metabolite plasma and CSF 
concentrations 
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ASYN=alpha-synuclein; CGII=Clinical Global Impression of Improvement; CGIS=Clinical Global Impression of 
Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; CSF=cerebrospinal fluid; DaT-SPECT=Dopamine 
Transporter Imaging with Single Photon Emission Computerized Tomography; ECG=electrocardiogram; 
ePD=early-stage PD; EQ-5D-5L=EuroQol-5-dimension-5-level; HADS=Hospital Anxiety and Depression Scale; 
MDS-NMS=Movement Disorder Society Non-motor Scale; MDS-UPDRS=Movement Disorder Society-Unified 
Parkinson’s Disease Rating Scale; MoCA=Montreal Cognitive Assessment; PD=Parkinson’s disease; 
PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of Severity; PK=pharmacokinetic; 
PRO=Patient-Reported Outcome; SAE=serious adverse event; SBR=specific binding ratio; SE-ADL=Schwab and 
England Activities of Daily Living; ST=symptomatic treatment; TEAE=treatment-emergent adverse event 
4 
STUDY DESIGN 
4.1 
Overall design 
PD0053 is a randomized, double-blind, placebo-controlled, 18-month Phase 2a study to evaluate 
the efficacy, safety, tolerability, and PK of orally administered UCB0599 in study participants 
with early PD who are not treated with symptomatic medications targeting motor symptoms of 
PD at the time of inclusion. Oral UCB0599 capsules or matching placebo capsules will be 
administered BID, approximately 12 hours apart. The primary objective of the study is to 
demonstrate the superiority of UCB0599 over placebo with regard to clinical symptoms of 
disease progression over 12 and 18 months in this patient population. The difference between 
UCB0599 and placebo will be evaluated for both the low and high doses of UCB0599 
(180mg/day and 360mg/day). The comparison of the high dose of UCB0599 with placebo will 
be considered as the primary evaluation. If the comparison of the low dose and placebo gives a 
positive result on the primary estimand but the comparison of the high dose and placebo does 
not, these results will have to be interpreted with caution. In all analyses, the 2 dose levels will 
be assessed separately against placebo, there will be no pooling of the 2 dose levels, and they 
will not be compared to each other.  
PD0053 includes a Screening Period of 3 to 6 weeks (including where available, a wearable 
sensor familiarization period for those participants who consent to its use), an 18-month 
Treatment Period (including, where available, a wearable sensor familiarization period for those 
participants who consent to its use after the Screening Period), and an SFU Period of 1 month. 
Study participants who complete the Treatment Period will have the option to transition into a 
dose-blinded extension study (PD0055). In this case, participants will not enter the SFU Period 
of PD0053. 
The outcomes of this study will inform the design and dose selection for confirmatory studies, 
and help to further validate novel endpoints and technologies and support strategic development 
program decisions. 
4.1.1 
Decentralized model 
The study will be conducted utilizing a partly decentralized model, ie, study visits may be 
composed of a combination of onsite visits and remote visits (except in France; for 
France-specific requirements, please refer to Section 10.9 Appendix 9). During remote visits, 
study assessments will be conducted with the study participant from his/her home. This is 
offered in order to reduce study participant burden and encourage greater study participation. 
In a decentralized model, video communication technology will be integrated into the clinical 
research process to support management of research activities, including data collection, and 
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providing study participants with a channel for direct feedback. Qualified and trained mobile 
healthcare personnel (ie, a qualified research nurse) may visit the study participant’s/caregiver’s 
home to complete certain study assessments (refer to the Schedule of Activities in Section 1.3). 
Some of the assessments performed during the remote visits may be conducted without direct 
observation by the Investigator; these are standard examinations and sampling for analysis that 
will be performed by the research nurse. The other assessments that are important for the 
evaluation of efficacy endpoints in the study require direct observation and instruction by the 
Investigator through the use of telemedicine technology. Please refer to Section 8 for 
specifications of all assessments planned in the study. The research nurse and Investigator will 
discuss all observations and findings during the remote visits. In case an observation (eg, an AE) 
requires follow up at the clinic, an unscheduled visit should be performed. Also, in case a 
research nurse is not available to perform a scheduled remote visit, eg, due to COVID-19 related 
contact and transportation restriction or other circumstances, a remote visit may be changed to a 
clinic visit. In addition, clinic visits can be changed to remote visits for reasons noted in 
Section 4.1.2. 
Video and communication technology will be provided for interactions among the Investigator, 
mobile healthcare personnel (research nurse), and study participants/caregivers for remote visits. 
The technology will allow for direct communication of the participant with the site staff.  
Where feasible, all data will be collected electronically using purpose-built technology and will 
be monitored remotely by clinical research associates while complying with all data privacy 
standards. Original paper source, eg, electrocardiogram (ECG) readings, will be provided to the 
clinical site for the source document filing shortly after completion of the remote visit. 
4.1.2 
Study conduct due to COVID-19 
The protocol-mandated visit schedule (Section 1.3) should be followed to the extent possible, 
considering the individual benefit-risk assessment by the Investigator. Where adherence to the 
protocol schedule of assessments is not possible, the Sponsor should be made aware of the 
details. If necessary, and after discussion with the Sponsor, clinic visits may be turned into 
remote visits and/or the study participants or caregivers will be contacted by telephone or 
videoconference. Ad hoc study participant contact may be warranted to understand the current 
health status of the study participants, to follow up on AEs, and inform them of any protective 
measures taken by the clinical site as a result of the COVID-19 pandemic (eg, any measures that 
may limit access to the site or may require additional actions by the study participant prior to 
entry to the site). 
Investigators and study coordinators may use discretion when determining the need to perform a 
home visit (safety laboratory parameters, PK samples), but will need to inform the Sponsor. 
If a participant needs to be discontinued and cannot come into the clinic, then appropriate 
instructions will be provided, and a visit will be scheduled to perform safety assessments as soon 
as possible. 
In situations where a study participant is unable to return to the study site, Investigators will 
assess and document the study participant’s safety via telephone contact and/or videoconference. 
Based on information gathered from the telephone contact, Investigators will confirm whether 
the participant could continue the current study medication based upon the outcome of the safety 
assessment. Study participants’ agreement to implement this procedure should be obtained and 
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documented prior to implementing any changes. Changes in the study medication supply in this 
situation are described in Section 6.2. 
If a study participant visits another facility for a medical issue (or has to switch sites for a 
COVID-19-related reason), the Investigator should request contact with the physician providing 
care to provide a detailed explanation of the study participant’s condition and his/her 
participation in the clinical study. Study participants or caregivers shall be reminded to collect 
and keep complete records of this visit. 
If laboratory assessments cannot be conducted via the central laboratory vendor due to restricted 
site access and home visits by study health care providers are not an option, local laboratory 
safety assessments may need to be conducted in a format that allows the Investigator to 
receive/review these results and include them as source documentation. 
Deviations to data collection including inability to perform any assessments, such as ECG, blood 
collection for safety laboratory assessments and PK, or alternative methods of assessment, such 
as phone calls, should be recorded in the source documentation and notated as “not done” in the 
eCRF. 
4.2 
Scientific rationale for study design 
The main objective of PD0053 is to provide POC for the efficacy of the ASYN misfolding 
inhibitor UCB0599 in reducing disease progression in study participants with early-stage PD, 
and to instruct later stage development. The ultimate goal is to provide novel treatment options to 
PD patients which have the potential to modify the progression of the disease. 
Two types of data supporting an intervention as a Disease Modification Therapy have been 
identified (Cummings, 2017): 
1. The intervention produces a significant drug-placebo difference on accepted clinical 
outcome(s), AND has a consistent effect on (fluid or imaging) biomarkers considered 
reflective of the fundamental pathophysiology of a neurodegenerative disease (NDD), ie, 
neurodegeneration. 
2. The intervention produces a positive outcome on a randomized-start clinical study design 
consistent with an enduring (positive) change (ie, treatment effect) in the clinical course of 
disease. 
In both cases, slowing of disease progression on clinical measures is evident; in the former, 
biological evidence of disease modification (DM) supports the clinical measures. 
To this aim, the proposed study, PD0053, is a Phase 2a study with a double-blind parallel-group, 
placebo-controlled design and a treatment duration of 18 months. 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
Parts I-III sum score, the primary clinical outcome, is the best-established functional scale to 
evaluate disease progression in PD populations and to assess the effect of STs. In the case of 
drugs with the potential of slowing disease progression in this population, MDS-UPDRS would 
have considerable limitations if applied as a solitary and standalone endpoint. As it is currently 
the best characterized and most widely used scale, MDS-UPDRS will have a prominent role in 
this study to assess the effect of UCB0599 in delaying the progression of clinical symptoms; 
however, it is understood that it almost exclusively captures neuromotor dysfunction and thus in 
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isolation would not have the bandwidth to provide a holistic picture of disease progression. To 
address this limitation and to ensure a more holistic view, the suggested POC study incorporates 
multiple measures and scales capturing non-motor domains (including cognition and 
neurovegetative function). 
Evaluation of how study participants feel and function through the use of patient-reported 
outcome (PRO) measures has become an increasingly important component of therapeutic 
assessment. In an effort to best measure the patient perception of motor and non-motor signs and 
their impact in early-stage PD, UCB, together with the patient organizations Parkinson’s UK and 
Parkinson Foundation USA, has collaborated on large patient-centered research to define an 
optimized PRO strategy for the context of use of early-stage PD. Research findings across over 
50 patients and 10 caregivers highlighted that bradykinesia (particularly function slowness), 
tremor, rigidity/stiffness, mobility (particularly gait and upper limb issues), and fatigue are the 
cardinal concepts of interest in early-stage PD. Research outcomes also suggested that the legacy 
PROs traditionally used in clinical research may not be fit for purpose in early-stage PD, as most 
of them were developed for use in later stages of disease. As a result, UCB developed with 
patients an exploratory set of novel PROs for early-stage PD, composed of: the Early 
Parkinson’s Disease Function Slowness PRO, the Early Parkinson’s Disease Mobility PRO, and 
Fatigue-PRO. UCB hypothesizes that this exploratory PRO strategy will generate interpretable 
PRO data for the demonstration of treatment benefit in early-stage PD patients and adequately 
complement MDS-UPDRS evidence. It is intended to test the new UCB PRO strategies in 
PD0053 as exploratory endpoints. 
Rescue medication currently available for PD patients, namely levodopa and other dopamine 
agonists, will interfere with motor symptoms and therefore bias any MDS-UPDRS measures 
collected postinitiation of rescue medication. The intention with this study is to provide a 
measure of the effect of UCB0599 on the MDS-UPDRS clinical scale, free of confounding by 
rescue medication. However, for all scheduled visits, study participants that do start to receive 
ST over the study observation period will be asked to refrain from taking ST for at least 12 hours 
before the clinic visit and to bring the medication to the site. Please refer to Section 6.5.3 for 
further details. 
To assess neurodegeneration, the biomarker Dopamine Transporter Imaging with Single Photon 
Emission Computed Tomography (DaT-SPECT) will be used, which is the best-established in 
vivo method to monitor dopaminergic neurodegeneration. It has been reported in the literature 
that DaT-SPECT results are not impacted (or are only marginally impacted) by using the ST 
(Ikeda et al, 2019). Therefore, DaT-SPECT will be used as an assessment in the study to identify 
the effect of UCB0599 treatment. Moreover, DaT-SPECT at Screening will allow identification 
of the relevant target population by identifying patients without evidence of dopaminergic 
deficit. 
Identifying participants with early motor deficits in conjunction with confirming reduction of 
dopamine transporter levels has been shown to be a useful and EMA-qualified means of 
selecting participants who will have detectable progression rates over the course of clinical 
studies (EMA/CHMP/SAWP/765041/2017). In this study, DaT-SPECT will be used at Screening 
as a means to confirm dopamine transporter level reduction. 
Previous studies that have attempted to demonstrate efficacy of nonsymptomatic treatments for 
PD in early-stage populations have failed to show DM. Among the reasons for failure, 
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insufficient treatment duration to detect delayed treatment effect and the high variability of 
disease progression have been identified. An 18-month duration was chosen because it is 
expected to be sufficient time for UCB0599 to reveal a disease modifying effect and to 
differentiate from ST. 
In addition, the impact of UCB0599 on time-to-initiation and overall intake of rescue medication 
will be investigated. Since UCB0599 treatment is expected to slow disease progression and 
disease progression is directly linked to onset of ST, UCB0599 would be expected to delay the 
time until the study participants require initiating ST, which therefore can be utilized as an event. 
The treatment duration of up to 18 months means that treatment effects of UCB0599 on the need 
for initiation of rescue medication will be able to be assessed in the majority of study 
participants. 
As UCB0599 has potential to slow disease progression in the non-motor domain, which 
prominently encompasses cognitive functioning, there is a need to include instruments which 
may capture a signal in this area. The Montreal Cognitive Assessments ([MoCA]; Nasreddine et 
al, 2005) will be used to complete the main assessments, as it covers different cognitive domains 
(visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and 
orientation). Practice effects have been observed on repeating MoCA assessments (Wong et al, 
2018) and therefore parallel versions are available which can be utilized for longitudinal 
observations. Furthermore, the MoCA will play a role in Screening, to exclude participants with 
a pronounced cognitive impairment, which specifically in younger participants could be 
indicative of a neurodegenerative disorder other than PD. 
For each efficacy objective, the precise treatment effect of interest is defined on the selected 
endpoints referred to as the estimands. As this is a Phase 2 study, we will focus on estimands 
which measure efficacy (as opposed to effectiveness). 
4.3 
Justification for dose 
The rationale for testing the proposed clinical dose levels of UCB0599 180mg/day (90mg BID) 
and 360mg/day (180mg BID) in PD0053 is based on (1) the safety margin estimates comparing 
systemic exposures at the no observed adverse effect level (NOAEL) in monkey with human 
observed exposures in study participants with PD treated in UP0077, and (2) exposures that have 
shown pharmacological activity in transgenic mice that overexpress the human wildtype ASYN 
gene (SNCA) in the CNS. 
Potential food effect, as well as potential drug-drug interaction with itraconazole, a strong 
CYP3A4 inhibitor, were evaluated in UP0078 after UCB0599 single dose (180mg). Data from 
UP0078 confirmed that no food restriction is needed in PD0053. However, strong CYP3A4 
inhibitors (and inducers) should not be co-administered with UCB0599 (see Section 6.5.2). 
4.3.1 
Safety-based dose levels 
UCB0599 exposure data in the most sensitive nonclinical species (monkey) are presented in 
Table 4-1. The UCB0599 Cmax and AUC0-24h following daily dosing of 60mg/kg/day for 
39 weeks in male monkeys were 4090ng/mL and 28000h*ng/mL, respectively. These PK 
parameters were used to determine the human safety margins, comparing nonclinical exposures 
with human observed exposures. 
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Across the dose range tested, UCB0599 behaved approximately linearly when relating dose and 
exposure; therefore, the projected equivalent AUC0-24h at steady state at (180mg/day [90mg 
BID]) is 8072h*ng/mL (mean AUC0-12h,ss 4036h*ng/mL multiplied by 2; and at 360mg/day 
[180mg BID]) is 15908h*ng/mL (mean AUC0-12h,ss 7954h*ng/mL multiplied by 2) (Table 4-1). 
 
Table 4-1: 
Cmax and AUC and unbound (Cmax[u] and AUC[u]) UCB0599 exposures 
calculated on measured plasma protein binding in monkey or human 
plasma samples 
Cmax 
ng/mL 
Cmax(u) 
ng/mL 
AUC0-24h 
h*ng/mL 
AUC0-24h(u) 
h*ng/mL 
Male monkey 
(39-week) 
(at 60mg/kg/day) 
4090 
200.4 
28,000 
1372.0 
Observed human 
exposures  
(90mg BID, 
180mg/day) 
730 
6.6 
8072 
72.6 
Observed human 
exposures  
(180mg BID, 
360mg/day) 
1330 
12 
15,908 
143.2 
BID=twice per day 
Note: Mean AUC0-24h, calculated as 2x the measured AUC0-12h, in UP0077 (Investigator Brochure Table 4-7 and 4-
8). 
Note: Plasma unbound fraction in monkeys and humans are 4.9% and 0.9%, respectively (Study NCD2777). 
Comparing these human observed Cmax and AUC parameters with the nonclinical data 
(Table 4-1) indicates that mean expected drug exposures remain below the observed mean 
NOAEL levels obtained in the 39-week monkey study. To further provide reassurance on the 
safety exposures, Table 4-1 also provides calculated unbound PK parameters, ie, Cmax(u) and 
AUC(u), based on the concept of unbound drug being a pharmacologically active moiety. In 
monkey plasma, the mean bound percentage was 95.1±3.4% at 37°C. The protein binding in 
human plasma was 99.1±0.1% at 37°C (UCB study number NCD2777). Using the unbound 
fraction to convert to unbound (pharmacologically active) drug comparing the average exposure 
in human study participants vs the observed monkey exposure data, a safety margin of >15 is to 
be expected on the basis of this calculation. 
4.3.2 
Pharmacology-based dose levels 
The projected exposures in humans at UCB0599 180mg/day (90mg BID) and 360mg/day 
(180mg BID) are predicted to correspond to efficacious CNS exposures in the transgenic mouse 
model overexpressing human wildtype ASYN gene (SNCA). Therefore, UCB0599 dose selection 
for UP0030 was projected to achieve systemic exposures in humans that were comparable to the 
efficacious exposures obtained in the pharmacological animal model (transgenic mice 
overexpressing SNCA), and, in particular, a range of exposures encompassed within those 
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expected after chronic administration at UCB0599 1mg/kg and UCB0599 5mg/kg. The AUC and 
Cmax exposures (expressed as total and unbound) estimated after administration at 
UCB0599 1mg/kg were 308ng*h/mL (unbound: 6.5h*ng/mL) and 332ng/mL (unbound: 
7.0ng/mL), respectively (Table 4-2). AUC and Cmax exposures (total and unbound) estimated 
after administration at UCB0599 5mg/kg were 1648ng*h/mL (unbound: 34.6h*ng /mL) and 
1317h*ng/mL (unbound: 27.7ng/mL), respectively. 
 
Table 4-2: 
UCB0599 exposure at pharmacological dose 
Dose 
(mg/kg/day) 
Gender 
AUC0-24 
(h*ng/mL) 
Cmax 
(ng/mL) 
Unbound 
AUC0-24 
(h*ng/mL) 
Unbound Cmax 
(ng/mL) 
1  
Male 
308 
332 
6.5 
7.0 
5  
Male 
1648 
1317 
34.6 
27.7 
At UCB0599 180 or 360mg/day in UP0077, the projected exposure (AUC0-24h ) in humans at 
these doses were 8072 and 15908h*ng/mL, respectively (unbound: 72.6 and 143.2h*ng/mL, 
respectively), and the Cmax were 730 and 1330ng/mL, respectively (unbound: 6.6 and 12ng/mL, 
respectively), at steady state. This exposure covers the range of both Cmax and AUC exposure in 
mice at the highest pharmacological dose of UCB0599 5mg/kg. 
4.4 
End of study definition 
Participants are considered to have completed the study if they have completed all phases of the 
study, including the SFU Visit (30 days after the End of Treatment [EOT] Visit). Participants 
opting to enter PD0055 will not enter the SFU Period of PD0053, and are considered to have 
completed the study if they have completed all visits up to and including EOT. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1a. Study participant must be 40 to 75 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2a. Study participant has PD, with a diagnosis made by a neurologist according to the 2015 
Movement Disorder Society criteria within 2 years of Baseline Visit (including diagnosis 
during Screening). 
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3. The following diagnostic criteria must be met: bradykinesia AND at least ONE of the 
following: muscular rigidity, or resting tremor. 
4b. A Screening DaT-SPECT, or a historical DaT-SPECT within 3 months of the Screening Visit 
(V1) that has been qualified by the central reader, shows evidence of dopamine transporter 
deficit per study requirements (refer to Section 4.2) and as determined by a central reader. 
5a. Criterion removed. 
6a. Study participant is in the ≤2.5 modified Hoehn and Yahr stage at Screening. 
7a. Study participant has never taken medications for the treatment of motor symptoms of PD 
and is not expected to require starting ST with a high likelihood in the next 6 months as far 
as clinical judgement allows. These medications include: 
a. Levodopa 
b. Catechol-O-methyltransferase (COMT) inhibitors 
c. Dopamine agonists 
d. Monoamine oxidase-B (MAO-B) inhibitors 
e. Anticholinergic drugs 
f. Trihexyphenidyl 
g. Amantadine 
h. Safinamide 
Exceptions to the above would be the following: 
i. 
Acute pharmacological testing for diagnostic purposes is allowed until 1 week before 
first Screening Visit. 
ii. 
Historical treatment with symptomatic treatment (ST) for a duration of up to 1 month 
is allowed until 3 months before first Screening Visit (refer to details in exclusion 
criterion #26a). 
8. 
Study participant has never taken part in disease-modifying treatment studies directed at 
NDD. 
9. 
Study participant does not take N-acetyl cysteine or other cysteine donors or glutathione 
precursors on a regular basis as a food supplement. 
10. Study participant is willing, competent, and able to comply with all aspects of the protocol, 
including follow-up schedule and biospecimen collection. 
Weight 
11. 
Study participant has a body mass index (BMI) of 16 to 34kg/m² (inclusive). 
Sex 
12. 
Contraception 
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− A male participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) during the Treatment Period and for at least 90 days after the last dose of 
study medication and refrain from donating sperm during this period. 
− A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies: 
◦ 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4 ) 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the Treatment Period and for at least 1 month after the last dose 
of study medication. The study participant must have a negative serum pregnancy test 
at Screening (Visit 1), which is to be confirmed negative by urine testing prior to the 
first dose of study medication at Baseline (Visit 3). If oral contraception is used, an 
additional barrier method will be required during the study as a study medication 
related-gastrointestinal upset or a drug interaction by CYP3A4 induction could 
interfere with efficacy. 
Informed consent 
13. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Study participant has any current or past medical or psychiatric condition that, in the opinion 
of the Investigator, could jeopardize or would compromise the study participant’s safety or 
ability to participate in this study. 
2. Study participant has a current history of alcohol or drug use disorder, as defined in the 
Diagnostic and Statistical Manual of Mental Disorders V, within the previous year before 
Screening. 
3. Study participant has a known hypersensitivity to any components (and/or its excipients) of 
the study medication or comparative drugs as stated in the protocol. 
4a. Study participant has a known relevant allergy (not including mild seasonal hay-fever and/or 
conjunctivitis or low-grade food intolerances), a pre-existing history of a relevant and 
clinically significant allergic condition, or a predisposition for an allergic reaction (eg, total 
immunoglobulin E value above normal range according to the study’s central laboratory 
reference range) at Screening in the opinion of the Investigator. 
5. Study participant wearing any kind of implantable device, including cardiac pacemakers, 
pumps, and implantable cardioverters, will be excluded from wearing the wearable sensor, 
but may participate in the main study. 
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6. Study participant with a known nickel allergy severe enough to preclude 24 hours a 
day/7 days a week wearing of a sensor device with a nickel alloy-containing housing will be 
excluded from wearing the wearable sensor, but may participate in the main study. 
7. Study participants with any condition or in any circumstances that in the opinion of the 
Investigator, makes the participant inappropriate for wearing of the wearable sensor. These 
study participants will be excluded from wearing the wearable sensor but may participate in 
the main study. 
8. Study participant has a brain magnetic resonance imaging (MRI) scan performed during 
Screening indicative of a clinically significant abnormality or a historical MRI scan during 
the 6 months before Screening Visit 1 of sufficient quality to show such abnormalities. In 
case of doubt, the significance is determined on a case-by-case basis in close collaboration 
with the Medical Monitor and should not include abnormalities like age-appropriate brain 
atrophy, minor white matter signals, or mild vasculopathy. 
9. Study participant has any contraindication for the brain MRI or DaT-SPECT imaging. 
10. Study participant has ongoing significant inflammatory gastrointestinal disorders and/or 
clinical signs of significant gastrointestinal problems at Screening. Study participants with 
PD-associated gastrointestinal motility problems need not be excluded. 
11. Study participant has a MoCA score less than 23, indicating mild cognitive impairment or 
other significant cognitive impairment or clinical dementia at Screening that, in the opinion 
of the Investigator, would interfere with study evaluation. 
12. Study participant has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as 
indicated by positive responses (“Yes”) to either Question 4 or Question 5 of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. 
13. Study participant has a diagnosis of a significant CNS disease other than PD or history of 
epilepsy or seizure disorder other than febrile seizures as a child. 
14a. Study participant has abnormalities in lumbar spine previously known or determined by a 
Screening lumbar x-ray (if conducted) that could preclude lumbar puncture, in the opinion of 
the Investigator. The participant must be excluded from lumbar puncture but not from study 
participation. 
15a. Study participant has a history of clinically significant back pain, back pathology, and/or back 
injury (for example, degenerative disease, spinal deformity, or spinal surgery) that in the 
opinion of the Investigator is sufficiently severe as to potentially predispose participant to 
complications or technical difficulty with lumbar puncture. The participant must be excluded 
from lumbar puncture but not from study participation. 
16a. Evidence or history of significant active bleeding or coagulation disorder or use of drugs that 
affect coagulation or platelet function within 14 days prior to lumbar puncture. The 
participant must be excluded from lumbar puncture but not from study participation. 
17a. Allergy to lidocaine (Xylocaine®) or its derivatives. The participant must be excluded from 
lumbar puncture but not from study participation. 
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18a. Medical or surgical conditions which in the opinion of the Investigator represent a 
contraindication for lumbar puncture. The participant must be excluded from lumbar puncture 
but not from study participation. 
19. Total bilirubin >upper limit of normal (ULN) (≥1.5xULN total bilirubin if known Gilbert’s 
syndrome). If study participant has elevations in total bilirubin that are >ULN and 
<1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, 
direct bilirubin <35%). 
20. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with 
the exception of Gilbert's syndrome or asymptomatic gallstones). 
a. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline 
phosphatase (ALP) are >1.5xULN. 
b. For randomized study participants with a Baseline result >ULN for ALT, AST, ALP, or 
total bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful 
elevation must be understood and recorded in the eCRF. 
c. If the study participant has >ULN ALT, AST, or ALP that does not meet the exclusion 
limit at Screening, repeat the tests, if possible, prior to dosing to ensure there is no further 
ongoing clinically relevant increase. In case of a clinically relevant increase, inclusion of 
the study participant must be discussed with the Medical Monitor. 
d. Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be 
repeated for confirmation. This includes reScreening. 
21. Study participant has a history or present condition of respiratory or cardiovascular disorders 
at Screening (eg, cardiac insufficiency, coronary heart disease, uncontrolled hypertension, 
arrhythmia, tachyarrhythmia, or myocardial infarction) which is considered clinically 
significant by the Investigator. 
22a. Study participant has medical history or current diagnosis of Type 1 diabetes or uncontrolled 
Type 2 diabetes. Well controlled type 2 diabetes in line with local clinical practice is 
acceptable. 
23a. Study participant has clinically significant ECG abnormality at Screening, in the opinion of 
the Investigator. In addition, any study participant with any of the following findings will be 
excluded: 
a. QT corrected for heart rate using Fridericia's formula (QTcF) interval >450ms (in males) 
or >470ms (in females) in 2 of 3 ECGs. 
b. Bundle branch blocks (complete bundle branch block with QRS>120ms), marked right or 
left axis deviation or second and third degree atrioventricular block are excluded. Mild 
first degree atrioventricular block (defined as PR interval ≤230ms) is acceptable. Mild 
axis deviation, incomplete right bundle branch block (QRS≤120ms), or left anterior 
hemiblock is acceptable if no underlying disease is suspected by the Investigator. 
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c. Irregular rhythms other than sinus arrhythmia or occasional, rare supraventricular or rare 
ventricular ectopic beats. 
d. In the judgment of the Investigator, T-wave configurations that are not of sufficient 
quality for assessing QT interval duration. 
24. Study participant has a history of recurrent unexplained syncopes or a family history of 
sudden death due to long QT syndrome. 
25a. Study participant has had significant blood loss or has donated or received 1 or more units 
(450mL) of blood within 30 days prior to Baseline Visit, or has donated plasma or platelets 
within 14 days prior to Baseline Visit. 
Prior/Concomitant therapy 
26a. Study participant has past history of use of medications for the treatment of motor symptoms 
of PD. Short (up to 4 weeks) past use of medications for the treatment of motor symptoms is 
permitted following a sufficient washout period. Medications included are: levodopa 
(maximum 400mg per day), dopamine agonists, MAO-B inhibitors, anticholinergics, or 
amantadine. A sufficient washout period is at least 3 months prior to the Baseline Visit.  
27. Study participant received an investigational medicinal product (IMP), or has participated in 
another study of an IMP within a period of 90 days (or 5 half-lives of the drug, whichever is 
longer) before Baseline. 
28. Study participant has had prior treatment with an investigational medical device, or 
participated in a study of an investigational medical device within a period of 90 days before 
Baseline. 
29. Study participant has had prior treatment with an investigational vaccine, gene therapy, or 
stem cell therapy for PD (including active immunization or passive immunotherapy with 
monoclonal antibodies). 
30a. Criterion removed. 
31b. (1) Study participant has prior use of any of the following (drugs that may affect DaT-
SPECT scan) within 50 days prior to Baseline: metoclopramide, alpha methyldopa, 
olanzapine, flunarizine, amoxapine, reserpine, bupropion, buspirone, cocaine, mazindol, 
methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, 
modafinil, clozapine. 
 
(2) Study participant has prior use of any of the following (drugs with possible Parkinson’s 
disease-modifying effects) within 5 days prior to Baseline: pioglitazone, ambroxol, nilotinib, 
inosine, deferiprone, liraglutide, lixisenatide, N-acetylcysteine, phenylbutyrate, transdermal 
nicotine, exenatide, and isradipine. 
32. Study participant has had prior treatment of PD involving intracranial surgery or 
implantation of a device (including deep brain stimulation). 
33. Study participant has received prohibited prescription or nonprescription medicines 
(Section 6.5.2) (including over-the-counter medicines and herbal and dietary supplements 
[including St John’s Wort]) that have been taken within 14 days prior to Baseline. 
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Prior/Concurrent clinical study experience 
34. Participant has previously participated in this study or participant has previously been 
assigned to treatment in a study of the medication under investigation in this study. 
Diagnostic assessments 
35a. Positive prestudy medication/alcohol/recreational drug screen, unless reasonably explained 
by concomitant use of a medication. 
36. Positive human immunodeficiency virus antibody test. 
37. Presence of hepatitis B surface antigen at Screening. 
38. Positive hepatitis C antibody test result at Screening or within 3 months prior to starting 
study medication. NOTE: Participants with positive hepatitis C antibody due to prior 
resolved disease can be enrolled, only if a confirmatory negative hepatitis C ribonucleic acid 
(RNA) test is obtained. 
39. Positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of 
study medication. NOTE: Test is optional and participants with negative hepatitis C 
antibody test are not required to also undergo hepatitis C RNA testing. 
a. The hepatitis C antibody test is a standard test used at Screening to determine eligibility, 
and hepatitis C RNA testing is optional and only performed when the antibody test is 
positive in order to consider participants with positive hepatitis C antibody test for 
enrollment into the study. Where hepatitis C RNA testing is unavailable, a positive 
hepatitis C antibody test will be used for exclusion. 
b. NOTE: Stable chronic liver disease (including Gilbert’s syndrome and asymptomatic 
gallstones) is acceptable if the participant otherwise meets entry criteria. 
40b. Study participant has medical history or current diagnosis of renal impairment and/or 
Screening laboratory results show any of the following confirmed by repeat test: 
a. Criterion removed. 
b. Abnormal urinalysis considered clinically significant by the Investigator, eg, red cell 
casts or hematuria in microscopy. 
Abnormal urinalysis may be treated during the Screening Period and retested prior to 
Baseline, providing that study participants are still within the Screening Period window 
and the treatment medication is stopped 14 days prior to Baseline. 
c. Results for urine test of albumin/creatinine ratio of ≥30mg/mmol. 
d. Study participants with evidence of urinary tract infection during the Screening Period. 
Urinary tract infection may be treated during the Screening Period and retested prior to 
Baseline, providing that study participants are still within the Screening Period window 
and the treatment medication is stopped 14 days prior to Baseline. 
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e. The estimated glomerular filtration rate of <45mL/min/1.73m2 (using the Chronic Kidney 
Disease Epidemiology Collaboration formula). 
f. Clinically significant electrolyte abnormalities. 
41. History of significant renal disease. 
Other exclusions 
42a. The study participant must not ingest grapefruit, starfruit, or pawpaw (as beverage, fruit or 
supplements) within 72 hours before the study medication administration or be under 
treatment with any known strong CYP3A4 inhibitor or inducer within 72 hours before study 
drug administration or throughout the entire study period (Section 6.5.2). 
43a. Vulnerable participants (eg, participants kept in detention, soldiers, adults with legally 
authorized representative, employees of the Sponsor or the CRO with direct involvement in 
the proposed study or other studies under the direction of the Investigator or the CRO, as 
well as family members of the employees or the Investigator. In France, another example of 
vulnerable participants includes participants who do not benefit from social security 
schemes such as health insurance. (For specific requirements in France, please refer to 
Section 10.9, Appendix 9.) 
44. A female study participant who tests positive for pregnancy, plans to get pregnant during the 
participation in the study, or who is breastfeeding. 
45. Study participant with hypokalemia, defined as a serum potassium level below the lower 
limit of the laboratory’s reference range. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
The study participant must not ingest grapefruit, starfruit, or pawpaw (as beverage, fruit or 
supplements) within 72 hours before the study medication administration and throughout the 
study. 
5.3.2 
Caffeine, alcohol, and tobacco 
There are no restrictions for caffeine or tobacco during the study. Prior documentation of alcohol 
abuse is an exclusion criterion, and study participants are requested to practice only moderate 
alcohol consumption. 
5.3.3 
Activity 
There are no restrictions on any activities. 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study medication. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
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from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
For study participants otherwise fully eligible but not able to be randomized as planned for 
personal reasons, rescreening may be allowed once per participant at the discretion of the 
Investigator, following discussion with the Medical Monitor. If Visit 2 was completed during 
screening, only Visit 1 needs to be completed for rescreening. However, the maximum period 
between DaT-SPECT, MRI assessment, and V1 need to be adhered to as per inclusion criteria. 
Rescreened participants will be assigned a new participant number.  
Rescreening in case of abnormal laboratory results can be considered only in case of test results 
for which there are strong reasons to be considered transitory and/or without clinical safety 
significance. In these cases, the assessments might be repeated after consultation with the 
Medical Monitor. 
6 
STUDY TREATMENTS/INVESTIGATIONAL DEVICE 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
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6.1 
Treatments administered 
ARM Name 
UCB0599 180mg/day 
UCB0599 360mg/day 
Placebo 
Intervention 
name 
UCB0599 
UCB0599 
Placebo 
Type 
Drug 
Drug 
Placebo 
Dose 
formulation 
Granules in capsules and 
matching placebo 
capsules 
Granules in capsules 
Matching placebo 
capsules 
Unit dose 
strength(s) 
90mg and 0mg 
90mg 
0mg 
Dosage level(s)a 
180mg/day [90mg BID]  
360mg/day [180mg BID] 
NA, BID intake 
Route of 
administration 
Oral – 2 capsules 90mg 
and 2 matching placebo 
capsules per day 
BID approximately 12 
hours apart 
Oral – 4 capsules 90mg 
per day 
BID approximately 12 
hours apart 
Oral – 4 matching 
placebo capsules per day 
BID approximately 12 
hours apart 
Use 
Experimental 
Experimental 
Placebo-comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
IMP will be supplied by 
UCB Clinical Trial 
Supply or designee. 
IMP will be supplied by 
UCB Clinical Trial 
Supply or designee. 
IMP will be supplied by 
UCB Clinical Trial 
Supply or designee. 
Packaging and 
labeling 
UCB0599 and placebo 
capsules are 
manufactured, packaged, 
and labeled according to 
Good Manufacturing 
Practice guidelines and 
applicable laws or 
regulations. 
UCB0599 and placebo 
capsules are 
manufactured, packaged, 
and labeled according to 
Good Manufacturing 
Practice guidelines and 
applicable laws or 
regulations. 
UCB0599 and placebo 
capsules are 
manufactured, packaged, 
and labeled according to 
Good Manufacturing 
Practice guidelines and 
applicable laws or 
regulations. 
Current/Former 
name(s) or 
alias(es) 
NA 
NA 
NA 
BID=twice per day; IMP=investigational medicinal product; NA=not applicable 
a Participants will be randomized to either UCB0599 360mg/day (180mg BID), UCB0599 180mg/day (90mg BID), 
or placebo to achieve a final randomization ratio of 1:1:1 when the IMP for low dose UCB0599 180mg/day (90mg 
BID) will be available to supply sites. 
6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medication received and any discrepancies are reported 
and resolved before use of the study medication. 
Only participants enrolled in the study may receive study medication, and only authorized site 
staff may supply or administer study medication. All study medications must be stored in a 
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secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The Investigator (or designee) will instruct the participant to store the study medication 
following the instructions on the label. 
Further guidance and information for the final disposition of unused study medication are 
provided in the IMP Handling Manual. 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication lost, damaged (due to breakage or wastage), not 
used, partially used, disposed of at the study site, or returned to the Sponsor or designee must 
also be recorded on the appropriate forms. All supplies and pharmacy documentation must be 
made available throughout the study for UCB (or designee) to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the study medication is used only in accordance with the 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB standard operating 
procedures or returned to UCB (or designee). Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: randomization and blinding 
Interactive response technology (IRT) will be used for assigning eligible participants to a 
treatment regimen (as applicable) based on a predetermined production randomization and/or 
packaging schedule provided by UCB (or designee). The randomization schedule will be 
produced by the IRT vendor. The IRT will generate individual assignments for kits of study 
medication, as appropriate, according to the visit schedule. 
To enroll a study participant (Visit 1), the Investigator or designee will contact the IRT and 
provide brief details about the participant to be enrolled. Each participant will receive a 5-digit 
number assigned at Screening that serves as the participant identifier throughout the study. The 
participant number will be required in all communication between the Investigator or designee 
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and the IRT regarding a particular participant. Participant numbers and kit numbers will be 
tracked via the IRT. Enrolled participants who withdraw from the study prior to randomization 
will retain their participant number without receiving a randomization number (ie, participant 
numbers will not be reassigned). 
To randomize a participant, the Investigator or designee will contact the IRT and provide brief 
details about the participant to be randomized. The IRT will automatically inform the 
Investigator or designee of the participant’s randomization number. The IRT will allocate kit 
numbers to the participant based on the participant number during the course of the study. The 
randomization number must be incorporated into the eCRF. 
All participant treatment details will be allocated and maintained by the IRT. The following 
individuals will receive the randomization code at the start of the study: 
• Designated CRO bioanalytical staff analyzing PK samples 
• Sponsor clinical study supply staff 
• Interactive response technology provider 
The following individuals may have access to the randomization code as indicated: 
• Sponsor patient safety staff as needed for reporting SAEs to regulatory authorities 
• On request, members of the Data Monitoring Committee (DMC) who participate in 
unblinded (closed) sessions will be given information about the IMP allocation for those 
participants for whom data are provided at these sessions 
• Unblinded CRO staff supporting preparation of the data outputs for the DMC review 
• Unblinded pharmacometrics staff and statistical programmers, independent from the study 
team, who have access to the 12-month data for the preparation of the exposure-response 
analysis  
To balance prognostic factors across treatment groups, randomization of study participants will 
be stratified using permutation blocks by gender. 
In the Parkinson Progression Markers Initiative (PPMI) database, variability in MDS-UPRDS 
was observed to differ between male and female PD patients. Men and women also behave 
differently with respect to start of ST. Therefore, the study will balance treatment groups 
according to gender. 
In the three-arm study, only participants who are recruited after the introduction of the 
randomization schedule which include the low-dose arm will have a chance of being assigned to 
low-dose UCB0599, causing a small time bias. This time bias will be considered to have no 
impact on how the participants respond to their assigned treatment, ie, the data collected from 
participants assigned to the placebo and high-dose arms prior to the introduction of the full 
randomization schedule will be assumed comparable to the data collected from participants 
assigned to the placebo and high-dose arms after the introduction of the full randomization 
schedule. 
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6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of study treatment blind 
All participant treatment details will be allocated and maintained by the IRT system. 
6.3.1.2 
Breaking the treatment blind in an emergency situation 
In the event of an emergency, it will be possible to determine to which treatment arm and dose 
the participant has been allocated by contacting the IRT. All sites will be provided with details of 
how to contact the system for code breaking at the start of the study.  
The Clinical Project Manager will be informed immediately via the IRT when a code is broken, 
but will remain blinded to specific treatment information. Any unblinding of the study 
medication performed by the Investigator must be recorded in the source documents and on the 
Study Termination eCRF page. 
6.4 
Treatment compliance 
At each in-clinic visit after study medication is dispensed, participants must return all unused 
study medication and empty study medication containers. Drug accountability must be done in 
the participant’s presence in order to obtain explanations regarding discrepancies in compliance 
with the dosing regimen. Drug accountability must be recorded on the Drug Accountability form. 
If a participant is found to be persistently noncompliant (<80% or >120% compliant), the 
Sponsor, in conjunction with the Investigator, will make a decision as to whether the participant 
should be withdrawn from the study. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
DaTSCAN tracer for DaT-SPECT imaging will be sourced from GE-Healthcare via Invicro. The 
tracer is approved for commercial use in Europe, the US, and Canada and will be used according 
to the product label. Approximate radioactivity per dose is 185 MBq. 
Thyroid-blocking agents such as lugol must be applied before DaT-SPECT. 
Should a COVID-19 vaccine be administered during study participation, full details will be 
recorded in the concomitant medication eCRF page. The specific name of the vaccine and the 
exact date of administration should be recorded, as instructed in the completion guideline.   
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
No concomitant medications for the treatment of motor symptoms of PD or medications with PD 
disease modifying effect will be allowed at inclusion (eg, levodopa, COMT inhibitors, dopamine 
agonists, MAO-B inhibitors). For rescue treatment of PD symptoms, refer to Section 6.5.3. 
Strong CYP3A4 inhibitors and inducers, as well as sensitive CYP3A4 substrates with narrow 
therapeutic index are not allowed during the study. 
The following medications are not allowed during the 50 days before DaT-SPECT imaging: 
• Metoclopramide 
• Alpha methyldopa 
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• Clozapine 
• Olanzapine 
• Flunarizine 
• Amoxapine 
• Amphetamine derivatives 
• Reserpine 
• Bupropion 
• Buspirone 
• Cocaine 
• Mazindol 
• Methylamphetamine 
• Methylphenidate 
• Norephedrine 
• Phentermine 
• Phenylpropanolamine 
• Modafinil 
6.5.3 
Rescue medication 
Investigators will be encouraged to carefully document all changes and dose adaptations, 
particularly when considering ST initiation which should always consider the individual 
participant needs and standard of care recommendations. Guidance on the initiation of rescue 
medication will be provided in a separate manual. 
The study site will supply rescue medication that will be obtained locally. 
Levodopa is determined as first choice for participants who are determined to require ST. Other 
ST options are only permitted in exceptional cases, where levodopa has an unsatisfactory effect, 
where contraindications against levodopa are identified by the Investigator, or where an 
alternative ST drug is medically indicated for any other reason. Monoamine Oxidase Type B 
inhibitors will not be allowed. 
The date and time of onset of rescue medication administration, as well as the name and dosage 
regimen of the rescue medication, must be recorded in the eCRF. Any dose adjustments also 
need to be recorded. 
For all scheduled visits, study participants that start to receive ST over the study observation 
period will be asked to refrain from taking ST for at least 12 hours before the clinic visit and to 
bring the medication to the site. A 12-hour washout is considered sufficient to achieve a 
practically defined off-state for the range of STs specified in this section and has proven 
tolerable in clinical practice (Bloem et al, 2019). All tests which are expected to be sensitive to 
the effects of ST will take place throughout the first part of the study visit to allow resuming 
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dosing of ST at the earliest possible point. If a participant does not comply with the 12-hour ST 
washout prior to any visit, the data from that particular visit will be censored.  
6.6 
Dose modification 
There is no dose modification allowed in PD0053. 
6.7 
Criteria for study hold or dosing stoppage 
UCB will halt further dosing for all study participants at all sites if any of the following criteria 
are met during the course of the study and following case review to confirm causality and 
seriousness and/or severity of reported events. 
Possible reasons for discontinuation or suspension of the study include (but are not limited to): 
1. A pattern of AEs, abnormal lab results, or other safety findings that would be unacceptable 
for this patient population. 
2. A pattern of hypersensitivity reactions that are considered study medication-related and that 
would be unacceptable for this patient population. 
If any criterion is potentially met, the SMC will request for the DMC to meet as soon as possible 
to make a recommendation to the Sponsor as to whether discontinuation, pausing, or suspension 
of IMP dosing or the study should occur. 
Consideration will be given to severity and relatedness of events. Further details on the role and 
process of ensuring close safety monitoring through the DMC are provided in the DMC charter. 
3. If the Sponsor or its designees judges it necessary for medical, safety, regulatory, or any 
other reasons consistent with applicable laws, regulations, and Good Clinical Practices 
(GCP). 
4. Sponsor’s decision that continuation of the study is unjustifiable for medical or ethical 
reasons. 
5. Discontinuation of development of the Sponsor’s study medication. 
Detailed procedures for reporting SAEs and other safety events which may meet study hold 
criteria are provided in Appendix 3 (Section 10.3). 
6.8 
Treatment after the end of the study 
Study participants who complete the Treatment Period will have the option to transition into a 
dose-blinded extension study (PD0055). In this case, participants will not enter the SFU Period 
of PD0053. For those participants who do not roll over to PD0055, the study ends with an SFU 
Visit (Visit 16) approximately 30 days after the last dose. In case of early termination of a 
participant’s study medication, the participant will be asked to attend the EOT and the SFU Visit 
(30 days after the last dose) and will not be eligible for PD0055.   
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7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Study medication will be stopped if the study participant develops a medical condition (or 
laboratory abnormality or ECG change) that, in the opinion of the Investigator, compromises the 
study participant’s ability to participate or compromises the study participant’s safety. 
Any new clinically relevant safety finding should be reported as an AE. 
In all cases, the study participant should be followed until the condition has resolved as agreed 
by the Investigator and the UCB Study Physician. 
See the Schedule of Activities (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow up and for any further evaluations that need to be completed. 
7.1.1 
Hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) 
Study participants will be informed that if they develop any symptoms suggestive of a 
hypersensitivity reaction (eg, rash, angioedema, or anaphylaxis) they should contact the 
Investigator immediately.  
The Investigator should assess the presenting symptoms to determine if this is possibly a 
hypersensitivity reaction.  
If the event is not considered to be a hypersensitivity reaction (eg, a rash due to another cause) 
the Investigator should document this and the participant may continue dosing.  
If the event is possibly a hypersensitivity reaction the Investigator should advise the participant 
to withhold dosing and arrange additional investigations as per Section 8.3.6.1. The event should 
be reported to UCB as an AESI. In this scenario dosing may only be recommenced following 
agreement of the Investigator and the SMC. 
7.1.2 
Liver Chemistry Stopping Criteria 
Discontinuation of study medication for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the participant. 
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Figure 7-1: Phase 2 liver chemistry stopping criteria and increased monitoring 
algorithm 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal. 
Specific assessments and follow up actions for potential drug-induced liver injury are provided 
in Appendix 6 (Section 10.6). 
7.1.3 
QTc Stopping Criteria 
A participant who meets either bulleted criterion based on the average of triplicate 12-lead ECG 
readings will be withdrawn from study medication. 
• QTcF >500ms OR Uncorrected QT >600ms 
• Change from Baseline of QTcF >60ms 
For participants with underlying bundle branch block, follow the discontinuation criteria listed 
below: 
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Baseline QTc with bundle branch block 
Discontinuation QTc threshold with bundle 
branch block 
<450ms 
>500ms 
450 to 480ms 
≥530ms 
If a clinically significant finding is identified (including, but not limited to, changes from 
Baseline in QTcF after enrollment) the Investigator or qualified designee will determine if the 
participant can continue in the study and if any change in participant management is needed. 
This review of the ECG printed at the time of collection must be documented.  
7.1.4 
Temporary Discontinuation  
The Investigator, SMC, or DMC may consider temporary discontinuation of dosing of study 
participants on a case-by-case basis. 
7.1.5 
Rechallenge 
The Investigator after agreement with the SMC (and endorsement by the DMC if requested by 
the SMC) may consider rechallenge of study participants on a case-by-case basis. 
7.2 
Participant Discontinuation/Withdrawal from the study 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator, SMC, or DMC for safety, behavioral, 
compliance, or administrative reasons. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
See the Schedule of Activities (Section 1.3) for data to be collected at the time of study 
discontinuation and follow-up, and for any further evaluations that need to be completed. The 
DaT-SPECT will occur at EOT (End of Treatment), provided that the previous DaT-SPECT 
occurred more than 6 months prior to EOT visit. 
Participants should be withdrawn from the study if any of the following events occur: 
1. Withdrawal of consent by the study participant 
2. A regulatory agency requests withdrawal of the participant from the study 
3. Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness or throughout quarantine conditions. 
Participants must be discontinued from study medication (but not necessarily from the study) if 
any of the following occurs: 
1. Study participant develops an illness that would interfere with his/her continued dosing. 
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2. Study participant takes prohibited concomitant medications as defined in the protocol. 
Outcome should be decided on a case-by-case basis. 
3. There is confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test. 
4. Study participant has actual suicidal ideation since last visit as indicated by a positive 
response (“Yes”) to either Question 4 or Question 5 of the “Since Last Visit” version of 
C-SSRS. The study participant should be referred immediately to a mental healthcare 
professional and must be discontinued from study medication. 
5. Study participant is confirmed positive for recreational drug use or for alcohol at a 
Baseline Visit (Day 0), which is deemed significant enough to impair the study 
participant’s safety or the quality of the collected data. Outcome should be decided on a 
case-by-case basis. 
6. Renal toxicity considered possibly related to the IMP. Laboratory tests suggestive of 
renal toxicity which should trigger further assessment may include: 
• Increase in serum creatinine ≥0.3mg/dL OR 
• Increase in serum creatinine to ≥1.5 times from Baseline OR 
• New persistent albuminuria or clinically significant increase in pre-existing 
albuminuria, over 6 consecutive weeks 
Any clinically significant findings in laboratory results for renal function will be 
monitored until resolution or stabilization. 
7. The Sponsor requests withdrawal of the participant. 
8. Study participant takes part in any other interventional study during the duration of this 
study. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a participant in advance. 
7.3 
Lost to follow up 
A participant will be considered lost to follow up if he or she repeatedly fails to attend scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to attend a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant), and document his/her effort (date and summary of the phone call and copy 
of the written message in the source documents), to complete the final evaluation. All results 
of these evaluations and observations together with a narrative description of the reason(s) 
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for removing the participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow up documented in the eCRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
The order of assessments is optimized for consistency, logistic requirements by the site, and 
minimized participant burden. Slight variations among the sites do not constitute a protocol 
deviation, while sites are encouraged to keep the order of assessments consistent over time. As a 
general rule, all assessments with a high likelihood of being sensitive to previous intake of ST 
need to be conducted in a practically defined off-state (as defined in Section 6.5.3) before intake 
of ST is resumed. To avoid bias and to maintain consistency over time, this rule should also 
apply to participants not (yet) on ST. The assessments in the timeslot preceding intake of ST 
should comprise: 
• PROs (at home prior to a clinic visit or first assessments at the clinic) 
• MDS-UPDRS (all parts) 
• Virtual Motor Exam (VME) (after a period of rest) 
• ECGs 
• Laboratory and PK blood sampling 
• Vital signs 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study medication. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3), is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a Screening log to record details of all 
participants screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities. 
The maximum amount of blood collected from each participant will not exceed 50mL at any 
visit and will not exceed 510mL over the duration of the study, including any extra assessments 
that may be required. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
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8.1 
Efficacy assessments 
8.1.1 
Clinical assessments 
8.1.1.1 
MDS-UPDRS 
The primary efficacy objective will be assessed by comparing the mean slope of progression of 
the MDS-UPDRS Parts I-III sum score estimated using all available data during the Treatment 
Period, from Baseline to Month 12 or up to intake of ST (Primary Estimand) between UCB0599 
and placebo. The difference in population means between treatment groups at 18 months or up to 
intake of ST will also be estimated (Key Secondary Estimand). In addition, the treatment 
difference in population mean slope of progression in MDS-UPDRS Part III subscale and in time 
to 5-point increase in MDS-UPDRS Part III will be estimated (Key Secondary Estimands). See 
Section 9.3 for more information on the planned efficacy analyses. 
The MDS-UPDRS (Goetz et al, 2008) will be completed according to the Schedule of 
Assessments (Section 1.3). 
The MDS sponsored a new version of the UPDRS in 2003 consisting of 4 parts (subscales): 
• Part I (non-motor experiences of daily living) has 2 components: 
− Part IA includes cognitive impairment, hallucinations and psychosis, depressed mood, 
anxious mood, apathy, and features of dopamine dysregulation syndrome; it is assessed 
by the rater with all pertinent information from study participants and caregivers. 
− Part IB includes sleep problems, daytime sleepiness, pain and other sensation, urinary 
problems, constipation problems, lightheadedness on standing, and fatigue; it is 
completed by the study participant with or without the aid of the caregiver, but 
independently of the rater. 
Both sections can be reviewed by the rater to ensure that all questions are answered clearly and 
the rater can help explain any perceived ambiguities. 
• Part II (motor experiences of daily living): 
− Includes speech, saliva and drooling, chewing and swallowing, eating tasks (cutting food 
and handling utensils), dressing, hygiene, handwriting, doing hobbies and other activities, 
turning in bed, tremor, getting out of bed, a car or a deep chair, walking and balance, and 
freezing. 
− Is designed to be a self-administered questionnaire like Part IB, but can be reviewed by 
the rater to ensure completeness and clarity. 
• Part III (motor examination) 
− Includes speech, facial expression, rigidity, finger tapping, hand movements, 
pronation-supination movements of hands, toe tapping, leg agility, arising from chair, 
gait, freezing of gait, postural stability, posture, global spontaneity of movement (body 
bradykinesia), postural tremor of the hands, kinetic tremor of the hands, rest tremor 
amplitude, and constancy of rest tremor. Motor function will be measured in an off-state 
with regard to ST intake (Section 6.5.3; Bloem et al, 2019). 
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− Has instructions for the rater to give or demonstrate to the study participant; it is 
completed by the rater. 
• Part IV (motor complications) 
− Includes time spent with dyskinesias, functional impact of dyskinesias, time spent in the 
"off" state, impact of fluctuations, complexity of motor fluctuations, and painful 
"off"-state dystonia. 
− Has instructions for the rater and also instructions to be read to the study participant. This 
part integrates study participant-derived information with the rater's clinical observations 
and judgments and is completed by the rater. 
Where possible, the same person should assess the study participant at each time point to avoid 
inter-individual rating differences. Study participants who do start to receive ST during the study 
Treatment period will be asked to refrain from taking ST for at least 12 hours before clinic visits 
and to bring the medication to the site. A 12-hour washout is considered sufficient to achieve a 
practically defined "off" state (please refer to Section 6.5.3 for further details). If a participant 
does not comply with the 12-hour ST washout prior to any visit, the data from that particular 
visit will be censored. 
8.1.1.2 
Modified Hoehn and Yahr staging 
The Hoehn and Yahr scale (Hoehn and Yahr, 1967) describes how the symptoms of PD progress 
through 5 stages: Stage 1=unilateral disease; Stage 2=bilateral disease without impairment of 
balance; Stage 3=mild to moderate bilateral disease, some postural instability, physically 
independent; Stage 4=severe disability, still able to walk or stand unassisted; and 
Stage 5=wheelchair bound or bedridden unless aided. The Hoehn and Yahr scale has since been 
modified with the addition of stages 1.5 (unilateral and axial involvement) and 2.5 (mild bilateral 
disease with recovery on pull test) to account for the intermediate course of PD. 
8.1.1.3 
Dopamine Transporter Imaging with Single Photon Emission 
Computed Tomography 
Dopamine Transporter Imaging with Single Photon Emission Computed Tomography will be 
conducted at the visits specified in Section 1.3. 
123I-Ioflupane (DaTSCAN®, GE Healthcare) is a radiopharmaceutical approved in the EU, 
Canada, and US. 
Each study participant will receive a maximum of 3 injections of 123I-Ioflupane during the study, 
according to the approved label. The target single injection dose of 185MBq is estimated to 
result in a radiation burden of 4.63mSv and the total effective dose for the study will be 
13.89mSv. This is categorized as a category III substantial risk level (ICR62), which is balanced 
by the substantial societal benefit from the results of this clinical study. 
On scanning days, study participants will be admitted to the imaging center. A dose of a 
thyroid-blocking agent will be given before the radiotracer dose. Approximately 4 hours prior to 
scanning, a venous canula will be inserted into an arm vein and from 111 to 185MBq DaTSCAN 
will be injected. Hydration should be encouraged before the injection, as well as good hydration 
and frequent voiding for 48 hours after the scan. 
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Approximately 4 hours post-injection of DaTSCAN, study participants will be placed supine in 
the SPECT scanner and positioned with comfortable head fixation. A single scan will be 
acquired over approximately 30 to 45 minutes. 
At Screening, the DaTSCAN imaging data will be transferred to a central imaging lab and 
analyzed visually to determine the status of dopamine deficit. 
For the Screening, Month 12 (no scan will be performed at Month 12 for participants in 
Germany [please see Appendix 9, Section 10.9]), and Month 18 scans; DaTSCAN imaging data 
will be analyzed quantitatively using region of interest analysis methods to determine tracer 
uptake and the mean striatum specific binding ratio. Other exploratory analysis may also be 
done. 
A historical DaT-SPECT scan within the previous 3 months before Screening Visit 1 is 
acceptable if the same specifications as in protocol were followed and if scan quality is 
acceptable by central imaging (InVicro). 
The DaTSCAN tracer for DaT-SPECT imaging must be sourced from GE-Healthcare, the 
participant must have avoided the medications listed in Section 6.5.2 which are not allowed 
during the 50 days before DaT-SPECT imaging and the DaTSCAN imaging data will be 
transferred to the central imaging lab (InVicro) and analyzed visually for dopamine deficit status 
(Baseline) and quantitatively for mean striatum specific binding ratio at Baseline, 12 months, and 
18 months. 
8.1.1.4 
ST intake 
Differences in ST intake between UCB0599 and placebo will be assessed at 12 and 18 months 
regardless of assigned study medication (Secondary efficacy estimand). 
For details on ST initiation, see Section 6.5.3. 
8.1.1.5 
Montreal Cognitive Assessment 
The difference between UCB0599 and placebo in target population mean (measured at 
Screening) in Montreal Cognitive Assessment (MoCA) at 18 months regardless of concomitant 
ST intake is a secondary efficacy endpoint. 
The MoCA (Nasreddine et al, 2005) assesses different cognitive domains 
(visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and 
orientation). Participants are assessed on a 30-point scale. A score of 26 or above is considered 
normal. 
The MoCA will be assessed at the visits specified in the Schedule of Activities (Section 1.3). 
8.1.1.6 
Clinical Global Impression of Improvement 
For the Clinical Global Impression of Improvement (CGII), the Investigator will assess change 
observed in the study participant’s condition compared with his/her condition at Baseline. 
Response options include: 0=not assessed; 1=very much improved; 2=much improved; 
3=minimally improved; 4=no change; 5=minimally worse; 6= much worse; 7=very much worse. 
The CGII will be assessed at the visits specified in the Schedule of Activities (Section 1.3). 
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8.1.1.7 
Clinical Global Impression of Severity 
With the Clinical Global Impression of Severity (CGIS), the Investigator will assess the current 
overall severity of Parkinson's Disease observed in the study participant. Response options 
include: 0=not assessed; 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; and 7=among the most extremely ill participants. 
The CGIS will be assessed at the visits specified in the Schedule of Activities (Section 1.3). 
8.1.1.8 
Movement Disorder Society Non-motor symptom scale 
The Movement Disorder Society Non-motor symptom scale (MDS-NMS; Martinez-Martin et 
al, 2019) is a revision of the Non-Motor Symptoms Scale. The rater-administered scale measures 
frequency and severity of 13 non-motor domains with over 52 items, covering a range of key 
non-motor symptoms that are PD and treatment related. In addition, the scale also includes a new 
8-domain Non-Motor Fluctuations subscale to assess changes in non-motor symptoms in relation 
to the timing of anti-PD medications. 
The MDS-NMS will be assessed at the visits specified in Schedule of Activities (Section 1.3). 
8.1.1.9 
Schwab and England Activities of Daily Living Scale 
The Schwab and England Activities of Daily Living (SE-ADL) is a short assessment of an 
individual's level of functional independence. In PD patients, the SE-ADL is typically assessed 
in conjunction with the MDS-UPDRS. For the SE-ADL, the examiner prompts the individual to 
select the rating that most accurately describes their level of functional independence. The SE-
ADL scoring ranges, in 11 steps, from 100% (Completely independent; able to do all chores 
without slowness, difficulty, or impairment; Essentially normal; unaware of any difficulty) to 0% 
(Vegetative functions such as swallowing; Bladder and bowel functions are not functioning; 
Bedridden). 
The SE-ADL will be assessed at the visits specified in Schedule of Activities (Section 1.3). 
8.1.1.10 
Starkstein Apathy Scale 
The Starkstein Apathy Scale (Starkstein et al, 1992) is a 14-item questionnaire to assess the 
severity of apathetic symptoms. The questions are read aloud to the participant by the examiner. 
For questions 1 to 8, each item is scored on a 4-point scale: “not at all” (3 points), "slightly" 
(2 points), "some" (1 point) and “a lot” (0 points). For questions 9 to 14, response options are: 
“not at all” (0 points), "slightly" (1 point), "some" (2 points), and “a lot” (3 points). 
The Starkstein Apathy Scale will be assessed at the visits specified in Schedule of Activities 
(Section 1.3). 
8.1.2 
Patient-reported outcomes 
Patient-reported outcomes must be completed as per time points mentioned in the Schedule of 
Activities (Section 1.3). 
Patient-reported outcomes must be completed by study participants in a quiet place by 
themselves without the help of a partner or caregiver, before any clinical examination takes 
place. During the Treatment Period, PROs will be completed prior to dosing. 
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Study participants should be informed of the importance of the PRO questionnaires and should 
be instructed to read the PRO items and instructions carefully. They should be informed that 
there are no right or wrong answers. 
Study personnel are not allowed to interpret the items for the participant. If a participant asks for 
guidance, study personnel should instruct him/her to respond according to their best 
understanding of the item. 
In the specific context of telemedicine visits, an automatic alert mechanism should be put in 
place to remind study participants to complete the PROs prior to any interactions with study 
personnel. Date and time of completion of the PROs will be recorded electronically. 
In the event study personnel finds out that the PROs have not been completed before the visit, 
study participants should be allowed to complete before any study related assessment is initiated. 
Patient-reported outcomes should only be checked for completeness by study personnel. In the 
event a few questionnaire items have not been completed, study personnel should merely enquire 
to the study participant if this results from an omission. Study personnel shall neither complete 
missing data nor suggest changes to participant responses. Like any other study data, responses 
to the questionnaire should be treated as confidential information. Data privacy considerations 
apply. 
The PROs should be completed in the following order: Fatigue-PRO; Early PD Function 
Slowness PRO; Early PD Mobility PRO; Patient Global Impression of Severity (PGIS) on 
Symptoms and Fatigue; Patient Global Impression of Change (PGIC) on Symptoms and Fatigue; 
Hospital Anxiety and Depression Scale (HADS); Euro Quality of life 5-Dimensions 5-Level 
(EQ-5D-5L). 
Time required to complete the first 5 PROs listed above was tested with a sample of 
6 participants with early-stage PD and was approximately 12 to 15 minutes. Completion of 
HADS and EQ-5D-5L requires approximately 10 additional minutes. 
8.1.2.1 
Fatigue PRO 
Fatigue PRO consists of 31 items across 3 domains: 9 ‘physical fatigue’ domain items, 
11 ‘mental and cognitive’ domain items, and 11 ‘susceptibility to fatigue’ domain items. 
Participants are asked to score each item based on how frequently they experienced the fatigue 
item over the past 7 days, using a 5-point Likert scale (“none of the time” to “all of the time”). 
Domain scores range from 0 to 100, with higher scores indicating higher levels of fatigue. 
Fatigue-PRO translates into 3 domain scores: 'Physical Fatigue', 'Mental Fatigue' and 
'Fatigability' scores. It currently does not include a total score summary. 
8.1.2.2 
Early PD Function Slowness PRO 
The Early PD Function Slowness PRO instrument consists of 45 items across 4 domains: 
19 motor (upper limb) items, 9 motor (complex or lower limb) items, 9 complex activities (motor 
and cognitive) items and 8 cognitive items. Participants are asked to score each item based on 
how slow they may have been when performing daily activities over the past 7 days, using a 
5-point Likert scale (“Not at all” to “Extremely slow”). Being an exploratory PRO instrument, no 
scoring algorithm currently exists. Final PRO content and scoring structure will be informed by 
generated data in the future. 
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8.1.2.3 
Early PD Mobility PRO 
The Early PD Mobility PRO instrument consists of 23 items. Participants are asked to score each 
item based on whether they have experienced any issue with walking and moving over the past 
7 days, using a 5-point Likert scale (“Not at all” to “Extremely”). Being an exploratory PRO 
instrument, no scoring algorithm currently exists. Final PRO content and scoring structure will 
be informed by generated data in future. 
8.1.2.4 
PGIS 
The PGIS is a 2-item, self-report measure that rates a participant's severity of their PD symptoms 
and overall fatigue over the past week. The PGIS is a 4-point scale (“none,” “mild,” “moderate,” 
“severe”). 
8.1.2.5 
PGIC 
The PGIC is a 2-state, self-report measure that reflects a participant's assessment of overall 
change in their PD symptoms and overall fatigue since they started taking the study medication. 
The PGIC is a 7-point scale (“much improved,” “moderately improved,” “a little bit improved,” 
“no change,” “a little bit worse,” “moderately worse,” “much worse”). 
8.1.2.6 
HADS 
The Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983) is a patient-
administered questionnaire that consists of 2 subscales for anxiety and depression. Each subscale 
consists of 7 items which are scored separately on a 4-point (0–3) scale, leading to a total score 
range from 0 to 21 for each of the 2 subscales. 
8.1.2.7 
EQ-5D-5L 
The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ-VAS). 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: “no problems,” “slight 
problems,” “moderate problems,” “severe problems,” and “extreme problems”. The study 
participant is asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses 
the level selected for that dimension. The digits for the 5 dimensions can be combined into a 
5-digit number that describes the study participant’s health state. 
The EQ-VAS records the study participant’s self-rated health on a vertical visual analogue scale, 
where the endpoints are labeled ‘The best health you can imagine’ and ‘The worst health you can 
imagine.’ The VAS can be used as a quantitative measure of health outcome that reflects the 
study participant’s own judgement. 
8.1.3 
Wearable sensor 
Data generated from the wearable sensor will be included within the panel of exploratory 
assessments and comprise changes in objective measures of motor function, sleep, and selected 
neurovegetative parameters assessed with a customized, wrist-worn digital sensor (hereinafter 
referred to as “wearable sensor,” which will be worn on the usual wristwatch side for comfort, 
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even if it is not the most affected side). The multisensor unit will continuously collect 
physiological and environmental data, including acceleration/orientation, pulse rate, skin 
impedance, ambient pressure, ambient temperature (in device chamber), and ambient light level. 
Digital data collection is initiated during an approximately 2-week adaptation period 
(Section 1.3) to address technical issues and handling errors and to ensure robust Baseline data 
before initiation of dosing. Where it is not possible to access the sensor during the Baseline 
period, participants may start wearing it until Visit 8 (M4). To yield a solid Baseline for the 
VMEs, these home-based structured activities will be conducted every day throughout the 
familiarization period. If necessary, the frequency will be adjusted on an individual basis. Study 
participants will be encouraged to identify a most appropriate time-window in their daily 
schedule, where the home-based structural activities should be placed. This routine should be 
maintained until the end of the study. In case of initiation of symptomatic treatment, the home-
based VME should be conducted in the practically defined off-state (typically before the intake 
of the morning medication). Throughout the first 12 months of the study, spontaneous activity 
data coming from the various sensors included in the wearable sensor will be continuously (up to 
23 hours/day) collected in a usual home-setting (or work setting, if applicable) and throughout all 
non-home-based activities. Even though the laterality of the most pronounced motor symptoms 
should shift to the contralateral side over time, the wearable sensor will continue to be worn on 
the initially selected side. In addition to the continuous data collection, a series of 8 simple 
structured motor tasks will be performed on a weekly basis in the study participant’s home 
environment. 
Screening Period (Visit 2 to Visit 3): 
During the Screening Period between Visit 2 and Visit 3 (or any 2-week period before Visit 9 
[M6] for participants consenting to using the wearable sensor after having completed the 
Screening Period), one VME per day will be performed by the participants at home to familiarize 
themselves with the wearable sensor. Participants will rate their individual performance of each 
VME Skill Check directly on the wearable sensor after each task (5-option smiley face scale, 
with description provided in the VME training guide). 
Baseline (Visit 3): 
During the Baseline Visit (Visit 3), participants will perform the VME in the clinic before the 
first dose of the study treatment, following the MDS-UPDRS Part III assessments. Investigators 
will rate participant performance of each VME Skill Check following the Investigator Rating 
Scale (refer to Section 10.12 [Appendix 12]). 
The frequency of the VME will be changed after the familiarization period to weekly on the 
wearable sensor by the Investigator at the next clinical study visit. Participants will be requested 
to select the day of the week and the time to plan the VME Skill Check Schedule. 
Treatment Period: 
At in-clinic visits and during telemedicine visits when MDS-UPDRS is assessed, the participants 
will perform 1 VME, back-to-back after their MDS-UPDRS Part III assessments. Each VME 
task will be scored by the Investigator. 
The participant will also be asked to perform 1 VME per week at home, first thing in the 
morning before intake of any PD treatment. 
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The wearable sensors will be finally returned by the participant to the site on Visit 15 (M18) or 
Early Termination Visit in case of early study termination). 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.2.1 
Physical examination 
Physical examinations will be performed at the scheduled time points presented in the Schedule 
of Activities (Section 1.3). A complete physical examination will include, at a minimum, general 
appearance; ear, nose, and throat; eyes, hair, and skin; and assessments of the cardiovascular, 
respiratory, gastrointestinal, musculoskeletal, hepatic, and neurological systems (including 
sensation, muscle strength, reflexes, balance, and mental state) (a brief neurological exam will 
only be performed as part of the physical assessment on days when the full neurological exam is 
not already scheduled). 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen. A physical examination of the skin will include, at a 
minimum, a visual check of the skin (including an inspection of the oral cavity), and may be 
conducted by a nurse or physician. Investigators and site staff should pay special attention to 
clinical signs related to previous serious illnesses and hypersensitivity reaction (such as rash, 
angioedema, or anaphylaxis). For any emergent lesion or abnormality on the skin, a full 
examination of skin and close observation is required to exclude possibility of a hypersensitivity 
reaction as per Section 8.3.6.1. 
During telemedicine video call visits, physical examinations will be limited to focused body 
examinations performed by research nurses. These will include, at a minimum, an assessment of 
the cardiovascular system (absence/presence of swelling of feet/ankles, absence/presence of 
pallor), respiratory system (absence/presence of cyanosis), gastrointestinal system 
(absence/presence of ulcers, rash, lumps, or exudate in the mouth, absence/presence of jaundice, 
absence/presence of abdominal pain on palpitation), and skin (absence/presence of rash, ulcers, 
lumps). The examination by the nurses will be guided and assessed by the Investigator via 
telemedicine video call. 
Any abnormal finding from the focused body examinations by the research nurses will be 
highlighted to the Investigator. The research nurses should pay special attention to clinical signs 
related to previous serious illnesses and hypersensitivity reaction (such as rash, angioedema, or 
anaphylaxis). Any abnormal findings, specifically skin changes potentially related to 
hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) (Section 8.3.6.1), should be 
highlighted to the Investigator and should be photographically documented, if the participant 
provides consent. The Investigator will provide instructions regarding further activities. Any 
abnormal finding from the focused body examinations by the research nurses will be highlighted 
to the Investigator.  
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
Height and weight will be measured and recorded at the Screening Visit, and the study 
participant’s BMI will be calculated. Height will be measured with the study participant not 
wearing shoes and the outcome will be rounded to the nearest 1cm. Body weight will be 
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measured with the study participant wearing light clothing and without wearing shoes; the 
outcome will be rounded to the nearest 0.1kg. The BMI will be calculated 
(weight [kg]/[height (m2)]) and will be reported to 1 decimal place. 
8.2.2 
Neurological examination 
The complete neurological examination will include selected assessment of general neurological 
status (level of consciousness, mental status, speech), cranial nerves, reflexes, motor system 
(general motor status, muscle strength, muscle tone), coordination/cerebellar function, and 
sensation. The day before or the day of the lumbar puncture, a complete neurological 
examination should be performed in accordance with local safety procedures and results should 
be available prior to performing the lumbar puncture. Clinically significant neurological 
examination findings are to be reported as AEs. 
A brief neurological exam will include, at a minimum, assessment of the general neurological 
status (level of consciousness, mental status, speech), reflexes, and motor system (general motor 
status, muscle strength, muscle tone). 
During telemedicine video call visits, neurological examinations will be limited to focused 
neurological examinations performed by the research nurses. These will include, at a minimum, 
determination of the level of consciousness, major psychopathological abnormalities, motor 
function, sensation, cerebellar function, muscle reflexes, and cranial nerve function. Study 
participants will be actively encouraged to verbally describe any neurological changes they have 
experienced since the last visit. This information will be captured by the nurse. Any significant 
new abnormal findings emerging on the brief neurological examination may entail a more formal 
investigation by a trained neurologist for accurate characterization and determination of the level 
of consciousness, major psychopathological abnormalities, motor function, sensation, cerebellar 
function, muscle reflexes, and cranial nerve function. The examination by the nurses will be 
guided and assessed by the Investigator via telemedicine video call. 
8.2.3 
Vital signs 
Vital signs, including pulse rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), 
respiratory rate, and tympanic body temperature will be measured with a completely automated 
device after 5 minutes of rest in supine position (in a quiet setting without distractions such as a 
television or cell phones) and erect to assess autonomous dysregulation. Manual techniques will 
be used only if an automated device is not available. Any observation by the research nurse will 
be discussed with the Investigator during the video communication part of the remote visit. Any 
clinically significant abnormality in the view of the Investigator will be recorded as an AE. 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 3 pulse and 
3 blood pressure (BP) measurements (3 consecutive BP readings will be recorded at intervals of 
at least 1 minute). All pulse and BP readings will be recorded on the eCRF and the average will 
be derived for analyses. 
8.2.4 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the Schedule of Activities (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and measures PR, 
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QRS, QT, and QTcF intervals. Refer to Section 7.1.3 for QTcF withdrawal criteria and any 
additional QTc readings that may be necessary. 
The study participant should be resting in the supine position for at least 10 minutes before the 
start of the recordings. At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 10 minutes. Electrocardiograms 
will be obtained by the research nurse during remote visits. Any observation by the research 
nurse will be discussed with the Investigator during the video communication part of the remote 
visit. 
The Investigator should review all ECG recordings and, if there are abnormalities that are 
considered clinically significant for a particular study participant, then the Investigator should 
initiate a review by a specialist of all ECG data pertaining to that study participant. The 
following ECG parameters will be recorded in the eCRF: heart rate, PR interval, QRS duration, 
QT interval, QTcF, and Investigator’s conclusion on ECG profile. 
8.2.5 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
Schedule of Activities (Section 1.3) for the timing and frequency. Blood/urine sampling and 
urine pregnancy testing will be performed by the research nurses during remote visits. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition.  
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study medication should be repeated until the 
values return to normal or Baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the Schedule of Activities (Section 1.3). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE), then the results must be recorded in 
the eCRF. 
8.2.6 
Suicidal risk monitoring 
UCB0599 is a CNS-active study medication. There has been concern that some CNS-active 
study medications may be associated with an increased risk of suicidal ideation or behavior when 
given to some participants with PD. 
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Suicidality will be assessed by trained site study personnel using the C-SSRS (Posner et al, 
2011). During remote visits, the assessment will be performed remotely via telemedicine. This 
scale will be used for Screening as well as to assess suicidal ideation and behavior that may 
occur during the study. All study participants will complete the “Baseline/Screening” version of 
the C-SSRS at Visit 1 (assessing the past 6 months), followed by the “Since Last Visit” version 
at the visits indicated on the Schedule of Activities (Section 1.3). 
Participants being treated with UCB0599 should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. Families and 
caregivers of participants being treated with UCB0599 should be instructed to monitor 
participants for the emergence of unusual changes in behavior, as well as the emergence of 
suicidal ideation and behavior, and to report such symptoms immediately to the study 
Investigator. Consideration should be given to discontinuing UCB0599 in participants who 
experience signs of suicidal ideation or behavior. Study stopping behavior for study participants 
with suicidal ideation or behavior is described in Section 7.2. 
8.2.7 
MRI assessments 
Structural brain MRIs will be performed at the Screening Visit (Visit 2) for study participants 
without an acceptable historical scan within 6 months before this visit, on an MRI scanner of at 
least 1.5 Tesla, using a standardized acquisition protocol and without contrast. At a minimum, 
the following sequences will be performed per local standard practice: T1, T2, and T2 FLAIR.  
8.2.8 
Wearable sensor data 
Physiological and environmental data obtained from the wearable sensor will not be used for 
safety monitoring and reporting of UCB0599 because the sensor is unvalidated for this purpose 
and will be only used for exploratory endpoints in this study. 
The Investigator is expected to record any AEs in the eCRF and assess causality as it might 
relate to the wearable sensor. The eCRF page will allow the Investigator to assess causality in 
relation to the wearable sensor. 
Serious adverse events should be reported in the eCRF and expedited to the Sponsor according to 
Appendix 3 (Section 10.3). 
The Sponsor will send reports of SAEs relating to the wearable sensor to Verily so that the 
manufacturer can comply with its reporting obligations. 
See Appendix 7 (Section 10.7) for more information about sensor deficiencies, accountability, 
handling, and discontinuation. 
8.3 
Adverse events and serious adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver or 
surrogate). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study medication or study procedures, or that caused 
the participant to discontinue UCB0599 or PD0053 (see Section 7). 
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On the AE eCRF page, there is the possibility to assess causality to the IMP and to any 
concomitant medication. If an AE is considered related to COVID-19 vaccine, a causality 
assessment should be entered in the AE eCRF.  
Note that in this case the national recommendation for reporting AEs related to COVID-19 
vaccines should be followed.  
If an AE is the result of an interaction between a COVID-19 vaccine and IMP in the study, then 
the clinical study causal association should be for both IMP and COVID-19 vaccine.  
For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the SFU Visit at the time 
points specified in the Schedule of Activities (Section 1.3). 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no study medication was taken but specific study 
procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs 
that recurred or worsened after the initial visit. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each participant, and to also inform 
participants of the need to inform the Investigator of any SAE within this period. Serious AEs 
that the Investigator thinks may be associated with the study medication must be reported to 
UCB regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and nonserious AESIs (as defined in 
Section 8.3.6) will be followed until resolution, stabilization, the Investigator determines that it is 
no longer clinically significant, the event is otherwise explained, or the participant is lost to 
follow up (as defined in Section 7.3). Further information on follow up procedures is given in 
Appendix 3 (Section 10.3). 
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8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
medication under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study medication under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study medication and until at least 12 months after 
the delivery date. 
If a pregnancy is reported, the Investigator must immediately inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
The participant should be withdrawn from the study as soon as pregnancy is known (by positive 
pregnancy test), and the following should be completed: 
• The participant should return for an early discontinuation visit. 
• The participant should immediately stop the intake of the study medication as instructed at 
the early discontinuation visit. 
• An SFU Visit should be scheduled 14 days after the participant has discontinued her study 
medication. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse events of special interest 
An AESI is any AE that a regulatory authority has mandated be reported on an expedited basis, 
regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a 
UCB product/compound.For UCB0599, the following events require immediate reporting 
(within 24 hours regardless of seriousness) to UCB: 
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• Hy’s Law 
− Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the 
biochemical abnormality (ie, without waiting for any additional etiologic investigations 
to have been concluded). Follow-up information should be reported if an alternative 
etiology is identified during investigation and monitoring of the participant. 
• Hypersensitivity reactions (such as rash, angioedema, or anaphylaxis) 
8.3.6.1 
Hypersensitivity reaction monitoring and management 
If a study participant experiences hypersensitivity reaction (such as rash, angioedema, or 
anaphylaxis), he or she will contact the clinical site immediately (24 hours a day) or seek urgent 
medical advice in accordance with instructions from the Investigator. 
The advice will be based on the clinical presentation and may be to present to the clinical site or 
seek medical attention in the community. 
The study participant should be rapidly and thoroughly assessed in line with actions below.  
Hypersensitivity reactions (such as rash, angioedema, or anaphylaxis) will be AESIs and require 
expedited reporting to UCB, regardless of seriousness, expectedness, or relatedness in line with 
Section 8.3.6. This will allow for rapid evaluation. 
In case of a suspected hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) or 
any clinical indication of an unexpected immune response, the points described in 
Sections 8.3.6.1.1 through 8.3.6.1.4 should be observed. 
Consideration for restarting study medication is provided in Section 7.1.1. 
8.3.6.1.1 
Medical history 
Detailed history of the hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) with 
onset time of symptoms and signs, location of symptoms and signs, first appearance, its 
evolution (eg, where the rash appeared and to where it spread), any other symptoms (eg, pruritus, 
swelling, breathlessness, etc), especially if showing a systemic involvement (anaphylaxis), will 
be recorded. The criteria for anaphylaxis are described in Section 8.3.6.1.1.1. 
The clinical progression of the hypersensitivity reactions symptoms should be recorded and any 
change in symptoms or severity should also be recorded together with the timing. 
All AEs reported concurrently should be included within the review. 
It will also be important to investigate any recent intake of new medications, herbs, supplements, 
or the recent use of any topical substances. 
8.3.6.1.1.1 
Anaphylaxis 
Sampson et al. listed criteria for the diagnosis of anaphylaxis. This was developed at the Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium (Sampson et al, 2006). 
Acute onset=minutes to a few hours. 
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Criteria for diagnosis-1 or more of the following: 
• Acute onset of an illness with symptom complex 1 (see below) 
• Acute onset of symptom complex 2 (see below) after exposure to a likely allergen 
• Acute onset of a reduced SBP after exposure to a known allergen for the participant. 
Symptom complex 1: both of the following: 
• At least 1 of the following: 
 
Skin involvement (generalized hives, pruritis, flushing) 
 
Mucous membrane involvement (swollen lips, swollen tongue, swollen uvula) 
• At least 1 of the following: 
 
Respiratory compromise (dyspnea, wheezing, bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
 
Reduced SBP, collapse, syncope, incontinence or other symptom of end-organ 
dysfunction 
Symptom complex 2: 2 or more of the following: 
• Skin or mucous membranes (as above) 
• Respiratory compromise (as above) 
• Reduced BP (as above) 
• Persistent gastrointestinal tract symptoms (cramping, abdominal pain, vomiting) 
Reduced SBP is indicated by 1 of the following: 
• Blood pressure <70% of Baseline SBP 
• Age ≥11 years AND <90mmHg 
Limitations: 
Treudler et al. found that the criteria may not perform as well as others for the recognition of 
severe, immediate reactions (Treudler et al, 2008). 
8.3.6.1.2 
Complete physical examination 
Evaluation of a possible hypersensitivity reaction (such as rash, angioedema, or anaphylaxis) 
includes a complete physical examination of the entire body as soon as feasible after reporting by 
the study participant. The complete physical examination includes a detailed description of the 
signs such as rash or angioedema, the location of the signs, and an examination for other possible 
signs, such as: 
• Blanched or flushed skin 
• Mucous membrane erosions or ulceration 
• Maculae 
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• Papulae 
• Blisters 
• Confluent erythema 
• Angioedema: face, lips, and/or tongue swelling, also back of hands or feet 
• Wheeze, stridor, dyspnea 
• Palpable purpura 
• Lymphadenopathy 
An examination of the entire skin surface, not just local to the site of reaction, is required. 
Furthermore, a complete physical examination will also include: 
• Vital signs (high fever, dyspnea, or hypotension) 
 
Vital signs (pulse rate, SBP, DBP, respiratory rate, body temperature, and oxygen 
saturation) will be taken when the AE of hypersensitivity is reported and at regular 
intervals (approximately 20-30 minutes) for a minimum of 2 hours. The frequency 
thereafter will be based on clinical judgement. If there is worsening of clinical status, the 
Investigator will apply the appropriate treatment and safety procedures (eg, call 
emergency) and contact the UCB Study Physician. 
• Photography of rash and other symptoms at the first opportunity and with reasonable time 
sequence to document resolution. If timely site visit is not possible the participant may be 
requested to take photos to ensure photos of active symptoms. If participant is requested to 
provide photos the Investigator should advise the participant in data protection requirements 
(eg, avoidance of identifying features such as characteristic tattoos, parts of the face). The 
Investigator will ensure that identifiable characteristics are removed / hidden before sharing 
the pictures with the Sponsor. 
• Re-examination should the symptoms significantly worsen 
• Occurrence of other recent or current symptoms, even if they appear not related 
8.3.6.1.3 
Additional investigations 
Investigators should arrange for the following investigations; further investigations may be 
requested after consultation with the Medical Monitor: 
• Additional blood sampling for extended etiological characterization of the hypersensitivity 
reaction including: 
− Basophil Activation Test 
− Lymphocyte Transformation Test assays 
− Tryptase  
− IgE 
• Rapid referral to experts (ie, dermatologist, allergist, or immunologist) 
Additionally a skin biopsy should be considered following review by expert. 
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8.3.6.1.4 
Treatment 
Investigators will administer the appropriate treatment as deemed necessary in cases of 
hypersensitivity. This includes the use of antihistamines for urticaria and the appropriate 
management in case of potentially life-threatening events such as anaphylaxis, Stevens-Johnson 
Syndrome, and toxic epidermal necrolysis. 
8.3.6.2 
Renal function safety monitoring and management 
If a participant develops clinically significant renal dysfunction, repeat laboratory testing should 
be undertaken as soon as possible and other appropriate investigations may be arranged. An 
increase in serum creatinine of >25% from the previous value will trigger repeat testing within 
48 hours. The Medical Monitor should be notified and consideration should be given to more 
frequent monitoring. 
Clinically significant renal dysfunction will trigger an SMC and DMC review. 
Participants must be discontinued from study medication (but not necessarily from the study) if 
laboratory tests suggest evidence of renal toxicity (see Section 7.2). Any clinically significant 
findings in laboratory results for renal function will be monitored until resolution or stabilization. 
The SMC and DMC charters will include further details regarding the assessment of renal 
function. 
8.3.7 
Anticipated serious adverse events 
The following Anticipated SAEs are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure. 
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 8.3.1 and Appendix 3 (Section 10.3). 
 
Table 8-1: 
Anticipated serious adverse events for Parkinson’s disease 
population 
MedDRA System Organ Class 
MedDRA Preferred Term 
Nervous system disorders 
Syncope 
Psychiatric disorders 
Hallucination  
MedDRA=Medical Dictionary for Regulatory Activities 
8.3.8 
Wearable sensor – adverse events (adverse sensor effects, 
unanticipated adverse sensor effects, SAEs, serious adverse drug 
events, and unanticipated serious adverse drug events) and sensor 
deficiencies 
The wearable sensor is being provided as a noninvasive exploratory tool for use in this study for 
the evaluation of digital measurements for aspects of motor function, sleep, and neurovegetative 
parameters.  
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In order to fulfill regulatory reporting obligations worldwide, the Investigator is responsible for 
the detection and documentation of events meeting the definitions of incident or malfunction that 
occur during the study with the wearable sensor. 
Adverse Events associated with the wearable sensor will be reported to the appropriate 
regulatory agencies and sensor developer. Adverse event reporting will be conducted as per the 
specific laws, regulations, directives, standards and/or guidelines as appropriate and as required 
by the countries in which the clinical investigation is conducted. 
The definition of a sensor deficiency can be found in Appendix 7 (Section 10.7). 
NOTE: Events fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.3.3 and Appendix 3 (Section 10.3). 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Patient Safety 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.5 
Treatment of overdose 
For this study, any administration of UCB0599 totaling greater than 360mg within 
approximately a 24-hour time period will be considered an overdose. 
Overdose events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess study medication itself is an AE or SAE (eg, suicide 
attempt). 
UCB does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator or treating physician should: 
• Stop dosing and contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until UCB0599 
can no longer be detected systemically (approximately 5 days). 
• Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
medication if requested by the Medical Monitor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
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8.6 
Pharmacokinetics 
Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of UCB0599 and its N-oxide metabolite as specified in the Schedule of Activities 
(Section 1.3). A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between the Investigator and the Sponsor. Instructions for 
the collection and handling of biological samples will be provided by the Sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Participant confidentiality will be maintained. At visits during which plasma samples will be 
taken for the determination of UCB0599 and its N-oxide metabolite concentrations. Drug 
concentration information that would unblind the study will not be reported to investigative sites 
or blinded personnel until the study has been unblinded. 
Samples will be used to evaluate the PK of UCB0599 and its N-oxide metabolite. One sample of 
sufficient volume can be used. Each plasma sample will be divided into 2 aliquots (1 each for PK 
and a back-up). Samples collected for analyses of UCB0599 and its N-oxide metabolite 
concentrations may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study. 
Cerebrospinal fluid samples will be taken at 12 months and EOT to measure concentrations of 
UCB0599 and metabolites. Timing of CSF sampling will be done close to blood sampling time. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
8.7 
Genetics 
Refer to Section 8.9 for more information. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 
Biomarkers 
Genetic sampling will be mandatory for study participation. Collection of samples for potential 
exploratory biomarker research forms part of the study objectives (where biomarkers can 
include, but are not limited to, deoxyribonucleic acid (DNA), RNA, protein, and metabolites). 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the PD0053 laboratory manual for this study. All collected samples may be used for 
research purposes focusing on method development and assay development or to better 
understand the association between biomarkers and disease progression, clinical phenotypes, or 
the correlation between different biomarkers or biomarkers and clinical scales. Collection of 
these samples will enable evaluation of biomarkers relative to disease biology and progression, 
study medication treatment and response, and/or mechanism of action of the study medication 
treatment. The following samples will be collected and stored from all participants in this study 
to support potential future exploratory biomarker research. These samples are a required 
component of the protocol as specified in the Schedule of Activities (Section 1.3). 
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• Blood samples for DNA specified in the Schedule of Activities (Section 1.3). See 
Appendix 5 (Section 10.5) for information regarding genetic research. 
• Cerebrospinal fluid and blood samples for measurement of biomarkers will be collected at 
the time points specified in the schedule of Schedule of Activities (Section 1.3). Candidate 
biomarkers might include, but are not limited to: monomeric, oligomeric ASYN, 
pS129-ASYN, and total ASYN. At dosing visits, blood samples will be drawn prior to 
dosing, and will be drawn at the same time of the sampling for clinical laboratory tests. The 
time and date of collection will be recorded in the eCRF. 
− As part of each individual CSF sampling procedure, a maximum of 12mL of CSF during 
each lumbar puncture will be collected and a CSF quality control check (total cell count 
and/or hemoglobin measurement) will be done to identify a possible contamination with 
blood caused by lumbar puncture. 
• All samples collected may be used for exploratory purposes. 
These samples will only be used to further understanding of PD and/or how biomarkers, 
including genetic variation, may affect response or be affected by treatment with UCB0599 in 
the treatment of PD. 
8.10 
 Medical resource utilization and health economics 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP).  
9.1 
Definition of analysis sets 
The following analysis sets will be used: 
• All Study Participants Set: All study participants who sign the ICF 
• Randomized Set (RS): All study participants who are randomized 
• Safety Set (SS): All randomized study participants who receive at least a partial dose of study 
medication. The SS will be used for demographic and safety analyses and analyses will be 
based on treatment received. 
• Full Analysis Set (FAS): All randomized study participants who receive at least a partial dose 
of study medication and who have at least 1 post-Baseline assessment. The FAS will be used 
for all efficacy analyses, and analyses will be conducted based on randomized treatment. 
• Pharmacokinetic Set (PKS): All study participants in the Safety Set who have at least 
1 observable PK measurement. The PKS will be used for PK analyses. 
For all analyses, the target population will be the ‘entire study population’ as selected according 
to the inclusion/exclusion criteria described in Section 5. 
The FAS will be used for all analyses with intercurrent events (ICEs) and other protocol 
deviations to be handled according to the policy specified for each estimand (Section 9.3). 
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9.2 
General statistical considerations 
All analyses will be performed using SAS® version 9.4 or later (SAS Institute, Cary, NC, USA). 
For continuous variables, summary statistics will include the number of study participants, mean, 
median, standard deviation (SD), minimum, and maximum, unless stated otherwise. Categorical 
endpoints will be summarized using frequency counts and percentages. Further details on which 
summary statistics will be presented for each variable type will be given in the SAP. 
9.3 
Planned efficacy/outcome analyses 
An overview of the planned efficacy analyses is presented in Table 9-1. For all estimands, the 
difference between UCB0599 and placebo will be evaluated for both the low and the high doses 
of UCB0599 (180mg/day and 360mg/day). The comparison of the high dose of UCB0599 with 
placebo will be considered as the primary evaluation. If the comparison of the low dose and 
placebo gives a positive result on the primary estimand but the comparison of the high dose and 
placebo does not, these results will have to be interpreted with caution. In all analyses, the 2 dose 
levels will be assessed separately against placebo, there will be no pooling of the 2 dose levels, 
and they will not be compared to each other. 
 
Table 9-1: 
Overview of planned efficacy analyses 
Objectives 
Estimands 
Primary Efficacy Objective 
Target population: Entire study population 
To demonstrate the superiority of UCB0599 
over placebo with regard to clinical 
symptoms of disease progression over 12 
and 18 months in participants diagnosed with 
early-stage PD 
Primary Efficacy Estimand 
• Difference between UCB0599 and 
placebo in target population mean slope of 
progression in MDS-UPDRS Parts I-III 
sum score over 12 months in the absence 
of concomitant ST intake 
 
 
Key Secondary Efficacy Estimands 
• Difference between UCB0599 and 
placebo in target population mean in 
MDS-UPDRS Parts I-III sum score at 
18 months in the absence of concomitant 
ST intake 
• Difference between UCB0599 and 
placebo in target population mean slope of 
progression in MDS-UPDRS Part III 
subscale score over 12 months in the 
absence of concomitant ST intake 
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Table 9-1: 
Overview of planned efficacy analyses 
• Difference between UCB0599 and 
placebo in target population mean in 
MDS-UPDRS Part III ePD subscore at 
12 months in the absence of concomitant 
ST intake 
• Difference between UCB0599 and 
placebo in target population RMET, in 
this case, time to worsening of the disease 
as defined by a 5-point increase in MDS-
UPDRS III, within the 18-month period, 
in the absence of concomitant ST intake 
Secondary Efficacy Estimands 
• Difference between UCB0599 and 
placebo in target population mean MDS-
UPDRS Part I/II subscales at 12 months 
in the absence of concomitant ST intake 
• Difference between UCB0599 and 
placebo in target population mean MDS-
UPDRS Part I/II/III subscales at 
18 months in the absence of concomitant 
ST intake 
• Difference between UCB0599 and 
placebo in target population mean in 
MDS-UPDRS Part III ePD subscore at 
18 months in the absence of concomitant 
ST intake 
• Ratio between UCB0599 and placebo 
based on population annualized rate of 
emerging symptoms assessed by 
MDS-UPDRS Part II subscale over the 
18-month period 
• Difference between UCB0599 and 
placebo in target population mean MDS-
UPDRS Part I subscale at 12 months 
regardless of concomitant ST intake 
• Difference between UCB0599 and 
placebo in target population mean MDS-
UPDRS Part I subscale at 18 months 
regardless of concomitant ST intake 
• Difference between UCB0599 and 
placebo in target population mean MoCA 
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Table 9-1: 
Overview of planned efficacy analyses 
at 18 months, regardless of concomitant 
ST intake 
Exploratory Efficacy Endpoints 
• Time to worsening on MDS-UPDRS 
Part I subscale  
• Modified Hoehn and Yahr staging 
• CGII 
• CGIS 
• Fatigue-PRO 
• Early PD Function Slowness PRO 
• Early PD Mobility PRO 
• Composite endpoint (based on 
MDS-UPDRS and/or Early PD PROs) 
• PGIS, overall and fatigue-specific 
• PGIC, overall and fatigue-specific 
• SE-ADL 
• HADS 
• MDS-NMS 
• Starkstein Apathy Scale 
• EQ-5D-5L 
• Wearable sensor 
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Table 9-1: 
Overview of planned efficacy analyses 
Secondary Efficacy Objectives 
Target population: Entire study population 
To demonstrate the superiority of UCB0599 
over placebo with regard to 
neurodegeneration of dopaminergic 
neurons over 12 and 18 months in 
participants diagnosed with early-stage PD 
Secondary Efficacy Estimand 
• Difference between UCB0599 and 
placebo in target population mean change 
from Baseline (Screening) in DaT-
SPECT mean Striatum SBR at 18 
months regardless of concomitant ST 
intake 
• Difference between UCB0599 and 
placebo in target population mean change 
from Baseline (Screening) in DaT-
SPECT mean Striatum SBR at 12 
months regardless of concomitant ST 
intake 
Exploratory Efficacy Endpoints 
• DaT-SPECT mean SBR in striatal 
subregions 
• CSF total ASYN 
• CSF ASYN oligomers/seeding capacity 
To assess the effect of UCB0599 vs placebo 
with regard to intake of ST over 18 months in 
participants diagnosed with early-stage PD 
Secondary Efficacy Estimands 
• Difference between UCB0599 and 
placebo in target population RMET, in 
this case, time to start of ST, within the 
18-month period, regardless of adherence 
to assigned study medication 
• Target population odds ratio between 
UCB0599 and placebo in ST intake at 
18 months, regardless of adherence to 
assigned study medication 
Other Secondary Efficacy Estimand 
• Target population odds ratio between 
UCB0599 and placebo in ST intake at 
12 months, regardless of adherence to 
assigned study medication 
Exploratory Efficacy Endpoints 
• Levodopa cumulative daily dose 
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ASYN=alpha-synuclein; CGII=Clinical Global Impression of Improvement; CGIS=Clinical Global Impression of 
Severity; CSF=cerebrospinal fluid; DaT-SPECT=Dopamine Transporter Imaging with Single Photon Emission 
Computerized Tomography; ePD=early-stage PD; EQ-5D-5L=EuroQol-5-dimension-5-level; HADS=Hospital 
Anxiety and Depression Scale; MDS-NMS=Movement Disorder Society-Non-motor Scale; 
MDS-UPDRS=Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; MoCA=Montreal 
Cognitive Assessment; PD=Parkinson’s Disease; PGIC=Patient Global Impression of Change; PGIS=Patient 
Global Impression of Severity; PRO=Patient-Reported Outcome; RMET=restricted (t-year) mean event time; 
SBR=specific binding ratio; SE-ADL=Schwab and England Activities of Daily Living; ST=symptomatic 
treatment 
Note: “In the absence of concomitant ST intake” means that all data recorded after a participant initiates ST will be 
censored. “Regardless of concomitant ST intake” means that participant data will be included in the analyses even 
after they have initiated ST. If a participant does not comply with the 12-hour ST washout prior to any visit, the data 
from that particular visit will be censored. 
Efficacy data analysis at 12 and 18 months will take place once all participants have completed 
their 18-month Visit. All efficacy analyses will be carried out for the FAS and adjusted for the 
randomization stratification factor (ie, gender) and age at Baseline. 
Treatment will be coded as a categorical variable with 3 levels (placebo, UCB0599 high dose, 
and UCB0599 low dose) with placebo as the reference category. 
For change from Baseline analysis, treatment will be fitted as a fixed (main) effect. For 
longitudinal analyses of covariance and repeated measures modeling in which Baseline value is 
used as outcome, a treatment by time interaction will be included in this model as implicitly, the 
Baseline values for all groups are assumed to be equal and are reflected in the intercept of the 
models (Twisk, 2013). 
Where applicable, explanatory continuous covariates will be mean-centered so that the intercept 
term can be interpreted as the expected value of the response when the dependent variables are 
set to their means. 
Where reported alongside estimates and corresponding confidence intervals (CIs), p-values will 
always be presented as continuous values. 
Estimands will be described as a function of their attributes: (1) the population of interest, (2) the 
treatment effect of interest, (3) the participant-level variable (or endpoint) of interest, (4) the 
specification of how ICEs are reflected in the scientific question of interest, and (5) the 
population-level summary for the variable/endpoint.  
9.3.1 
Analysis of the Primary Efficacy Objective: “Clinical symptoms at 
12 and 18 months” 
9.3.1.1 
Analysis of “Clinical symptoms at 12 months” 
To demonstrate the superiority of UCB0599 over placebo with regard to clinical symptoms of 
disease progression over 12 months in participants diagnosed with early-stage PD. 
9.3.1.1.1 
Primary Efficacy Estimand: MDS-UPDRS Parts I-III sum score at 
12 months (“De Jure” Estimand) 
Participant-level endpoint 
Slope of progression in MDS-UPDRS Parts I-III sum score measured bimonthly over 12 months 
or up to the initiation of ST, including Baseline score, and scores at 2, 4, 6, 8, 10, and 12 months. 
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ICEs and handling strategies 
ST initiation will be handled using a ‘hypothetical’ strategy, where post-ICE data will be 
censored. 
Handling strategies for other ICEs are given in Table 9-2. 
Population-level summary 
Difference in population mean slope of progression in MDS-UPDRS Parts I-III sum score over 
12 months in the absence of concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo  
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
A Linear Mixed Effect Model (LMEM) for longitudinal data/repeated measures will be applied 
to the data up to the initiation of ST. 
Baseline MDS-UPDRS data will be fitted as part of the dependent variable. Time as a continuous 
variable, ie, assuming linear development over 12 months, and treatment by time interaction 
(fixed slope) will be fitted as fixed effects (Twisk et al, 2018). To adjust for the dependency of 
the repeated observations within the individual, a participant-specific random intercept and a 
participant-specific random effect on time (ie, participant by time interaction or random slope) 
will be fitted as random effects (Twisk, 2013). The random eﬀects will induce the correlation 
structure in the marginal model (ie, the model not conditional on random effects following 
integrating them out). 
A fixed effect for treatment is not included in this model: implicitly, the Baseline values for all 
groups are assumed to be equal and are reflected in the intercept of the model. The treatment 
effects can therefore be directly obtained from the regression coefficients for the treatment by 
time interactions. 
Estimates 
Estimates for the treatment effects of interest (see above) over 12 months (MDS-UPDRS units 
increase per month) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
Supporting statistics 
To support clinical interpretation, the following descriptive statistics will be reported separately 
for each treatment groups: 
1. Number of participants who have initiated ST by 2, 4, 6, 8, 10, and 12 months. 
2. Mean change from Baseline at 2, 4, 6, 8, 10, and 12 months for participants who have not 
initiated ST. 
3. Mean change from Baseline at 2, 4, 6, 8, 10, and 12 months for participants who have 
initiated ST. 
4. Plots of individual progression of MDS-UPDRS Parts I-III sum score grouped according to 
when each participant initiated ST; further details on these plots will be given in the SAP. 
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9.3.1.1.1.1 
Supplementary Efficacy Estimand to MDS-UPDRS Parts I-III sum 
score at 12 months (“De Facto” Estimand) 
Participant-level endpoint 
MDS-UPDRS Parts I-III sum score measured bimonthly over 12 months, regardless of 
concomitant ST intake, including Baseline score, and scores at 2, 4, 6, 8, 10, and 12 months. 
ICEs and handling strategies 
ST initiation will be handled using a ‘treatment policy’ strategy, where post-ICE data are kept as 
part of the analysis. 
If a participant does not comply with the 12-hour ST washout prior to any visit, the data from 
that particular visit will be censored.  
Population-level summary 
Difference in population mean MDS-UPDRS Parts I-III sum score at 8, 10, and 12 months, 
regardless of concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
See Section 9.3.1.2.1.1 (LMEM estimator based on Baseline to Month 18 data). 
Estimates 
Estimates for the treatment effects of interest (see above) at 8, 10, and 12 months (MDS-UPDRS 
units difference at month specified) adjusted for gender and age at Baseline, with corresponding 
95% CIs. 
9.3.1.1.2 
Key Secondary Efficacy Estimand: MDS-UPDRS Part III subscale at 
12 months (“De Jure” Estimand) 
Participant-level endpoint 
Slope of progression in MDS-UPDRS Part III measured bimonthly over 12 months or up to the 
initiation of ST, including Baseline score, and scores at 2, 4, 6, 8, 10, and 12 months. 
These definitions and analyses are further detailed in the SAP. 
Other attributes: As per Primary Efficacy Estimand (Section 9.3.1.1.1) 
Estimator and estimates: As per Primary Efficacy Estimand (Section 9.3.1.1.1) 
Supporting statistics: As per Primary Efficacy Estimand (Section 9.3.1.1.1) 
Supplementary analyses: As per Primary Efficacy Estimand (Section 9.3.1.1.1) 
9.3.1.1.3 
Key Secondary Efficacy Estimand: MDS-UPDRS Part III subscale and 
Part III early-stage PD subscore at 12 months 
In collaboration with the Critical Path for Parkinson’s (CPP) consortium, UCB is developing a 
subscore more specifically targeted at the early-stage PD population based on items from the 
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MDS-UPDRS Part III subscale. A new estimand is proposed based on this early-stage PD (ePD) 
subscore measured up to Month 12. 
Participant-level endpoint 
MDS-UPDRS Part III subscale or ePD subscore measured bimonthly over 12 months or up to 
the initiation of ST, including Baseline score, and scores at 2, 4, 6, 8, 10, and 12 months. 
ICEs and handling strategies 
A different ‘hypothetical’ handling strategy of ST initiation will be implemented, where 
Month 12 data recorded after a participant initiates ST will be corrected using a de-mediation 
approach. 
Prior to the de-mediation approach, intermittent missing data will be imputed using multiple 
imputation (MI) according to randomized treatment and ST intake status. 
Population-level summary 
The population-level summary of interest will be the difference in target population mean 
observed MDS-UPDRS Part III subscale/ePD subscore at Month 12 as if the participants had not 
initiated ST between the following treatment arms: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
Monotone missing data from participants who dropped out of the study will be imputed using 
reference-based imputation (RBI) and according to ST intake status.  
Imputed datasets for those dropouts will be summarized into a single dataset to obtain Month 12 
estimates, which will then be combined with the de-mediated Month 12 estimates. 
An analysis of covariance (ANCOVA) will be applied to the complete Month 12 data. Treatment 
will be included in the model as a categorical fixed effect, gender, age at Baseline, and Baseline 
MDS-UPDRS Part III subscale (ePD subscore) data will be fitted as covariates. 
Estimates 
Estimates for the treatment effects of interest (see above) at Month 12 (MDS-UPDRS units 
difference) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
9.3.1.1.4 
Secondary Efficacy Estimands: MDS-UPDRS Part I/II subscales at 12 
months (“De Jure” Estimands) 
Participant-level endpoint 
MDS-UPDRS Part I/Part II measured bimonthly over 12 months or up to the initiation of ST, 
including Baseline score, and scores at 2, 4, 6, 8, 10, and 12 months. 
ICEs and handling strategies 
For MDS-UPDRS Part I/II subscales, ST will be handled using a ‘hypothetical’ strategy, where 
post-ICE data will be censored. 
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Population-level summary 
Difference in population mean MDS-UPDRS Part I/II subscales over 12 months (in the absence 
of concomitant ST intake) between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
See Section 9.3.1.2.3 (LMEM estimator based on Baseline to Month 18 data). 
Estimates 
Estimates for the treatment effects of interest (see above) at 8, 10, and 12 months (MDS-UPDRS 
units difference at month specified) adjusted for gender and age at Baseline, with corresponding 
95% CIs.  
9.3.1.1.4.1 
Supplementary Efficacy Estimand to MDS-UPDRS Part I/II subscales 
at 12 months (“De Facto” Estimand) 
Participant-level endpoint 
MDS-UPDRS Part I/Part II subscale measured bimonthly over 12 months regardless of 
concomitant initiation of ST, including Baseline score, and scores at 2, 4, 6, 8, 10, and 
12 months. 
ICEs and handling strategies: As per the Supplementary Efficacy Estimand (Section 9.3.1.1.1.1). 
Population-level summary 
Difference in population mean MDS-UPDRS Part II subscale at 12 months, regardless of 
concomitant ST intake, between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator, estimates, and sensitivity analyses:  
See Section 9.3.1.2.1.1 (LMEM estimator based on Baseline to Month 18 data). 
9.3.1.1.5 
Exploratory Efficacy Endpoints at 12 months 
• Time to worsening in MDS-UPDRS Part I subscale 
• Modified Hoehn and Yahr staging 
• SE-ADL 
• CGII 
• CGIS 
• Fatigue-PRO 
• Early PD Function Slowness PRO 
• Early PD Mobility PRO 
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• Composite endpoint (based on MDS-UPDRS and/or Early PD PROs) 
• PGIS, overall and fatigue-specific 
• PGIC, overall and fatigue-specific 
• HADS 
• Starkstein Apathy Scale 
• MDS-NMS 
• EQ-5D-5L 
• Wearable sensor 
Details of these analyses are provided in the SAP. 
9.3.1.2 
Analysis of “Clinical symptoms at 18 months” 
To demonstrate the superiority of UCB0599 over placebo with regard to clinical symptoms of 
disease progression over 18 months in participants diagnosed with early-stage PD. 
9.3.1.2.1 
Key Secondary Efficacy Estimand: MDS-UPDRS Parts I-III sum score 
at 18 months (“De Jure” Estimand) 
Participant-level endpoint 
MDS-UPDRS Parts I-III sum score measured bimonthly over 18 months in the absence of 
concomitant ST intake, including Baseline score, and scores at 2, 4, 6, 8, 10, 12, 14, 16, and 
18 months. 
ICEs and handling strategies 
As per Primary Efficacy Estimand (Section 9.3.1.1.1). 
Population-level summary 
Difference in population mean MDS-UPDRS Parts I-III sum score at 18 months in the absence 
of concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
A LMEM for longitudinal data/repeated measures, similar to the one described for the Primary 
Efficacy Estimand Estimator (Section 9.3.1.1.1) but with time set as a categorical variable, will 
be applied to the data up to the initiation of ST. 
Estimates 
Estimates for the treatment effects of interest (see above) at 18 months (MDS-UPDRS units 
difference) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
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9.3.1.2.1.1 
Supplementary Efficacy Estimand: MDS-UPDRS Parts I-III sum score 
at 18 months (“De Facto” Estimand) 
Participant-level endpoint 
MDS-UPDRS Parts I-III sum score measured bimonthly over 18 months, regardless of 
concomitant ST intake, including Baseline score, and scores at 2, 4, 6, 8, 10, 12, 14, 16, and 
18 months. 
ICEs and handling strategies 
As per the Supplementary Efficacy Estimand (Section 9.3.1.1.1.1) 
Population-level summary 
Difference in population mean MDS-UPDRS Parts I-III sum score at 18 months, regardless of 
concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
A LMEM for longitudinal data/repeated measures, similar to the one described for the 
Supplementary Efficacy Estimand to the Primary Estimand (Section 9.3.1.1.1.1), with time set as 
a categorical variable, will be applied to all observed data, up to the end of the intended 
follow-up period, including ST data. 
Estimates 
Estimates for the treatment effects of interest (see above) at 18 months (MDS-UPDRS units 
difference) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
9.3.1.2.2 
Key Secondary Efficacy Estimand: Worsening on MDS-UPDRS Part 
III subscale at 18-month (“De Jure” Estimand) 
Participant-level endpoint 
Time from Baseline to the participant’s first 5-point increase in MDS-UPDRS Part III subscale 
(or to last censored time observation due to initiation of ST) within the 18-month period. 
ICEs and handling strategies 
The main ICE will be initiation of ST, and will be handled using a ‘composite’ strategy where 
initiation of ST is part of the endpoint definition. Study termination and loss to follow up will be 
handled using a ‘hypothetical’ strategy where post-ICE data is set to missing. For all other ICEs, 
see Table 9-2. 
Population-level summary 
Difference in target population RMET, in this case, time to 5-point increase in MDS-UPDRS 
Part III subscale, within the 18-month period in the absence of concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
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An RMET analysis has been chosen as (i) it has been shown to be a robust method under no-PH, 
(ii) it can be estimated even under heavy censoring, and (iii) it has an easy clinical interpretation 
as the average time until an event occurs during a defined time period ranging from time 0 to a 
specific follow-up time point (Royston and Parmar, 2013). 
Estimator 
The RMET will be estimated as the area under the Kaplan-Meier ‘survival’ curve up to a 
prespecified point in time (Royston & Parmar, 2013) or in other words, the integral of the 
survival function over the study period. However, a modeling approach will need to be used here 
in order to adjust for gender. As the main analysis for time to the first 5-point increase in MDS-
UPDRS Part III subscale, RMET from Baseline to the last observed event time will be estimated. 
This will be done by fitting a generalized linear model with a linear link function for the RMET, 
with gender and age at Baseline as covariates and treatment group as the effect of interest. 
Further details on this analysis will be given in the SAP. 
Estimates 
Estimates for the treatment effects of interest (see above) within the 18-month period assessed 
(time difference in months) adjusted for gender and age at Baseline, with corresponding 95% CI. 
Sensitivity analyses 
The RMET will be estimated for each combination of treatment group and gender as the area 
under the Kaplan-Meier “survival” curve up to the last observed event time (ie, without using a 
modeling approach). A plot of these Kaplan-Meier curves will also be produced. 
9.3.1.2.3 
Secondary Efficacy Estimand: MDS-UPDRS Part I/Part II/Part III 
subscales at 18 months (“De Jure” Estimand) 
Participant-level endpoint 
MDS-UPDRS Part I/Part II/Part III measured bimonthly over 18 months or up to the initiation of 
ST, including Baseline score, and scores at 2, 4, 6, 8, 10, 12, 14, 16, and 18 months. 
ICEs and handling strategies 
For MDS-UPDRS Part II and Part III, ST initiation will be handled using a ‘hypothetical’ 
strategy, where post-ICE data will be censored. 
For MDS-UPDRS Part I, ST initiation will be handled using a ‘treatment policy’ strategy, where 
post-ICE data are kept as part of the analysis. 
Population-level summary 
Difference in population mean MDS-UPDRS Parts I/II/III subscale at 18 months, in the absence 
of concomitant ST intake for Part II/III, or regardless of concomitant ST initiation for Part I 
between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
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Estimator 
A LMEM for longitudinal data/repeated measures, similar to the one described for the Primary 
Efficacy Estimand Estimator (Section 9.3.1.1.1) but with time set as a categorical variable, will 
be applied to the data. 
Estimates 
Estimates for the treatment effects of interest (see above) at 18 months (MDS-UPDRS units 
difference) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
Sensitivity analyses 
For MDS-UPDRS Part I and II, the main models will be refit using log-transformed data, as the 
normality assumption for the residuals does not appear to hold for this subscale when analyzing 
the PPMI data (UCB internal observation).  
The main model for Part II and Part III will be refit, adjusting for Baseline predictors of early 
initiation of ST. For MDS-UPDRS Part II this analysis will be performed on log-transformed 
data. This sensitivity analysis will not be performed for Part I.  
9.3.1.2.3.1 
Key Secondary Efficacy Estimand: MDS-UPDRS Part III subscale and 
Part III ePD subscore at 18 months 
A new estimand based on the MDS-UPDRS Part III ePD subscore targeted at the early-stage PD 
population is proposed based on the data measured up to Month 18. 
Participant-level endpoint 
MDS-UPDRS Part III subscale or ePD subscore measured bimonthly over 18 months or up to 
the initiation of ST, including Baseline score, and scores at 2, 4, 6, 8, 10, 12, 14, 16, and 18 
months. 
ICEs and handling strategies 
A different ‘hypothetical’ handling strategy of ST initiation will be implemented, where 
Month 18 data recorded after a participant initiates ST will be corrected using a de-mediation 
approach. 
Prior to the de-mediation approach, intermittent missing data will be imputed using MI according 
to randomized treatment and ST intake status. 
Population-level summary 
The population-level summary of interest will be the difference in target population mean 
observed MDS-UPDRS Part III subscale/ePD subscore at Month 18 as if the participants had not 
initiated ST between the following treatment arms: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
Monotone missing data from participants who dropped out of the study will be imputed using 
RBI and according to ST intake status. 
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Imputed datasets for those dropouts will be summarized into a single dataset to obtain Month 18 
estimates, which will then be combined with the de-mediated Month 18 estimates. 
An ANCOVA will be applied to the complete Month 18 data. Treatment will be included in the 
model as a categorical fixed effect, gender, age at Baseline, and Baseline MDS-UPDRS Part III 
subscale (ePD subscore) data will be fitted as covariates. 
Estimates 
Estimates for the treatment effects of interest (see above) at Month 18 (MDS-UPDRS units 
difference) adjusted for gender and age at Baseline, with corresponding 95% CIs. 
9.3.1.2.3.2 
Supplementary Efficacy Estimand: MDS-UPDRS Part II/Part III 
subscales at 18 months (“De Facto” Estimand) 
Participant-level endpoint 
MDS-UPDRS Part II/III subscales measured bimonthly over 18 months, regardless of 
concomitant ST intake, including Baseline score, and scores at 2, 4, 6, 8, 10, 12, 14, 16, and 
18 months. 
ICEs and handling strategies: As per the Supplementary Efficacy Estimand (Section 9.3.1.1.4.1). 
Population-level summary 
Difference in population mean MDS-UPDRS Parts II/III at 18 months, regardless of concomitant 
ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator, estimates, and sensitivity analyses 
As per Supplementary Efficacy Estimand (Section 9.3.1.2.1.1). For MDS-UPDRS Part II, this 
supplementary analysis will be carried out on log-transformed data. 
9.3.1.2.4 
Secondary Efficacy Estimand: MDS-UPDRS Part II emerging 
symptoms over 18 months 
Participant-level endpoint 
The emerging symptoms based on MDS-UPDRS Part II (Tosin et al, 2022) for individual 
participants are derived using the following steps: 
Identify the symptoms not present at Baseline, ie, MDS-UPDRS Part II items with score ‘0’ at 
Baseline. 
For the items identified in step 1, calculate change from Baseline at each visit. The participant is 
considered to have an emerging symptom for the item, if the change from Baseline for the item is 
greater than 0 for 2 consecutive visits. The magnitude of change from Baseline will not be 
considered to determine the emerging symptom. 
The sum of emerging symptoms for all items identified in step 1 is used as participant-level 
endpoint. 
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The annualized rate of events is calculated as total number of emerging symptoms divided by 
total duration of follow-up. 
ICEs and handling strategies 
ST will be handled using a ‘treatment policy’ strategy, where post-ICE data are kept as part of 
the analysis. Study termination and loss to follow up will be handled using a ‘hypothetical’ 
strategy (ie, rate of occurrence of the events is calculated only for observed duration).  
Population‑level summary 
Ratio of annualized rate of emerging symptoms based on MDS-UPDRS Part II over 18 months 
period between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
The annualized rate will be estimated using negative binomial regression. The model will include 
gender and age as covariates and log of observed duration as off-set. Further details on this 
analysis will be given in the SAP. 
Estimates 
Estimates for the treatment effects of interest (see above) over the 18-month period adjusted for 
gender and age at Baseline with corresponding 95% CI. 
9.3.1.2.5 
Secondary Efficacy Estimand: MoCA over 18 months 
Participant-level estimand 
MoCA at 18 months, regardless of concomitant ST intake. 
ICEs and handling strategies 
It will be assumed that the symptoms measured by the MoCA questionnaire are not affected by 
the recommended rescue medications, ie, levodopa, and as such ST initiation will be handled 
using a ‘treatment policy’ strategy, where post-ICE data are kept as part of the analysis. 
Population-level summary 
Difference in target population mean MoCA at 18 months, regardless of concomitant ST intake 
between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
An ANCOVA on data observed at 18 months will be applied to all observed MoCA data pairs 
(Baseline and 18-month data), ie, completers analysis. 
Treatment (placebo as reference) will be fitted as a categorical Fixed effect. Baseline MoCA 
data, gender and age at Baseline will be fitted as covariates. 
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Estimates 
Estimates for the treatment effects of interest (see above) at 18 months (MoCA units difference), 
adjusted for gender and age at Baseline, with corresponding 95% CIs. 
Supporting statistics 
To support clinical interpretation, the following descriptive statistics will be reported separately 
for each treatment group: 
1. Observed MoCA and change from Baseline (mean, median, SD, IQR, range) for participants 
who have not initiated ST. 
2. Observed MoCA and change from Baseline (mean, median, SD, IQR, range) for participants 
who have initiated ST. 
 
9.3.1.2.6 
Exploratory Efficacy Endpoints at 18 months 
• Time to worsening in MDS-UPDRS Part I subscale 
• Modified Hoehn and Yahr staging 
• CGII 
• CGIS 
• Fatigue-PRO 
• Function Slowness PRO 
• Mobility PRO 
• Composite endpoint (based on MDS-UPDRS and/or Early PD PROs)  
• PGIS, overall and fatigue-specific 
• PGIC, overall and fatigue-specific 
• SE-ADL 
• HADS 
• MDS-NMS 
• Starkstein Apathy Scale 
• EQ-5D-5L 
9.3.2 
Analysis of the Secondary Efficacy Objective: “Neurodegeneration at 
12 and 18 months” 
To demonstrate the superiority of UCB0599 over placebo with regard to neurodegeneration of 
dopaminergic neurons over 12 and 18 months in participants diagnosed with early-stage PD. 
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9.3.2.1 
Secondary Efficacy Estimand: DaT-SPECT mean Striatum SBR at 
Month 12 and Month 18  
Participants who do not have a Month 12 DaT-SPECT scan will only have their Baseline and 18 
months’ data included in these analyses. 
Participant-level endpoint 
Change from Baseline (Screening) in DaT-SPECT mean Striatum SBR measured at Month 12 
and Month 18, regardless of concomitant ST intake. 
ICEs and handling strategies 
It will be assumed that the DaT-SPECT signal will not be affected by the recommended rescue 
medication (levodopa). 
ST initiation will be handled using a ‘treatment policy’ strategy, where post-ICE data are kept as 
part of the analysis. 
Population-level summary 
Difference in population mean change from Baseline (Screening) in DaT-SPECT mean Striatum 
SBR at Month 12 and Month 18 regardless of concomitant ST intake between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
A LMEM for longitudinal data ANCOVA on change from Baseline (Screening) data will be 
applied to all observed data. 
Time (visit), treatment (placebo as reference) and treatment by time (visit) will be fitted as 
categorical fixed effects. Participant will be fitted as a random intercept. 
Baseline (Screening) DaT-SPECT mean Striatum SBR, gender, and age at Baseline will be fitted 
as covariates. 
Estimates 
Estimates for the treatment effects of interest (see above) at Month 12 and Month 18 (DaT-
SPECT SBR units difference), adjusted for gender and age at Baseline, with corresponding 95% 
CIs. 
Sensitivity analyses 
The model described in the previous section will be run on the original data (as opposed to the 
change from Baseline data). 
An additional LMEM will be fitted to the original data, with Baseline data included as part of the 
response/dependent variable, rather than as a covariate, and time as continuous (instead of 
categorical) so as to estimate the slope between Baseline and Month 18). 
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Supporting statistics 
To support clinical interpretation, the following descriptive statistics will be reported separately 
for each treatment group: 
1. Observed DaT-SPECT mean striatum SBR and change from Baseline (Screening) (mean, 
median, SD, IQR, range) for participants who have not initiated ST. 
2. Observed DaT-SPECT mean striatum SBR and change from Baseline (Screening) (mean, 
median, SD, IQR, range) for participants who have initiated ST. 
3. Number of participants who discontinued treatment due to lack of efficacy. 
4. Number of participants who discontinued treatment due to AEs. 
9.3.2.2 
Exploratory Efficacy Endpoints at Month 12 and Month 18 
• DaT-SPECT mean SBR in striatal subregions 
• CSF total ASYN 
• CSF ASYN oligomers/seeding capacity 
Further details will be given in the SAP. 
9.3.3 
Analysis of the Secondary Efficacy Objective: “Intake of ST at 12 and 
18 months” 
To assess the effect of UCB0599 vs placebo with regard to intake of ST over 18 months in 
participants diagnosed with early-stage PD. 
9.3.3.1 
Secondary Efficacy Estimand: Time to ST initiation over 18 months 
Participant-level endpoint 
Time from Baseline to initiation of ST or to last censored time observation within the 18-month 
period. 
ICEs and handling strategies 
Observations for some participants will end prior to occurrence of the event of interest, ie, start 
of ST. This is known as “right-censoring” adjusted in the time-to-event analysis by using actual 
observed times. 
The main ICEs will be study termination and lost to follow up: both will be handled using a 
‘hypothetical’ strategy where the post-ICE data will be set to missing. 
Population-level summary 
An RMET was chosen as it has been shown to be a robust method when the proportional hazards 
assumption does not hold, it can be estimated even under heavy censoring and it has an easy 
clinical interpretation (Royston and Parmar, 2013). 
The RMET can be interpreted as the average time until an event occurs during a defined time 
period ranging from time 0 to a specific follow-up time point. 
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The difference in target population RMET (here, time to initiation of ST) up to the last observed 
event time within the 18-month period will be estimated between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
The RMET from Baseline to the last observed event time will be estimated. This analysis will 
use the same modeling approach as described for the MDS-UPDRS Part III subscale time to 
worsening analysis (see Section 9.3.1.1.3 for further details). By default, this approach makes the 
assumption that the right-censoring mechanism is homogeneous among all participants, which 
may not be a valid assumption in this study; right-censoring in the context of this analysis will 
come from study termination and it is possible that termination may be higher or lower in the 
UCB0599 arms compared to placebo. To counter this potential bias, treatment group-specific 
weights will be obtained by applying the Kaplan-Meier estimation method separately to each 
group (ie, using treatment group as a stratification variable in the RMET model).  
Estimates 
Estimates for the treatment effects of interest (see above) within the 18-month period assessed 
(time difference in months) adjusted for gender and age at Baseline, with corresponding 95% CI. 
Sensitivity analyses 
1. The RMET will be estimated for each combination of treatment group and gender as the area 
under the Kaplan-Meier “survival” curve up to the last observed event time (ie, without using 
a modeling approach). A plot of these Kaplan-Meier curves will also be produced. 
Supporting statistics 
To support clinical interpretation, the following descriptive statistics will be presented for each 
treatment group: proportion of participants who initiated ST at 12 and 18 months, overall. 
9.3.3.1.1 
Supplementary Efficacy Estimand: Time to ST initiation over 18 
months 
As a supplementary analysis, a Cox regression model will be fitted to all observed data since this 
is the traditional way of modeling time-to-event data. This approach assumes proportional 
hazards for all individuals. Further details on this analysis will be given in the SAP. 
9.3.3.2 
Secondary Efficacy Estimand: Intake of ST at 18 months 
Participant-level endpoint 
Number of participants taking ST at 18 months, regardless of adherence to assigned study 
medication. 
ICEs and handling strategies 
The main ICEs will be study termination and lost to follow up: both will be handled using a 
‘hypothetical’ strategy where the post-ICE data will be set to missing. 
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Population-level summary 
Population ratio of odds of ST intake in the presence of UCB0599 over odds of ST intake in the 
absence of UCB0599 (ie, on placebo). In other words, population odds ratio in ST intake at 18 
months between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
Logistic regression of the effect of exposure to UCB0599 (high and low dose) on intake of ST at 
18 months will be performed. Further details on this analysis will be given in the SAP. 
Estimates 
Estimates (odds ratios) for the treatment effects of interest (see above) at 18 months adjusted for 
gender and age at Baseline, with corresponding 95% CIs. 
Sensitivity analyses 
A relative risk regression will be carried out, and further details on this analysis will be given in 
the SAP. 
Supporting statistics 
To support clinical interpretation, the following descriptive statistic will be reported separately 
for each treatment group: proportion of participants on ST by 18 months. 
9.3.3.3 
Other Secondary Efficacy Estimand: Intake of ST at 12 months 
Participant-level endpoint 
Number of participants taking ST at 12 months, regardless of adherence to assigned study 
medication. 
ICEs and handling strategies 
The main ICE will be study termination and lost to follow up: both will be handled using a 
‘hypothetical’ strategy where the post-ICE data will be set to missing. 
Population-level summary 
Population ratio of odds of ST intake in the presence of UCB0599 over odds of ST intake in the 
absence of UCB0599 (ie, on placebo). In other words, population odds ratio in ST intake at 12 
months between: 
• UCB0599 high dose (360mg/day) and placebo 
• UCB0599 low dose (180mg/day) and placebo 
Estimator 
Logistic regression of the effect of exposure to UCB0599 (high and low dose) on intake of ST at 
12 months will be performed. Further details on this analysis will be given in the SAP. 
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Estimates 
Estimates (odds ratios) for the treatment effects of interest (see above) at 12 months adjusted for 
gender and age at Baseline, with corresponding 95% CIs. 
Sensitivity analyses 
A relative risk regression will be carried out, and further details on this analysis will be given in 
the SAP. 
Supporting statistics 
To support clinical interpretation, the following descriptive statistics will be reported separately 
for each treatment group: proportion of participants on ST by 8, 10, and 12 months. 
9.3.3.4 
Exploratory Efficacy Endpoint at 18 months 
• Levodopa cumulative daily dose 
9.3.4 
Subgroup analyses 
Analyses by subgroup will be performed as part of exploratory analyses. 
9.3.5 
Center effects 
Since treatment assignment will not necessarily be balanced across countries or sites, no 
statistical analyses will be carried out to investigate center effects. However, for the primary 
endpoint and for some prespecified secondary endpoints, summary statistics will be produced by 
country and region (Europe and North America). Further details on which endpoints will be 
summarized and which summary statistics will be presented will be given in the SAP. 
If the inspection of the summary statistics tables (taking into account the number of study 
participants recruited at each center) leads to concerns with regards to a potential differential 
effect from specific centers on the overall study outcome, sensitivity analyses may be performed 
excluding the concerning centers. These sensitivity analyses will be performed as part of an 
exploratory SAP and will not be reported in the clinical study report. 
In addition, in response to the current pandemic situation, COVID-19 and COVID-19 
vaccination summaries will be presented by country and region; additional details will be 
presented in the SAP. 
9.4 
Planned safety and PK analyses 
9.4.1 
Safety analyses 
Safety will be assessed by analyzing incidence of any TEAE, study participant withdrawals, and 
changes in different parameters such as vital signs, safety laboratory data, 12-lead ECG 
assessment, physical examination findings, neurological examination findings, and suicidality 
using the C-SSRS. 
Further details on the planned safety analyses will be given in the SAP. 
9.4.2 
PK analyses  
Predose (trough, maximum of 15 minutes prior to next dose intake) and between 1 to 6 hours 
postdose (first dose on that day) blood samples will be collected to measure UCB0599 and 
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N-oxide-metabolite plasma concentrations at the specified visits in the Schedule of Activities 
(Section 1.3). 
The plasma concentrations will serve to collect further PK properties of UCB0599 and its 
N-oxide-metabolite, and these properties will be reported descriptively in the clinical study 
report. Detailed information on sample analysis will be provided in a bioanalysis report. The 
relationship between UCB0599 concentration and efficacy, pharmacodynamic or biomarker, and 
other (safety) endpoints may also be assessed. All collected concentration-time data will further 
be used to derive population approach PK parameters, and such models will be developed and 
reported separately. 
In addition, CSF samples will be collected as described in the Schedule of Activities 
(Section 1.3) to measure concentrations of UCB0599 and its N-oxide metabolite. 
9.5 
Handling of ICEs, protocol deviations, and resulting missing 
data 
The strategies/approaches for handling ICEs will be as follows: 
• ‘Treatment policy’: all data will be included in the analysis, regardless of whether the 
participant remains on the assigned investigational treatment or discontinued. This will 
reflect the treatment effect regardless of the ICE. 
• ‘Hypothetical’: data will be modified to mirror its value had an ICE not occurred (under 
some hypothetical conditions). One such hypothetical condition is that the ICE occurred 
completely at random. In this case, all post-ICE data are set as missing (removed) and 
imputed under the assumption of missing at random (MAR). This strategy can be applied to 
ICEs which are considered uninformative with respect to the definition of the intervention 
effect of interest, ie, treatment efficacy. As a default approach, this strategy will be applied to 
any occurrence of an ICE affecting the existence of measurements and maximum likelihood 
(ML) imputation will be used. Alternative imputation approaches will also be considered for 
ICEs which are considered informative with respect to the effect of interest, ie, 
treatment-related study termination, such as RBI approaches. This approach will reflect the 
treatment effect had the ICE not occurred. 
• ‘Composite’: ICE data will be incorporated into the endpoint being analyzed. This approach 
will be used for the MDS-UPDRS Part III time to worsening analyses; a composite endpoint 
of time to worsening or time to ST initiation will be used as ST initiation is considered 
representative of a negative outcome. 
An overview of handling strategies for MDS-UPDRS ICEs and study termination is presented in 
Table 9-2. For details on the handling strategies for all estimands (including approaches to 
imputation and de-mediation), please see the SAP. 
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Table 9-2: 
Overview of handling strategies for MDS-UPDRS ICEs and study 
termination 
MDS-UPDRS Part I-III sum score 
and Part I/II/III subscales 
Estimand 
Primary, key secondary 
and secondary 
Key secondary 
Secondary and 
supplementary 
 
In the absence of ST 
Initiation of ST as part of 
the response 
Regardless of ST 
Population 
summary 
measure 
For Part I-III sum score: 
Difference in slope of 
progression at 12 months 
(primary) and difference 
in mean at 18 months (key 
secondary) 
For Part III subscale: 
Difference in slope of 
progression at 12 months 
(key secondary)  
For Part III subscale 
and Part III ePD 
subscore: 
Difference in mean at 18 
months (key secondary) 
For Part I/II subscale: 
Difference in mean at 12 
and 18 months 
(secondary) 
For Part III subscale: 
Difference in RMET 
(time to first 5-point 
increase) within 18 
months (key secondary) 
 
For Part I-III sum score: 
Difference in mean at 12 
and 18 months 
(supplementary) 
For Part II/III 
subscales: 
Difference in mean at 12 
and 18 months 
(supplementary) 
For Part II subscale: 
Ratio of annualized rates 
in emerging symptoms 
within 18 months 
(secondary) 
For Part I subscale: 
Difference in mean at 12 
and 18 months 
(secondary) 
ICE 
 
 
 
Symptomatic 
treatmenta 
Hypothetical 
(set post-ICE data to 
missing) 
Composite 
(ICE is part of the 
endpoint) 
Treatment policy 
(include post-ICE data) 
AE-related 
treatment 
discontinuation 
Treatment policy 
(include post-ICE data) 
id 
id 
Treatment 
discontinuation 
Treatment policy 
(include post-ICE data) 
id 
id 
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Table 9-2: 
Overview of handling strategies for MDS-UPDRS ICEs and study 
termination 
MDS-UPDRS Part I-III sum score 
and Part I/II/III subscales 
Estimand 
Primary, key secondary 
and secondary 
Key secondary 
Secondary and 
supplementary 
(all other 
causes) 
Other protocol 
deviations - 
important 
Hypothetical  
(set post-ICE data to 
missing) 
id 
id 
Other protocol 
deviations – 
minorb 
Treatment policy 
(include post-ICE data) 
id 
id 
Death or serious 
injury 
(all causes) 
Hypothetical 
(set post-ICE data as 
missing) 
id 
id 
Confirmed or 
suspected cases 
of COVID-19 
without other 
ICE or study 
termination 
Treatment policy 
(include post-ICE data) 
id 
id 
COVID-19 
Vaccination 
Treatment policy 
(include post-ICE data) 
id 
id 
Study 
termination 
and loss to 
follow-up 
 
 
 
Treatment-
related 
Hypothetical 
(set post-termination data 
as missing) 
id 
id 
Other/unknown 
causes 
Hypothetical 
(set post-termination data 
as missing) 
id 
id 
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AE=Adverse effects, COVID-19=Coronavirus Disease-2019; ICE=intercurrent event, id=idem, “the same”, MDS-
UPDRS=Movement Disorder Society Unified Parkinson's Disease Rating Scale, RMET=Restricted (t-year) mean 
event time, SAP=Statistical analysis plan, ST=Symptomatic treatment 
Note: The handling strategies are defined as follows: ‘treatment policy’ – include post-ICE data; ‘hypothetical’ – set 
post-ICE data as missing; ‘composite’ - ICE data is part of the endpoint. 
a Where the participant did not respect the Washout Period for the ST, the visit data will be censored from the 
analysis. 
b In case of an event preventing a participant from attending a particular scheduled clinic visit with a MDS-UPDRS 
assessment (for example, due to COVID-19), this will be considered a minor protocol deviation and MDS-UPDRS 
data collected for this participant in clinic at future visits will be included in the analyses. When MDS-UPDRS is 
collected at home rather than in clinic not all MDS-UPDRS data will be collected (rigidity assessments will be 
missing) and the Part III and total scores cannot be calculated. 
9.5.1 
ICEs potentially affecting the interpretation of measurements 
Symptomatic Treatment Initiation 
Initiation of ST will be the main ICE affecting the interpretation of measurements. Handling of 
ST initiation as an ICE may vary depending on the exact type of ST prescribed; further details 
will be given in the SAP.  
MDS-UPDRS 
Initiation of ST will be considered to impact the definition of the intervention effect of interest 
when measured using MDS-UPDRS Part I-III sum score as well as using MDS-UPDRS Part II 
and Part III subscales. 
In the primary estimand analysis, the post-ICE data will be censored/set to missing 
(‘hypothetical’ strategy –assuming data is missing at random) and the data will be analyzed using 
a likelihood-based method of analysis, ie, an LMEM for longitudinal data/repeated measures 
with its implicit imputation approach (White et al, 2012) applied to all participants in the target 
population. This type of analysis will be referred to as ‘in the absence of early ST initiation’.  
An alternative ‘hypothetical’ strategy handling of ST initiation will also be implemented where 
Month 18 data (or Month 12 data, as applicable) recorded after a participant initiates ST will be 
corrected using a de-mediation approach. 
In the supplementary analysis to the primary estimand, the post-ICE data will be included in the 
analysis (‘treatment policy’ strategy) provided the participant has complied with the 12-hour 
washout period (see Section 6.5.3) required prior to the MDS-UPDRS Part III of the MDS-
UPDRS assessment. Where the participant did not respect the washout period for the ST, the 
visit data will be censored from the analysis. This type of analysis will be referred to as 
‘regardless of early ST initiation’. 
DaT-SPECT 
A secondary endpoint will be the mean striatal dopamine receptor SBR as measured by DaT-
SPECT. In this study, it will be assumed that DaT-SPECT signal is not affected by initiation of 
ST although there have been some reports of marginal impact (reviewed in Ikeda et al, 2019). 
Initiation of ST will be considered not to impact the definition of the intervention effect of 
interest for DaT-SPECT, and the post-ICE data will be included in this secondary estimand 
analysis ‘regardless of early ST initiation’ (‘treatment policy’ strategy). Missing data due to scan 
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not having taken place at the participant’s or Investigator’s discretion will be treated as missing 
at random. 
Treatment discontinuation/nonadherence 
Treatment discontinuation (see Section 7.1) will not be considered to impact the definition of the 
intervention effect of interest, and the post-ICE data will be included in the analyses (‘treatment 
policy’ strategy- see SAP for details). 
Minor treatment nonadherence (missing a dose or taking a dose at a different time of the day) or 
minor drug administration error will not be considered to impact the definition of the 
intervention effect of interest, and the post-ICE data will be included in the analyses (‘treatment 
policy’ strategy – see SAP for details). 
Major treatment nonadherence or drug administration error will be considered uninformative 
with respect to the definition of the intervention effect of interest, and the post-ICE data will be 
censored in the analyses (‘hypothetical’ strategy – see SAP for details). 
9.5.2 
ICEs potentially affecting the existence of measurements 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons (see Section 7). Where the cause for study termination is known to be 
unrelated to the assigned study medication, study termination will be considered uninformative 
with respect to the definition of the intervention effect of interest, and the post-ICE data will be 
set to missing (‘hypothetical’ strategy - see SAP for details). 
As a default approach, this strategy, accompanied with the implicit imputation of 
likelihood-based models, will be applied to any occurrence of study termination and the event 
will be ignored. Alternative approaches such as imputation (eg, control-based mean imputation) 
as sensitivity analyses, will also be considered. 
In well-designed clinical studies, it is reasonable to assume that dropout patterns follow the 
MAR mechanism, although missing not at random data cannot be ruled out (Liu-Seifert et al, 
2015). 
Local injuries (ie, to arms/hands or legs/feet for MDS-UPDRS and to head for DaT-SPECT), or 
systemic acute conditions such as a stroke or an accident-related coma may prevent the taking of 
measurements. Treatment-related death or death due to other causes (including COVID-19) may 
occur during the study. Death due to PD is unlikely, as participants have been selected in the 
early stage of PD, although an accident may be the consequence of PD symptoms. 
Parkinson’s disease-related and non PD-related serious injury or death will be considered 
uninformative with respect the definition of the effect of the intervention of interest, and the 
post-ICE data will be set to missing in the analyses (‘hypothetical’ strategy – see SAP for 
details). 
Loss to follow up will be considered uninformative with respect to the definition of the effect of 
the intervention of interest, and the post-ICE data will be set to missing in the analyses 
(‘hypothetical’ strategy – see SAP for details). 
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9.5.3 
Other protocol deviations 
Other protocol deviations which were not pre-defined as ICEs (Section 9.5.1 and Section 9.5.2) 
could also affect the conduct of the study and/or impact study participant safety as well as key 
efficacy or PK endpoints measurement. 
The criteria for identifying important protocol deviations will be defined within the relevant 
protocol deviation specification document, which is part of the data cleaning plan. 
All protocol deviations will be reviewed as part of the ongoing data cleaning process and all 
important deviations will be identified and documented before unblinding to confirm exclusion 
from analysis sets. Important protocol deviations will be listed and summarized. 
Important protocol deviations (not pre-defined as ICEs) will be considered uninformative with 
respect to the definition of the effect of the intervention of interest, and the post-ICE data will be 
censored in the analyses (‘hypothetical’ strategy – see details in Section 9.5.1). 
Minor protocol deviations (not pre-defined as ICEs) will be considered not to impact the 
definition of the effect of the intervention of interest, and the post-ICE data will be included in 
the analyses (‘treatment policy’ strategy – see details in Section 9.5.1). 
The strategies for handling ICEs will be as follows: 
‘Treatment policy’ will refer to an approach where all data will be included in the analysis, 
regardless of whether the participant remains on the assigned study medication or discontinued. 
‘Hypothetical’ will refer to an approach where data will be modified to mirror its value shall an 
ICE had not happened (under some hypothetical conditions). One such hypothetical condition is 
that the ICE occurred completely at random. In this case, all post-ICE data are set as missing 
under the assumption of missing completely at random. This strategy can be applied to ICEs 
which are considered to be uninformative with respect to the definition of the intervention effect 
of interest (ie, treatment efficacy). As a default approach, this strategy will be applied to any 
occurrence of study termination and the event will be ignored. Alternative approaches such as 
imputation (eg, control-based mean imputation) as sensitivity analyses, will also be considered. 
9.6 
Planned analysis at 12 months and data monitoring 
The primary analysis for the primary efficacy estimand (MDS-UPDRS Part I-III sum score) uses 
data from the first 12 months of the study; this analysis as well as the analyses for the secondary 
estimands at 12 months (where applicable) will be carried out at study end (see details in 
Section 9.3).  
A limited team of independent pharmacometricians and statistical programmers with access to 
the 12-month data will be unblinded to prepare for the exposure-response analysis to be finalized 
following completion of the study. Details of unblinding will be described in the unblinding 
charter, and care will be taken to ensure that the blinded study team remains blinded until 
database lock. Details of the exposure-response analysis will be provided in a separate analysis 
plan. The results of the final exposure-response evaluation will be provided outside of the 
clinical study report at study finalization. 
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Data Monitoring Committee and SMC: 
An independent DMC will conduct safety interim reviews of all available unblinded safety and 
PK data at the following time points: 
• When safety data for 3 months of treatment (ie, until Visit 7) are available for 100 
participants. 
• When safety data for 3 months of treatment (ie, until Visit 7) are available for at least 
50 participants per arm 
• After at least 50% of the participants have been treated for 8 months (ie, approximately 75 
participants per arm) 
• After at least 50% of the participants have been treated for 14 months (ie, approximately 75 
participants per arm), the DMC will review the available unblinded safety and PK data. 
• Ad hoc as required. 
The DMC will provide a recommendation on the continuation of the study. The activities of the 
DMC will be described in a separate charter. 
An SMC will review (approximately every 3 months, with the option to adapt the frequency 
based on recruitment rates) the available blinded safety data at the following time points:  
• After 5 participants/arm have been treated for 2 weeks  
• After 25 participants/arm have been treated for 1 month 
• After 50 participants/arm have been treated for 1 month 
• After 75 participants/arm have been treated for 1 month 
• After 100 participants/arm have been treated for 1 month  
• Subsequent SMC meetings will occur every 3 months 
Details will be described in a separate charter. 
9.7 
Determination of sample size 
The sample size for this study was determined based on the primary efficacy estimand as 
detailed in the sections below. Approximately 645 participants will be screened to achieve 
450 participants randomly assigned to study medication and 429 evaluable participants, for an 
estimated total of 143 evaluable participants per treatment group. Participants who terminate the 
study (withdraw consent) or are lost to follow-up will not be replaced. 
The primary comparison of interest is UCB0599 high dose (360mg/day) vs placebo. Given the 
limitations in our understanding of the PK/PD properties of the compound, the calculations 
below apply to both comparisons (UCB0599 high dose [360mg/day] and placebo and UCB0599 
low dose [180mg/day] and placebo) as similar assumptions for both doses are made with respect 
to variability and impact on progression.  
9.7.1 
Primary efficacy estimand 
The first efficacy objective of PD0053 is to show superiority of UCB0599 over placebo with 
regard to clinical symptoms of disease progression over 12 months in participants diagnosed 
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with early-stage PD. To measure clinical symptoms of disease progression, the MDS-UPDRS 
Part I-III sum score was selected as the variable of interest for the Primary Estimand and the 
population-level summary was chosen as the difference in the population mean slope of 
progression between UCB0599 and placebo up to 12 months or up to the initiation of ST, 
whichever comes first. 
Even though the duration of the study is 18 months, the sample size was estimated to ensure 90% 
power at 12 months, where the proportion of participants on ST is still limited. Beyond 
18 months, the number of participants under ST is expected to increase with significant potential 
for bias between UCB0599 groups and the placebo groups (should the compound be active), and 
power decrease due to data loss. The primary analysis of MDS-UPDRS is therefore planned at 
12 months, and additional analyses will be performed at 18 months including post-ST data in the 
analysis. 
In order to derive the parameters of interest for sample size estimation, an Estimator similar to 
the one planned for the Primary Estimand (a LMEM for longitudinal data/repeated measures, 
with Time as a continuous fixed effect, ie, assuming linear development over 12 months, and 
identical random effects to account for within-participant correlation between repeated 
observations was applied to a subset of the PPMI 1.0 de novo cohort, an observational study of 
early-stage PD participants (Parkinson’s Progression Markers Initiative, 2018). Further details on 
how participants were selected for inclusion in this analysis and how this analysis was carried 
out will be included in the SAP. This participant sample was assumed to be representative of the 
POC study placebo arm up to 12 months. 
For the purpose of sample size estimation, a closed-form sample size formula for longitudinal 
data was used (Ahn et al, 2014). Further details on the use of this formula will be provided in the 
SAP. 
A 5% data loss due to study termination by 3 months (all causes) will be assumed in this study, 
based on expert knowledge. The sample size will be inflated accordingly (see details below). 
Loss to follow up and loss to ST initiation by 3 months will be considered minimal in the study 
setting and ignored. 
Based on observations from the PPMI cohort data (further details in the SAP), 35% data loss was 
assumed in the study at 12 months: 
• 20% due to participants initiating ST, as they will be in a controlled setting and encouraged 
to delay start of ST intake for as long as it is deemed medically acceptable; 
• 5% due to participants lost to follow up as well as to death and serious injury; 
• 10% due to participants terminating the study (all causes). 
Based on the parameters obtained from the analysis performed on the restricted PPMI dataset for 
the placebo arm, a sample size of 143 participants per arm (N=429 total), randomized at a 1:1:1 
ratio to UCB0599 high dose, low dose or placebo would provide 90% power to detect a 
minimum of expected 30% decrease in population mean slope of PD disease progression (eq. to 
0.27 MDS-UPDRS points/month or 3.2 points/year) in the active treatment groups compared 
with placebo over 12 months of treatment, with 10% type I error. The sample size will be 
inflated by 5% (N=14) to account for participants terminating the study by 3 months, leading to a 
final sample size of 450 participants (N=150/arm). 
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Since it is assumed that between 12 and 18 months another 10% data loss (at a minimum) will be 
lost due to initiation of ST and another 10% due to study termination/loss to follow up, analyses 
at 18 months will be carried out regardless of ST intake (all data included). 
9.7.2 
Power for key secondary efficacy estimand (MDS-UPDRS Part III) 
A key secondary estimand to the primary efficacy objective of PD0053 is the difference in 
population mean slope of progression between UCB0599 and placebo at 12 months in the 
absence of concomitant ST intake for the MDS-UPDRS Part III subscale. 
Using the same approach as described in Section 9.7.1, the sample size estimated to achieve 90% 
power on the Primary Efficacy Estimand, MDS-UPDRS Part I-III sum score, ie, 143 participants 
per arm, would provide 90% power to detect a minimum of expected 35% relative decrease in 
population mean slope of progression on the MDS-UPDRS Part III subscale (eq. to 0.19 
points/month or 2.3 points/year) in the UCB0599 treatment groups compared with the placebo 
group over 12 months of treatment, with 10% type I error. 
9.7.3 
Power for secondary efficacy estimand (DaT-SPECT mean Striatum 
SBR) 
A Secondary Efficacy Objective of PD0053 is to show superiority of UCB0599 over placebo 
with regards to neurodegeneration over 18 months in participants diagnosed with early-stage PD. 
To assess neurodegeneration, the DaT-SPECT mean Striatum SBR was selected as a 
participant-level variable and the population-level summary chosen as the difference between 
UCB0599 and placebo in the population mean change from Baseline (Screening) at 18 months. 
Change from Baseline (Screening) data was derived from the PPMI 1.0 de novo cohort DaT-
SPECT mean Striatum SBR data. Further details on data selection for this analysis will be given 
in the SAP. 
Using a 2-sample t-test based sample size formula and the parameters for the placebo arm 
obtained from the PPMI 1.0 de novo DaT-SPECT data analysis, the sample size estimated to 
achieve 90% power on the Primary Efficacy Estimand, MDS-UPDRS Part I-III sum score, ie, 
143 participants per arm, would provide 90% power to detect a minimum of expected 37.5% 
relative increase in population mean change from Baseline in DaT-SPECT signal (equal to 0.067 
SBR unit) in the UCB0599 groups vs the placebo group at 18 months, with 10% type I error, and 
assuming 25% data loss (ie, an extra 10% loss to occur between 12 and 18 months due to study 
termination and loss to follow up at 18 months with effective N=107/arm). Data loss due to 
initiation of ST does not apply for the assessment of the DaT-SPECT signal as the assumption is 
being made that levodopa and dopamine agonists do not affect the neurodegeneration of 
dopamine neurons in the midbrain. 
To increase information regarding DaT-SPECT SBR signal, participants intending to terminate 
the study (assumed to be 10% by 12 months) should have a scan before study termination (as 
part of the EOT visit). Participants who choose to withdraw from the study at or after 6 months 
and accept to have a scan at time of study termination will have their scans analyzed as if it was 
taken at 12 months. 
Residual data attrition due to study termination and loss to follow up may be imbalanced 
between treatment arms by the time participants reach the 18-month timepoint, creating selection 
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bias (further details are provided in the SAP). This residual bias will be addressed at the analysis 
stage. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-GCP, and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant-related documents to be used for the study to the IRB/IEC for its review and 
approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
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Finance and insurance are addressed in the Investigator and/or CRO agreements, as applicable. 
10.1.3 
Informed consent process 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). The participant will be given as much time as needed to decide whether or not they 
wish to take part in the study. Each participant will have the opportunity to discuss the study and 
its alternatives with the Investigator or seek additional advice. The amount of time a potential 
participant takes to decide whether to participate or not will vary per participant. The potential 
participants will be under no pressure to make a decision. In France, participants will be given at 
least 3 days of reflection time before signing the ICF. For France-specific requirements, please 
refer to Section 10.9, Appendix 9. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant and by the person who conducted the informed consent discussion (Investigator or 
designee). The participant must receive a copy of the signed and dated ICF. As part of the 
consent process, each participant must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
Remote consent (eConsent) is permitted during this study, but not required. For those 
participants who are assessed as preliminarily eligible per the IRB/IEC-approved preScreening 
script, contact information will be collected, including a valid email address of the participant. A 
secure link to the eConsent web portal will be sent via email, along with unique login credentials. 
The participant will receive a prompt to change the temporary assigned password upon first 
login. The informed consent materials will be presented in the eConsent portal through an 
electronic rendition of the IRB/IEC-approved consent documents. The study Investigator and/or 
designated staff will complete the informed consent process with the participant by telephone. 
Participants who agree to take part in the study will provide their handwritten signature using a 
computer mouse, touchscreen, or stylus on a computer or tablet in the designated signature 
block; and the consenter will countersign. 
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The participant may withdraw his/her consent to participate in the study at any time. A 
participant is considered as enrolled in the study when he/she has signed the ICF. The eCRF 
must not be started, nor may any study specific procedure be performed for a given participant, 
without having obtained his/her written consent to participate in the study. 
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10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number 
assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’s primary medical records that directly concerns this study (including, but not limited 
to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
An independent DMC will conduct safety interim reviews of all available unblinded safety and 
PK data and an SMC will regularly review the available blinded safety data as described in 
Section 9.6. 
10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the Investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. The Investigator will contact UCB 
for authorization prior to the destruction of any study records or in the event of accidental loss or 
destruction of any study records. The Investigator will also notify UCB should he/she relocate or 
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move the study-related files to a location other than that specified in the Sponsor’s trial master 
file. 
Quality tolerance limits will be established for the study using parameters related to patient 
safety reporting and reliability of study results. The parameters will be monitored throughout the 
study to identify systematic issues. Parameters used, parameter values, important deviations from 
the quality tolerance limits, and actions taken will be summarized in the clinical study report. 
10.1.6.1 
Case Report form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.6.2 
Apps 
Not applicable. 
10.1.7 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, 
limited-access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the participant’s source documents. The 
Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.8 
Study and site closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study medication development 
10.1.9 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
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10.4 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
− A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
− Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following: 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in the table below when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition male participants must refrain from donating sperm for the duration of the study and 
for 3 months after the last dose of study medication. 
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Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame and for 3 months after the last dose of study medication. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
Highly Effective Contraceptive Methodsa 
Highly Effective Contraceptive Methods That Are User Dependentb 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationc 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independent 
 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study medication. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
NOTES: 
a) In case of newly started contraception pills/IUDs, PI should consider the correct timing of starting/applying such 
methods in relation to the menstrual cycle and the manufacturing instruction as when these newly started methods 
would become effective. 
b) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
c) If oral contraception is used, an additional barrier method will be required during the Treatment Period and for at 
least 30 days after the last dose of study medication. 
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Pregnancy testing 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
• Additional pregnancy testing should be performed at each visit during the Treatment Period 
and at the SFU visit and as required locally. In France, pregnancy testing should be 
performed monthly. For France-specific requirements, please refer to Section 10.9, 
Appendix 9. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed. 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study medication. If the study participant is later found 
to be on placebo, then pregnancy data collection can stop. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within one working day of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-
up will be at least 12 months after the delivery date. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female participants who become pregnant 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study medication. 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 1 working day of learning of a participant's 
pregnancy. The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, the follow-up will be at least 
12 months after the delivery date. Any termination of pregnancy will be reported, regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the Sponsor as described in Section 8.3.5. While the 
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Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
  
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10.5 
Appendix 5: Genetics 
Use and Analysis of DNA 
• Genetic variation may impact a participant’s response to study medication, susceptibility to, 
and severity and progression of disease. Variable response to study medication may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. 
• DNA samples will be used for research related to UCB0599 or PD and related diseases. They 
may also be used to develop tests/assays including diagnostic tests related to UCB0599 and 
PD. Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome. 
• RNA samples will be analyzed for nonhereditary pharmacogenomics biomarkers. Additional 
analyses may be conducted if it is hypothesized that this may help further understand the 
clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to UCB0599 or study medications of this class to understand study disease or 
related conditions. 
• The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
• The samples will be retained while research on UCB0599 continues but no longer than 
20 years or other period as per local requirements. 
 
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10.6 
Appendix 6: Liver safety – suggested actions and follow-up 
assessments 
Participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury should not be withdrawn from the 
study until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for study medication discontinuation and/or participant 
withdrawal (if applicable), must be recorded in the source documents. The eCRF must document 
the primary reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB study physician and the 
Investigator for study participants who have ALT >5 ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology (Table 10-1). 
Table 10-1: Phase 2 Liver Chemistry Stopping Criteria and Follow-up 
Assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT 5xULN 
ALT Increase 
ALT 3xULN persists for 4 weeks 
Bilirubina,b 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INRb 
ALT 3xULN and international normalized ratio (INR) >1.5, if INR measured 
Cannot Monitor 
ALT 3xULN and cannot be monitored weekly for 4 weeks 
Symptomaticc 
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity 
Suggested Actions and Follow-up Assessments 
Actions 
Follow-Up Assessments 
• 
Immediately discontinue study medication. 
• 
Report the event to the Sponsor within 24 hours. 
• 
Complete the liver event eCRF, and complete an SAE 
data collection tool if the event also met the criteria for 
an SAE. b 
• 
Perform liver chemistry follow-up assessments. 
• 
Viral hepatitis serology d 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis as soon as possible after the 
most recent dose e 
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Table 10-1: Phase 2 Liver Chemistry Stopping Criteria and Follow-up 
Assessments 
Liver Chemistry Stopping Criteria 
• 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to Baseline 
(see MONITORING). 
• 
Do not restart/rechallenge participant with study 
medication unless allowed per protocol and Sponsor 
approval is granted 
• 
If restart/rechallenge not allowed per protocol or not 
granted, permanently discontinue study medication and 
continue participant in the study for any protocol 
specified follow up assessments 
• 
Consider the need for a toxicology Screening 
MONITORING: 
If ALT 3xULN AND bilirubin 2xULN or INR >1.5: 
• 
Repeat liver chemistry tests (include ALT, aspartate 
transaminase [AST], alkaline phosphatase, bilirubin) 
and perform liver event follow-up assessments within 
24 hours. 
• 
Monitor participant twice weekly until liver chemistry 
test abnormalities resolve, stabilize, or return to 
Baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
If ALT 3xULN AND bilirubin <2xULN and INR 1.5:  
• 
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
chemistry follow-up assessments within 24 to 
72 hours. 
• 
Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to Baseline. 
• 
Serum creatine phosphokinase (CPK), lactate 
dehydrogenase (LDH), and (optional) 
gamma-glutamyl transferase (GGT) 
• 
Fractionate bilirubin, if total bilirubin 
 2xULN 
• 
Obtain complete blood count with differential 
to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, fatigue, 
nausea, vomiting, right upper quadrant pain), 
or hypersensitivity, on the adverse event 
(AE) report form 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications CRF 
• 
Record alcohol use on the liver event alcohol 
intake CRF 
• 
Exclude pregnancy 
If ALT 3xULN AND bilirubin 2xULN or 
INR >1.5: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma globulins 
• 
Serum acetaminophen (EAN paracetamol) 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; 
EAN=International Article Number; eCRF=electronic case report form; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B virus surface antigen; HPLC=high performance liquid chromatography; IgG=immunoglobin 
G; IgM=immunoglobin M; INR=international normalized ratio; LDH=lactate dehydrogenase; PBO=placebo; 
PK=pharmacokinetic; RNA=ribonucleic acid; SAE=serious adverse event; ULN=upper limit of normal. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study medication if ALT ≥3xULN and bilirubin ≥2xULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
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b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not 
apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as rash, angioedema, or anaphylaxis) 
d Includes:Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
e PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study medication prior to 
the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the 
Study Reference Manual. 
 
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10.7 
Appendix 7: Wearable sensor AEs, adverse sensor effects, 
SAEs, and sensor deficiencies: definition and procedures for 
recording, evaluating, follow-up, and reporting 
ADVERSE EVENTS 
Physiological and environmental data obtained from the wearable sensor will not be used for 
safety monitoring and reporting of UCB0599 because the sensor is unvalidated for this purpose 
and will only be used for exploratory endpoints in this study. 
The Investigator is expected to record any sensor-related AEs in the eCRF and assess causality 
as it might relate to the wearable sensor. The eCRF page will allow the Investigator to assess 
causality in relation to the wearable sensor. 
Serious adverse events should be reported in the eCRF and expedited to the Sponsor according to 
the protocol. 
The Sponsor will send reports of SAEs relating to the Wearable sensor to Verily so that the 
manufacturer can comply with its reporting obligations. 
SENSOR DEFICIENCIES 
Sensor deficiencies, also referred to as sensor performance issues, are defined as inadequacies of 
a wearable sensor with respect to its identity, quality, durability, reliability, safety, or 
performance. Upon identification of sensor deficiencies, participants will be provided with 
replacement sensor(s), and the sensor(s) will be returned when possible to Verily using a Return 
Materials Authorization number for failure analysis investigation. All sensor deficiencies will be 
reported in the appropriate eCRF. 
SENSOR ACCOUNTABILITY 
Sensors must be kept in a locked, secure location and may only be handled by trained clinical 
site staff. The Principal Investigator or an authorized designee shall keep records documenting 
the receipt, use, and return of wearable sensors, which shall include: The date of receipt, 
identification of each wearable sensor (batch number/serial number or unique code), the 
expiration date (if applicable), the date(s) of use, participant identification and date on which the 
wearable sensor was returned (if applicable). At the end of the clinical investigation, the sensor 
inventory records will be returned to the Verily and copies will be kept in the Study Binder at the 
investigational sites. 
DATA HANDLING 
Verily will receive and securely store the raw data from the wearable sensor throughout the 
course of the study, providing reports of daily wearable sensor Compliance Data for each study 
participant on an ongoing basis. Following completion of the double-blind Treatment Period, 
Verily will receive from UCB the Verily Licensed Data for use in analyses to be conducted 
based on a mutually agreed upon data analysis plan. 
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PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM USE OF THE 
WEARABLE SENSOR 
Participants are free to withdraw from using the wearable sensor at any time, without affecting 
their participation in the main study, and without prejudice to their continued care. A participant 
may withdraw at any time at his/her own request, or may be withdrawn at any time at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons. 
If the study participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of the sensor in advance. 
 
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10.8 
Appendix 8: Rapid Alert Procedures 
Not applicable 
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10.9 
Appendix 9: Country-specific requirements 
10.9.1 
Specific requirements for Germany 
The review of the protocol by the German Ethics Committee and Federal Office for Radiation 
Protection (Bundesamt für Strahlenschutz) led to the following specificity for Germany only 
which was implemented into the global protocol with Protocol Amendment 3, dated 04 Oct 
2021:  
Section 1.3 Schedule of Activities 
The DaT-SPECT assessment at 12 months was removed, ie, no scan will be performed at M12 
for German participants. 
10.9.2 
Specific requirements for France 
The French National Agency for Medicines and Health Products Safety (Agence Nationale de 
Sécurité du Médicament et des Produits de Santé [ANSM]) and the French ethics committee 
(Comités de Protection des Personnes) made recommendations specific for France which were 
implemented into the global protocol with Protocol Amendment 3, dated 04 Oct 2021, and are 
reflected in the following sections: 
Section 1.2 Schema 
A note has been added to clarify that all visits are in-clinic visits in France. 
Section 1.3 Schedule of Activities  
• Footnote “b” was added to reflect that telemedicine is not implemented in the study in France 
and all visits are in-clinic only. 
• Footnote “p”: The following country-specific requirement applies in France: Additional 
pregnancy testing will be performed monthly during the Treatment Period and at the SFU 
visit.  
Section 4.1.1 Decentralized model 
The following clarification (in bold) was added to clarify that the decentralized model is not 
applicable in France:  
• The study will be conducted utilizing a partly decentralized model, ie, study visits may be 
composed of a combination of onsite visits and remote visits (except in France; for 
France-specific requirements, please refer to Section 10.9, Appendix 9). 
Section 5.2 Exclusion criteria 
The following addition (in bold) applies in France for exclusion criterion 43:  
• Vulnerable participants (eg, participants kept in detention, soldiers, adults with legally 
authorized representative, participants who do not benefit from social security schemes 
such as health insurance), employees of the Sponsor or the CRO with direct involvement in 
the proposed study or other studies under the direction of the Investigator or the CRO, as well 
as family members of the employees or the Investigator. 
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Section 10.1.3 Informed consent process 
The following clarification (in bold) regarding the reflection time during the informed consent 
process applies in France:  
• Each participant will have the opportunity to discuss the study and its alternatives with 
the Investigator and will be given at least 3 days of reflection time before signing the 
ICF. 
Section 10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information 
The following change applies in France in the second bullet under “Pregnancy testing”:  
• Additional pregnancy testing should be performed monthly during the Treatment Period and 
at the SFU visit and as required locally. 
 
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10.10 
Appendix 10: Abbreviations and Trademarks 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ASYN 
alpha-synuclein 
BP 
blood pressure 
BID 
twice per day 
BMI 
body mass index 
CGII 
Clinical Global Impression of Improvement 
CGIS 
Clinical Global Impression of Severity  
CI 
confidence interval 
CNS 
central nervous system 
COMT 
catechol-O-methyltransferase 
COVID-19 
Coronavirus Disease-2019 
CPP 
Critical Path for Parkinson’s 
CRO 
Contract Research Organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome P450 3A4 
DaT-SPECT 
Dopamine Transporter Imaging with Single Photon Emission 
Computed Tomography 
DBP 
diastolic blood pressure 
DM 
disease modification 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EOT 
End of Treatment 
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ePD 
early-stage PD 
EQ-5D-5L 
Euro Quality of life 5-Dimensions 5-Level 
EQ-VAS 
EQ visual analogue scale  
FAS 
Full Analysis Set 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
IQR 
interquartile range 
HR 
Hazard Ratio 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LMEM 
Linear Mixed Effect Model 
MAO-B 
Monoamine oxidase-B 
MAR 
missing at random 
MDS-UPDRS 
Movement Disorder Society Unified Parkinson's Disease Rating Scale 
MDS-NMS 
Movement Disorder Society Non-motor symptom scale 
MI 
multiple imputation 
MoCA 
Montreal Cognitive Assessments 
MRI 
magnetic resonance imaging 
NDD 
neurodegenerative disease 
NOAEL 
No observed adverse effect level 
PD 
Parkinson’s disease 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Severity 
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PH 
proportional hazard(s) 
PK 
pharmacokinetic(s) 
POC 
proof-of-concept 
PPMI 
Parkinson’s Progression Markers Initiative 
PRO 
patient-reported outcomes 
PKS 
Pharmacokinetic Set 
QTcF 
QT corrected for heart rate using Fridericia's formula 
RBI 
reference-based imputation 
RMET 
restricted (t-year) mean event time 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus-2 
SBP 
systolic blood pressure 
SBR 
specific binding ratio 
SD 
standard deviation 
SE-ADL 
Schwab and England Activities of Daily Living  
SFU 
Safety Follow-up 
SMC 
Safety Monitoring Committee 
SNCA 
synuclein alpha 
SS 
Safety Set 
ST 
symptomatic treatment 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VME 
Virtual Motor Exam 
WOCBP 
women of childbearing potential 
 
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
10.11.1 
Amendment 5 (30 Jun 2023) 
Overall Rationale for the Amendment 
PD0053 Protocol Amendment 5 was enacted to incorporate additional laboratory tests at 
Day 150 in order to allow for close monitoring of liver function test parameters.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
The following changes were implemented: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
An in-clinic visit at Day 150 
(Month 5) (Visit 8a) was 
added. 
To increase the monitoring of liver 
function test parameters. 
Section 1.3 Schedule of 
Activities 
Section 2.3 Benefit/Risk 
assessment 
Text was updated to delete 
hematological, gastrointestinal, 
and musculoskeletal effects 
from the list of potential risks, 
to clarify that the potential risk 
of hepatotoxicity is based on 
clinical data, to clarify that 
renal laboratory abnormalities 
are kept under close safety 
monitoring, and to clarify the 
measures to mitigate the 
potential risk of hepatotoxicity. 
To align with the warnings and 
precautions provided in the 
updated Section 6.3.4 of the 
Investigator’s Brochure. 
Section 8 Study assessments 
and procedures 
The maximum blood volume 
collected from each participant 
during the study was updated 
to 510mL. 
To account for the blood sampling 
at the added study visit. 
Section 8.3 Adverse events and 
serious adverse events 
Text was updated to add that 
for results disclosure on public 
registries, TEAEs and 
treatment-emergent SAEs will 
be published. 
To clarify the disclosure of TEAEs 
and treatment-emergent SAEs. 
Section 10.11 Appendix 11: 
Protocol Amendment History 
The Protocol Amendment 
Summary of Changes Table for 
the previous amendment has 
been added. 
Minor administrative change. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
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10.11.2 
Amendment 4 (24 Feb 2022) 
Overall Rationale for the Amendment 
Based upon a review of data from completed studies and available blinded data to date from 
PD0053, Protocol Amendment 4 was completed to amend exclusion and discontinuation criteria 
regarding renal function, diabetes, and ECG abnormalities. Clarifications were added throughout 
the protocol. The amended eligibility criteria are intended to better reflect the parameters in the 
targeted study population. The following changes were implemented: 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Updates were made to the 
nomenclature and potential 
clinical presentations for 
hypersensitivity reaction, 
including updates to the role of 
the Investigator, SMC, and 
DMC in the assessment of 
hypersensitivity reactions and 
decisions on withholding 
dosing and restart, as well as 
updates to the activities for 
assessment and management of 
hypersensitivity reactions. 
To increase clarity and consistency 
in the communication and actions 
required for the Important 
Identified Risk of Drug 
Hypersensitivity. 
Global 
Descriptions of the estimand 
for MoCA have been changed 
throughout to remove “change 
from Baseline.” 
To clarify that the analysis of the 
MoCA estimand is no longer a 
change from Baseline analysis due 
to different versions of the form 
being used at Screening and at 
18 months. 
Section 1.3 Schedule of 
Activities 
Investigator assessment of ST 
benefit was removed. 
To remove an assessment that is 
not captured in the study. 
Section 1.3 Schedule of 
Activities 
MoCA assessment at 
12 months was removed. 
To prevent bias on the MoCA 
assessment at 18 months since 
practice effects have been 
observed on repeating MoCA 
assessments (Wong et al, 2018). In 
addition, a different version of the 
MoCA will be used at 18 months 
compared to the Screening 
version. The MoCA assessment at 
18 months (EOT) is considered the 
primary timepoint for MoCA.  
Section 1.3 Schedule of 
Activities 
CSF sampling timepoint in 
footnote “l” was updated from 
BL to V2 to match the 
Schedule of Activities table. 
To correct an error. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3 Objectives and 
endpoints 
CSF ASYN oligomers/seeding 
capacity was added as an 
Exploratory Efficacy Endpoint. 
To further clarify the exploratory 
ASYN endpoints. 
Section 4.2 Scientific rationale 
for study design 
Text was added to support the 
use of the DaT-SPECT at 
Screening as an EMA-qualified 
tool and to provide additional 
information on the MoCA. 
To further clarify the use of the 
DaT-SPECT at Screening and the 
MoCA throughout the study. 
Section 5.1 Inclusion criteria 
Inclusion criterion #4b 
(formerly #4a) on the 
DaT-SPECT reading was 
updated. 
To further clarify the role of 
DaT-SPECT at Screening. 
Section 5.2 Exclusion criteria 
Exclusion criterion #22a 
(formerly #22) on diabetes was 
updated to remove the HbA1c 
value and specify that inclusion 
of participants with well 
controlled type 2 diabetes in 
line with local clinical practice 
is acceptable. 
To allow Investigators the 
discretion to decide what 
constitutes stable type 2 diabetes. 
Section 5.2 Exclusion criteria 
Exclusion criterion #23a 
(formerly #23), subcriterion 
“a” on QTcF was updated: the 
QTcF values for males and 
females that would lead to 
exclusion were specified. 
To further clarify normal QTcF 
ranges in adult males and females 
in line with current ECG guidance. 
Section 5.2 Exclusion criteria 
Exclusion criterion #31a 
(formerly #31) on prohibited 
medication was split into drugs 
that may affect Parkinson’s 
disease, and drugs that may 
affect the DaT-SPECT scan. 
The time frame of the 
prohibition was amended based 
on drug metabolism. 
To clarify the exclusion criterion 
on co-medication. 
Section 5.2 Exclusion criteria 
Exclusion criterion #35a 
(formerly #35) on positive drug 
screen was updated to clarify 
that concomitant use of a 
medication would not lead to 
exclusion. 
To allow enrollment of 
participants taking medications 
that may lead to a positive drug 
screen.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2 Exclusion criteria 
Exclusion criterion #40b 
(formerly #40a) related to renal 
function was updated to revise 
subcriteria b, c, d, and e: 
further clarification was 
provided on Screening 
laboratory results considered 
acceptable. 
To expand the enrolled population 
to those with mild and moderate 
renal impairment (KDIGO 2012 
Clinical Practice Guideline) as 
representative of the target PD 
population. 
Section 6.1 Treatments 
administered 
Footnote “a” below the table 
was updated. 
To correct an error. 
Section 6.5.2 Prohibited 
concomitant treatments 
(medications and therapies) 
The time frame for prohibited 
concomitant medications taken 
before DaT-SPECT imaging 
was amended based on drug 
metabolism. 
To further specify the prohibition 
period for co-medication. 
Section 7.1.4 Temporary 
Discontinuation 
Text was updated to clarify 
that Investigator, SMC, or 
DMC (rather than the Sponsor 
in consultation with the DMC) 
may consider temporary 
discontinuation of dosing. 
To clarify roles and 
responsibilities. 
Section 7.1.5 Rechallenge 
Text was updated to clarify 
that Investigator and SMC 
(rather than the Sponsor in 
consultation with the DMC) 
may consider rechallenge. 
Endorsement by the DMC may 
be obtained if the SMC 
requests this. 
To clarify roles and 
responsibilities. 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the study 
Text was updated to clarify the 
role of SMC and DMC (in 
addition to the Investigator) in 
participant withdrawals. 
To clarify roles and 
responsibilities. 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the study 
Discontinuation criterion #6 
was updated to revise renal 
toxicity criteria. 
To permit participants with 
clinically insignificant fluctuations 
in mild and moderate renal 
impairment (KDIGO 2012 Clinical 
Practice Guideline) to remain in 
the study. 
Section 8.1.1.3 Dopamine 
Transporter Imaging with 
Single Photon Emission 
Computed Tomography 
The time frame for prohibitied 
concomitant medications taken 
before DaT-SPECT imaging 
was updated. 
To align with Section 6.5.2. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.3 Vital signs 
Text was updated to clarify 
that all pulse and BP readings 
(not only the average) will be 
recorded in the eCRF, and the 
average will be derived for 
analyses. 
To specify what will be recorded 
in the eCRF. 
Section 8.2.6 Suicidal risk 
monitoring 
C-SSRS version and timepoint 
of assessment at study start 
were updated to align with the 
Schedule of Activities. 
To correct an error. 
Table 9-1 Overview of planned 
efficacy analyses 
Terminology was updated from 
RMST to RMET; 
MDS-UPDRS Parts I/II/III 
subscales were separated out as 
individual endpoints; 
DaT-SPECT and ST intake at 
12 months were added. 
To further clarify the planned 
analyses. 
Table 9-1 Overview of planned 
efficacy analyses 
CSF ASYN oligomers/seeding 
capacity was added as an 
Exploratory Efficacy Endpoint. 
To further clarify the exploratory 
ASYN endpoints.  
Section 9.3 Planned 
efficacy/outcome analyses 
The planned list of predictors 
of early initiation of ST was 
removed. 
To move details into the SAP 
where the exact predictors used 
will be provided. 
Section 9.3.1.1.1 Primary 
Efficacy Estimand: MDS-
UPDRS Parts I-III sum score at 
12 months (“De Jure” 
Estimand) 
Sensitivity analysis #6 
regarding exclusion of data 
collected from home visits was 
removed since home visits 
were rescheduled to be clinic 
visits to ensure the full range of 
MDS-UPDRS Part III items to 
be measured by a MDS-trained 
physician (ie, rigidity items 
cannot be measured by a 
visiting nurse).  
To remove a sensitivity analysis 
that excludes home visit data; this 
analysis is no longer needed since 
there will be no MDS-UPDRS 
Part III data from home visits. 
Section 9.3.1.1.5 Other 
Secondary Efficacy Estimand: 
MoCA at 12 months 
Section was removed 
following removal of the 
MoCA assessment at 
12 months. 
To remove an analysis that is no 
longer needed. 
Section 9.3.1.2.3 Secondary 
Efficacy Estimand: MDS-
UPDRS Part I/Part II/Part III 
subscales at 18 months (“De 
Jure” Estimand) 
The description of sensitivity 
analyses for MDS-UPDRS Part 
I/Part II/Part III was updated. 
To further clarify the planned 
analyses. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.1.2.5 Secondary 
Efficacy Estimand: MoCA over 
18 months 
The MoCA assessment 
originally planned at 
12 months was removed, and 
therefore the analysis at 
18 months was simplified to a 
post-Baseline analysis adjusted 
for Baseline (Screening) as a 
covariate because versions to 
be used at Screening and 
18 months will differ. 
To align with the change in the 
Schedule of Activities for the 
MoCA assessment due to possible 
practice effects. 
Section 9.3.2.1.1 
Supplementary Efficacy 
Estimand: DaT-SPECT mean 
Striatum SBR at 12 months 
The planned analysis at 
12 months was updated to be a 
change from Baseline analysis 
(instead of a post-Baseline 
analysis), with adjustment for 
Baseline as a covariate. 
To improve the reporting of the 
analysis results.  
Section 9.3.2.2 Exploratory 
Efficacy Endpoints at 12 and 
18 months 
CSF endpoints were updated to 
include CSF ASYN 
oligomers/seeding capacity in 
addition to CSF total ASYN. 
To further clarify the exploratory 
ASYN endpoints.  
Table 9-2 Overview of 
handling strategies for MDS-
UPDRS ICEs and study 
termination 
Footnotes "b" and "c" were 
added in order to clarify what 
should happen when (i) a 
participant did not respect the 
Washout Period for the ST, (ii) 
in case of an event preventing a 
participant from attending a 
particular scheduled clinic visit 
with a MDS-UPDRS 
assessment, and (iii) in case of 
MDS-UPDRS being collected 
at home rather than in clinic. 
To further clarify the planned 
analyses with regard to handling of 
ICEs. 
Section 9.5.1 ICEs potentially 
affecting the interpretation of 
measurements 
A sentence was added to 
further clarify the handling of 
ST initiation as an ICE. 
To make sure ST initiation is 
handled correctly when the 
presribed ST is not the medication 
recommended in the protocol (ie, 
levodopa). 
Section 9.7 Determination of 
sample size 
The number of participants 
planned to be screened, 
randomized, and evaluated was 
added. 
To further clarify the sample size 
determination. 
Section 10.11 Appendix 11 
Protocol Amendment History 
The Protocol Amendment 
Summary of Changes Table for 
the previous amendment has 
been added. 
Minor administrative change. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
10.11.3 
Amendment 3 (04 Oct 2021) 
Overall Rationale for the Amendment 
PD0053 Protocol Amendment 3, dated 04 Oct 2021, was completed to add a treatment arm with 
a lower dose of UCB0599 180mg/day (which will come into effect with the availability of the 
IMP for the low dose), allow the use of historical symptomatic treatments, and to harmonize 
feedback from regulatory authories and ethic review boards received during the initial Clinical 
Trial Applications (CTA). The following changes were implemented:  
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Where applicable, the wording 
“Study Watch” was renamed to 
“wearable sensor.” 
To emphasize that the watch is 
not investigated in the clinical 
study. The generic term 
“wearable sensor” is used 
throughout. 
Global 
“Study Hub” was renamed to 
“Wearable Sensor Hub.” 
To reflect the updates of the 
reference to the wearable 
sensor. 
Global 
“Device deficiencies” was 
replaced with “sensor 
deficiencies.” 
To reflect the updates of the 
reference to the wearable 
sensor.  
Section 1.1 Synopsis (Overall 
study design) 
Clarification on low and high 
doses of UCB0599 (180mg/day 
and 360mg/day) was added. 
To provide justification for the 
selected new dose arm. 
Clarification on the wearable 
sensor familiarization period. 
To allow start of use of the 
sensor in the first months of the 
treatment period. 
Section 1.1 Synopsis 
(Treatment Groups and 
Duration) 
Duration of Screening period was 
added. 
Added for clarity. 
Section 1.1 Synopsis (Number 
of participants) 
The number of participants 
screened was increased. 
To reflect that more 
participants are to be enrolled 
due to the additional treatment 
arm. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
An additional dosage level was 
implemented to include 
180mg/day (90mg BID). 
To add a new lower dose 
treatment arm in support of 
dose selection for the pivotal 
studies. 
Change to the frequency of the 
DMC reviews. 
To account for the increase in 
number of participants and to 
ensure regular independent 
review. 
Visits 9 (Month 6), 11 (Month 
10), and 14 (Month 16) have been 
changed to in-clinic visits.  
Visits 4 (Day 10), 7 (Month 3), 
and 16 (Month 19) have been 
modified to include option of in-
clinic visit or telemedicine video 
call supported by a research 
nurse. 
Visits were changed to reduce 
potential rater variability. 
 
Remote visits were made 
optional in order to take into 
account the site’s and 
participant’s preference. 
For France only (refer to Section 
10.9, Appendix 9): A note has 
been added that all visits in 
France are in-clinic visits only. 
To exclude remote visits in 
France based on feedback from 
France.  
Section 1.3 Schedule of 
Activities 
“Participant experience survey” 
was renamed to “Optional 
participant experience survey.” 
To clarify that the survey is not 
mandatory. 
Not applicable to France: 
Addition of symbols to represent 
in-clinic visits or telemedicine 
video calls supported by a 
research nurse. 
Remote visits were made 
optional in order to take into 
account the site’s and 
participant’s preference. 
For France only (refer to Section 
10.9, Appendix 9): Footnote “b” 
included to clarify a 
country-specific requirement. 
To reflect the request from 
France that telemedicine is not 
implemented in the study. 
Footnote “j” included to clarify 
that the DaT-SPECT scan at 
Screening Visit 2 is only 
applicable to participants without 
an adequate historical DaT-
SPECT scan within the previous 3 
months before Screening Visit 1, 
as determined by the central 
reader. 
To allow participants with a 
previous DaT-SPECT that 
fulfills the quality criteria of 
the central reader. 
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Section # and Name 
Description of Change 
Brief Rationale 
Footnote “k” included to add that 
in case of early termination of 
study medication, the DaT-
SPECT will occur at EOT (End of 
Treatment), provided that the 
previous DaT-SPECT occurred 
more than 6 months prior to the 
EOT. For Germany only: A note 
was added to clarify country-
specific requirements. 
To clarify the process for DaT-
SPECT assessment in case of 
early termination of study 
participation. 
Footnote “l” was modified to add 
that participants have the 
opportunity to opt out of CSF 
sampling; however, the aim is to 
collect samples from at least 50 
participants/arm. 
To further clarify CSF 
sampling requirements. 
Footnote “o” was modified to 
clarify that study participants will 
be asked to take their study 
medication during the site visit 
after the blood sample is collected 
should the visit be scheduled 
before 11:00am. 
Rephrased for clarity. 
For France only: A note has 
been added to footnote "p" to 
clarify country-specific 
requirements. 
To implement a requirement 
from France for monthly 
pregnancy testing. 
Footnote “t” was modified to 
clarify that clinical tagging of 
Virtual Motor Exam (VME) on 
the wearable sensor is only 
applicable to the participants 
wearing the sensor. 
To provide clarification on the 
use of the wearable sensor. 
Section 2.3.1 Coronavirus 
Disease-2019 benefit/risk 
assessment 
Addition of text on the 
benefit/risk of Covid-19 
vaccinations in the study. 
To provide clarification on the 
benefit/risk of Covid-19 
vaccinations. 
Section 2.3.2 Wearable Sensor 
Regulatory Classification 
New section with details on the 
wearable sensor were added. 
To provide clarification on the 
regulatory classification of the 
wearable sensor across regions. 
Section 2.3.3 Wearable sensor 
benefit/risk assessment 
Section 2.3.3.1 Potential 
benefits 
New sections with details on the 
potential benefit of the wearable 
sensor were added. 
To provide clarification on the 
benefit/risk of the wearable 
sensor. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.3.3 Wearable sensor 
benefit/risk conclusion 
Language from the study risk 
determination was added. 
To provide clarification on the 
benefit/risk of the wearable 
sensor 
Section 4.1 Overall design 
Clarification on low and high 
doses of UCB0599 (180mg/day 
and 360mg/day) was added. 
To provide justification for the 
selected new dose arm. 
Section 4.1.1 Decentralized 
model 
Details on telemedicine visits 
were added. 
To provide further clarification 
on telemedicine visits. 
For France only: Text was added 
to clarify that this is not 
applicable to France. 
For clarification. 
Section 4.2 Scientific rationale 
for study design 
Clarification on 12-hour ST 
washout. 
For clarification. 
Section 4.3 Jusification for dose 
Updated to include new dosage 
level 180mg/day (90mg BID). 
To provide justification for the 
selected new dose arm. 
Section 4.3.1 Safety-based dose 
levels 
Table 4-1 was updated to include 
observed human exposures for 
new dosage level 180mg/day 
(90mg BID). 
To provide justification for the 
selected new dose arm. 
Section 4.3.2 Pharmacology 
based dose levels 
Text below Table 4-2 was 
updated to include observed 
human exposures for new dosage 
level 180mg/day (90mg BID). 
To provide justification for the 
selected new dose arm. 
Section 5.1 Inclusion criteria 
For Canada only (already 
implemented in other countries): 
The age-related inclusion criterion 
#1 was updated: “Study 
participant must be 40 to 75 years 
of age inclusive.” 
Increase the upper age limit for 
inclusion in the study which 
reflects the early PD 
population. This population 
does not present additional risk 
compared to the population 
initially included in the study. 
Inclusion criterion #2a 
(previously criterion #2) was 
updated to add in parenthesis 
"(including diagnosis during 
Screening)." 
To clarify that the PD 
diagnosis can be established at 
the time of screening for the 
study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Inclusion criterion #4a 
(previously criterion #4) was 
revised: “A Screening DaT-
SPECT, or a historical DaT-
SPECT within 3 months of the 
Screening Visit (V1) that has been 
qualified by the central reader, 
shows evidence of dopamine 
transporter deficit consistent with 
PD as determined by a central 
reader.” 
To allow participants with a 
previous DaT-SPECT that 
fulfills the quality criteria of 
the central reader and to further 
clarify the outcome of the 
readout by the central reader. 
Inclusion criterion #5a 
(previously criterion #5) was 
removed.  
The inclusion criterion was 
deleted since genetic forms of 
PD are of minor incidence in 
the selected study population of 
age 40 and above. 
Inclusion criterion #6a 
(previously criterion #6) updated 
≤2 to ≤2.5 modified Hoehn and 
Yahr staging. 
To extend the study population 
to participants with a subtle 
balance issue. 
Inclusion criterion #7a 
(previously criterion #7) updated 
to include exceptions to 
medications for the treatment of 
motor symptoms of PD.  
To reflect the update that 
participants that received short 
historical symptomatic 
treatment with an appropriate 
washout before trials start are 
allowed in the study. 
Section 5.2 Exclusion criteria 
Text about contacting the Medical 
Monitor to discuss enrollment for 
participants with allergies was 
removed from exclusion criterion 
#4a (previously criterion #4). 
To clarify that the medical 
monitor is not involved in the 
participant selection based on 
feedback from the UK. 
Text about the participant being 
excluded from lumbar puncture 
but not from study participation 
was added to exclusion criterions 
#14a to #18a (previously 
criterions #14 to #18).  
Rephrased for clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
Exclusion criterion #25a 
(previously criterion 25) was 
updated: 
“Study participant has had 
significant blood loss or has 
donated or received 1 or more 
units (450mL) of blood within 30 
days prior to first drug 
administration Baseline Visit, or 
has donated plasma or platelets 
within 14 days prior to Baseline 
Visit.” 
Rephrased for clarity. 
Exclusion criterion #26a 
(previously criterion #26) updated 
to add “Short (up to 4 weeks) past 
use of medications for the 
treatment of motor symptoms is 
permitted following a sufficient 
washout period. Medications 
included are levodopa, MAO-B 
inhibitors, COMT inhibitors, 
anticholinergics, or amantadine. A 
sufficient washout period is at 
least 3 months prior to the first 
screening visit”. 
To reflect the update that 
participants that received short 
historical symptomatic 
treatment with an appropriate 
washout before trials start are 
allowed in the study. 
Exclusion criterion #30a 
(previously criterion #30) was 
removed; covered by exclusion 
criterion #26a. 
To simplify the protocol. 
Renal exclusion criterion #40a 
(previously criterion #40) for 
serum creatinine > upper limit of 
normal was removed. 
Serum creatinine is included in 
the calculation of the estimated 
glomerular filtration rate and is 
already considered in renal 
exclusion criterion 40 part “e”. 
Exclusion criterion #43a 
(previously criterion #43) was 
updated to add “adults with 
legally authorized representative." 
A note has also been added for 
requirements specific for France. 
To further specify vulnerable 
groups. 
Exclusion criterion #45 was 
added to exclude participants with 
serum potassium level below the 
lower limit of the laboratory 
reference range.  
To add an exclusion criterion 
for participants with 
hypokalemia.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4 Screen failures 
Text was updated to clarify that if 
Visit 2 was completed during 
screening, only Visit 1 needs to be 
completed for rescreening. 
To clarify that MRI, CSF 
sampling, and DaT-SPECT 
should not be repeated for 
rescreening. 
Section 6.1 Treatments 
administered 
Inclusion of new dosage level 
“180mg/day (90mg BID).” 
To add a new dose arm in 
support of dose selection for 
the pivotal study. 
Section 6.3 Measures to 
minimize bias: randomization 
and blinding 
Addition of text clarifying time 
bias due to additional dose arm. 
Clarifying the potential bias of 
introducing a new dose arm in 
a running study. 
Section 6.3.1.2 Breaking the 
treatment blind in an emergency 
situation 
Removal of text “The Medical 
Monitor or equivalent should be 
consulted prior to unblinding, 
whenever possible.” 
To clarify procedures for 
breaking the treatment blind 
based on feedback from the 
UK. 
Section 6.5.1 Permitted 
concomitant treatments 
(medications and therapies) 
Text updated to add clarification 
on COVID-19 vaccinations in the 
study. 
For clarification. 
Section 6.5.3 Rescue 
medication  
Text was updated to clarify the 
considerations for initiating ST as 
rescue medication. 
Clarification regarding the use 
of rescue medication. 
Text was updated to clarify 
compliance of 12-hour ST 
washout. 
To highlight the importance of 
the washout period. 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the study 
Text updated to specify that the 
DaT-SPECT will occur at EOT 
(End of Treatment), provided that 
the previous DaT-SPECT 
occurred more than 6 months 
prior to the EOT. 
To clarify the process for DaT-
SPECT assessment in case of 
early termination of study 
participation. 
Withdrawal criterion #6 was 
updated to add criteria for renal 
toxicity. 
Added laboratory tests 
suggestive of renal toxicity to 
address a request from the UK. 
Section 8 Study assessments 
and procedures 
Bullet was added: “PROs (at 
home prior to a clinic visit or first 
assessments at the clinic).” 
To clarify the sequence of 
assessments for PROs. 
Text was updated to specify the 
maximum blood volumes 
collected at every visit (50mL) 
and during the study (500mL). 
To specify the maximum blood 
volumes collected based on 
feedback from France. 
Section 8.1.1.1 MDS-UPDRS 
Clarification on 12-hour ST 
washout. 
To highlight the importance of 
the washout period. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1.3 Dopamine 
Transporter Imaging 
A note has been added to clarify 
that no scan will be performed at 
Month 12 for German 
participants. 
To clarify a country-specific 
requirement. 
Clarification that a historical 
DaT-SPECT scan within the 
previous 3 months before 
Screening Visit 1 is acceptable.  
To allow participants with a 
previous DaT-SPECT that 
fulfills quality criteria of the 
central reader. 
Details on the DaTSCAN tracer 
were added. 
For clarification. 
Section 8.1.3 Wearable sensor 
Text was added to clarify that 
where it is not possible to access 
the sensor during the Baseline 
period, participants may start 
wearing it until Visit 8 (M4). 
To allow start of use of the 
sensor in the first months of the 
treatment period. 
Section 8.2.1 Physical 
examination 
Details on any abnormal finding 
from the focused body 
examinations found by the 
research nurse was added. 
To clarify the responsiblities of 
the research nurse. 
For telemedicine visits, 
auscultation was deleted from the 
assessments performed by the 
research nurse. 
Other assessments will be used 
for the identification of AEs 
and to discuss with the 
Investigator via video 
communication if an AE is 
suspected. 
Section 8.2.1 Physical 
examination 
Section 8.2.3 Vital signs 
Section 8.2.4 
Electrocardiograms 
Section 8.2.5 Clinical safety 
laboratory assessments 
Section 8.2.6 Suicidal risk 
monitoring 
Details for remote visit were 
added.  
To clarify the procedures 
during telemedicine visits 
based on feedback the from 
France. 
Section 8.3 Adverse events and 
serious adverse events 
Details on AEs related to 
COVID-19 vaccination was 
added.  
To clarify the documentation 
and reporting process for AEs 
related to COVID-19 
vaccination. 
Section 8.3.6.2 Renal function 
safety monitoring and 
management 
Text was added that an increase in 
serum creatinine of >25% from 
the previous value will trigger 
repeat testing within 48 hours. 
Clarification based on feedback 
from the Canadian health 
authority. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5 Treatment of 
overdose 
Text was added that a 
participant’s dosing will be 
stopped in the event of an 
overdose while the participant is 
being evaluated.  
Clarification based on feedback 
from the Canadian health 
authority. 
Throughout Section 9 Statistical 
considerations 
Updates were made throughout to 
refer to 3 treatment groups rather 
than 2. 
To implement the addition of a 
low dose arm. 
Population-level summaries were 
updated throughout to show the 
comparison of low dose vs 
placebo and high dose vs placebo. 
To implement the addition of a 
low dose arm. 
Symptomatic Treatment language 
was improved throughout. 
Reduced use of the term rescue 
medication and refer to “ST 
initiation” or “predictors of early 
ST initiation” rather ST intake or 
start of ST. 
Improved language and 
description. 
Adjust for age at baseline (as well 
as gender) in main models rather 
than as part of a sensitivity 
analysis throughout. 
Seen as standard adjustment. 
Sensitivity and Supplementary 
analysis sections were updated; 
some analyses removed and some 
added. 
To refine the overall analysis. 
Restricted Mean Survival Time 
(RMST) was changed to be 
Restricted Mean Event Time 
(RMET) throughout. 
To more accurately reflect the 
analyses being conducted. 
Section 9.1 Definition of 
analysis sets 
Definition of FAS was changed to 
refer to “1 post-baseline 
assessment” rather than “1 valid 
post-baseline assessment.” 
To add clarity to how this 
analysis set should be defined. 
Section 9.2 General statistical 
considerations 
SAS version was updated from 
9.3 to 9.4. 
Updated to align with current 
programming standards. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3 Planned 
efficacy/outcome analyses 
Updates were made to the list of 
predictors of early ST initiation. 
To reflect latest internal 
research. 
Text was added to explain how 
the three treatments will be 
evaluated/compared. 
To implement the addition of a 
low dose arm. 
PPMI dataset has been updated. 
To add more detail as there is 
now a PPMI 2.0 cohort. 
Text has been added to make the 
modelling approach clearer. 
To clarify the description of the 
model. 
Section 9.3.1.1.1.1 
Supplementary Efficacy 
Estimand to MDS-UPDRS 
Parts I III sum score at 12 
months (“De Facto” Estimand) 
Text was added to make it clear 
that categorical linear mixed 
effects models (LMEMs) will use 
baseline data as a covariate. 
To clarify the description of the 
model. 
Section 9.3.1.1.3 Key 
Secondary Efficacy Estimand: 
Worsening on MDS-UPDRS 
Part III subscale at 12 months 
(“De Jure” Estimand) 
Section 9.3.1.2.2 Key 
Secondary Efficacy Estimand: 
Worsening on MDS-UPDRS 
Part III subscale at 18-month 
(“De Jure” Estimand) 
Section 9.3.3.1 Secondary 
Efficacy Estimand: Time to ST 
intake at 18 months 
RMET modelling approach was 
improved. 
To reflect further research on 
this method. 
Section 9.3.5 Center effects 
Updated to state that any 
additional analyses by 
country/region will be done 
outside of the CSR.  
 
Additional text was included 
about COVID-19 by 
country/region summaries. 
Since treatment assignment 
will not necessarily be 
balanced across countries, any 
analyses by country will be 
done post-hoc. 
Detail added on COVID-19 
summaries. 
Section 9.5 Handling of ICEs, 
protocol deviations, and 
resulting missing data 
Re-ordered and more detail 
added. 
To add clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.6 Planned analysis at 
12 months and data monitoring 
Addition of bullet “When safety 
data for 3 months of treatment (ie, 
until Visit 7) are available for 100 
participants.” 
To keep a DMC at the 
timepoint expected before the 
low dose arm was included. 
Bulleted list was added to specify 
timepoints of SMC meetings. 
To clarify the SMC meeting 
frequency based on feedback 
from France. 
Section 9.7 Determination of 
sample size 
Updated to refer to 3 arms instead 
of 2. Text was added to explain 
how comparisons will be made 
for the 3 groups. 
To implement the addition of a 
low dose arm 
Section 9.7.1 Primary efficacy 
estimand 
Section 9.7.3 Power for 
secondary efficacy estimand 
(DaT-SPECT mean striatum 
SBR) 
PPMI dataset has been updated.  
To add more detail as there is 
now a PPMI 2.0 cohort. 
Section 10.1.3 Informed 
consent process 
Text was added to clarify that 
potential participants will have as 
much reflection time as needed 
during the informed consent 
process and will be under no 
pressure to decide on their 
participation in the study. 
To clarify the informed consent 
process based on feedback 
from the UK. 
Text was added to clarify 
potential participants will have 
the opportunity to discuss the 
study and its alternatives with the 
Investigator or seek additional 
advice. The amount of time a 
potential participant takes to 
decide whether to participate or 
not will vary per participant. A 
note has also been added for 
requirements specific for France 
(please refer to Section 10.9 
Appendix 9). 
To address request for clarity 
in the intial CTA review and to 
clarify a country-specific 
requirement. 
Text was updated to remove 
“legal representative.”  
To implement feedback from 
the initial CTA review. 
Section 10.1.6 Data quality 
assurance 
Addition of standard text on 
quality tolerance limits. 
Added for clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.2: Appendix 2: 
Clinical laboratory tests 
Text updated: RBC counts and/or 
Hemoglobin in CSF for quality 
control purposes. 
To clarify that quality control 
of CSF sampling will be done 
either by RBC counts or 
hemoglobin analysis. 
Section 10.4: Appendix 4: 
Contraceptive guidance and 
collection of pregnancy 
information 
A note has been added to the 
second bullet under “Pregnancy 
testing” for requirements specific 
for France (please refer to 
Section 10.9 Appendix 9). 
To clarify a country-specific 
requirement. 
Section 10.9: Appendix 9: 
Country-specific requirements  
Details added on country-specific 
requirements for Germany and 
France. 
To clarify all country-specific 
requirements. 
Section 10.11: Appendix 11 
Protocol Amendment History 
The Protocol Amendment 
Summary of Changes Table for 
the previous amendment has been 
moved to Appendix 11. 
Minor administrative change. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
10.11.4 
Amendment 2 (21 May 2021) 
Overall Rationale for the Amendment 
PD0053 Protocol Amendment 2, dated 21 May 2021, was completed to increase the upper age 
limit for participants’ inclusion in the study to 75 years, which reflects the early Parkinson’s 
Disease population. This population does not present additional risk compared to the population 
initially included in the study. The following changes were implemented: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion criteria 
 
The age-related inclusion 
criteria #1 was updated: “Study 
participant must be 40 to 70 
75 years of age inclusive” 
Increase the upper age limit for 
inclusion in the study.  
Section 2.3.1 Coronavirus 
Disease-2019 benefit/risk 
assessment 
Upper age limit of the 
participants to be included in the 
study was changed from 70 to 
75 years. 
Increase the upper age limit for 
inclusion in the study. 
10.11.5 
Amendment 1 (29 Oct 2020) 
Overall Rationale for the Amendment 
PD0053 Protocol Amendment 1, dated 29 Oct 2020, was completed to remove planned video 
recording of study participants during the the MDS-UPDRS Part III assessment due to 
operational limitations at this time (eg, procedures for de-identification, video processing, video 
data handling, access, and storage). Video recording may be re-introduced at a later time via an 
amendment. The following changes were implemented: 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schedule of 
Activities 
Video recording Informed 
Consent Form was removed. 
Removal of planned video 
recording during MDS-UPDRS 
Part III assessment due to 
operational limitations at this 
time 
Section 8.1.1.1 MDS-UPDRS 
MDS-UPDRS Part III motor test 
recording via video using the 
telemedicine technology was 
removed. 
Removal of planned video 
recording during MDS-UPDRS 
Part III assessment due to 
operational limitations at this 
time 
Section 10.11 Appendix 11 
Protocol Amendment History 
“Not applicable” was replaced 
by a note that the Protocol 
Amendment Summary of 
Changes Table for the current 
amendment is located directly 
before the Table of Contents. 
Minor administrative change  
 
 
 
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10.12 
Appendix 12: In-clinic VME Investigator rating scale 
Investigators are to rate participant performance with each VME using the following rating scale. 
Skill Check Task #1: Tap wearable sensor (sensor tapping) 
0: Normal: No problems 
1: Slight: Any of the following:  
a) the regular rhythm is broken with one or two interruptions or hesitations of the 
movement 
b) slight slowing 
c) the amplitude decrements near the end of the task 
2: Mild: Any of the following:  
a) 3 to 5 interruptions during the movements 
b) mild slowing 
c) the amplitude decrements midway in the task 
3: Moderate: Any of the following:  
a) more than 5 interruptions during the movement or at least one longer arrest (freeze) 
in ongoing movement 
b) moderate slowing 
c) the amplitude decrements starting after the first open-and-close sequence 
4: Severe: Cannot or can only barely perform the task because of slowing, interruptions, or 
decrements. 
Skill Check Task #2: Seated Rest (Rest Tremor) 
0: Normal: No tremor 
1: Slight: ≤1cm in maximal amplitude 
2: Mild: >1 cm but <3 cm in maximal amplitude 
3: Moderate: 3-10 cm in maximal amplitude 
4: Severe: >10 cm in maximal amplitude 
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Skill Check Task#3: Arm Raise (Postural Tremor) 
0: Normal: No tremor 
1: Slight: Tremor is present but less than 1 cm in amplitude 
2: Mild: Tremor is at least 1 but less than 3 cm in amplitude 
3: Moderate: Tremor is at least 3 but less than 10 cm in amplitude 
4: Severe: Tremor is at least 10 cm in amplitude 
Skill Check Task #4: Hand Open and Close 
0: Normal: No problems 
1: Slight: Any of the following:  
a) the regular rhythm is broken with one or two interruptions or hesitations of the 
movement 
b) slight slowing 
c) the amplitude decrements near the end of the task 
2: Mild: Any of the following:  
a) 3 to 5 interruptions during the movements 
b) mild slowing 
c) the amplitude decrements midway in the task 
3: Moderate: Any of the following:  
a) more than 5 interruptions during the movement or at least one longer arrest (freeze) 
in ongoing movement 
b) moderate slowing 
c) the amplitude decrements starting after the first open-and-close sequence 
4: Severe: Cannot or can only barely perform the task because of slowing, interruptions or 
decrement. 
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Skill Check Task #5: Arm Twist (Pronation/Supination) 
0: Normal: No problems 
1: Slight: Any of the following:  
a) the regular rhythm is broken with one or two interruptions or hesitations of the 
movement 
b) slight slowing 
c) the amplitude decrements near the end of the sequence 
2: Mild: Any of the following:  
a) 3 to 5 interruptions during the movements 
b) mild slowing 
c) the amplitude decrements midway in the sequence 
3: Moderate: Any of the following:  
a) more than 5 interruptions during the movement or at least one longer arrest (freeze) 
in ongoing movement 
b) moderate slowing  
c) the amplitude decrements starting after the first supination-pronation sequence 
4: Severe: Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
Skill Check Task #6: Foot Stomp 
0: Normal: No problems 
1: Slight: Any of the following: 
a) the regular rhythm is broken with one or two interruptions or hesitations of the 
movement 
b) slight slowing 
c) amplitude decrements near the end of the task 
2: Mild: Any of the following: 
a) 3 to 5 interruptions during the movements 
b) mild slowness; 
c) amplitude decrements midway in the task 
3: Moderate: Any of the following: 
a) more than 5 interruptions during the movement or at least one longer arrest (freeze) 
in ongoing movement 
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b) moderate slowing in speed 
c) amplitude decrements after the first tap 
4: Severe: Cannot or can only barely perform the task because of slowing, interruptions or 
decrements 
Skill Check Task #7: Up and Go 
Rising from chair: 
0: Normal: No problems. Able to arise quickly without hesitation. 
1: Slight: Arising is slower than normal; or may need more than one attempt; or may need to 
move forward in the chair to arise. No need to use the arms of the chair. 
2: Mild: Pushes self up from arms of chair without difficulty. 
3: Moderate: Needs to push off, but tends to fall back; or may have to try more than one time 
using arms of chair, but can get up without help. 
4: Severe: Unable to arise without help. 
 
Gait: 
0: Normal: No problems. 
1: Slight: Independent walking with minor gait impairment. 
2: Mild: Independent walking but with substantial gait impairment. 
3: Moderate: Requires an assistance device for safe walking (walking stick, walker) but not a 
person. 
4: Severe: Cannot walk at all or only with another person’s assistance. 
Skill Check Task #8: Stand Still (Postural Stability) 
0: Normal: No postural sway. 
1: Slight postural sway that is almost imperceptible. 
2: Mild postural sway that is noticeable but does not disrupt balance at all. 
3: Moderate postural sway that disrupts maintenance of balance in some way. 
4: Severe postural sway that causes the patient to be unstable at some point. 
 
 
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11 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
 
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