Interventional, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multi-centre Study to Assess the Efficacy, Safety and Tolerability of Lu AF82422 in Patients With Multiple System Atrophy
Phase: PHASE2
Conditions: Multiple System Atrophy
Sponsor: H. Lundbeck A/S

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 1 of 131
Clinical Study Protocol
Interventional, randomized, double-blind, parallel-group, placebo-con-
trolled, multi-centre study to assess the efficacy, safety and tolerability of 
Lu AF82422 in patients with Multiple System Atrophy
Lu AF82422
Study No.:
18331A (AMULET – Delay Multiple System Atrophy)
IND No.:
147370
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
6.0
Date of edition:
29 May 2024
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights. This document is 
confidential. It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
v. 2.0
CLI_02112413
NCT05104476

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 2 of 131
Major Changes Since Last Edition
The following summarizes the major changes from Protocol Edition No. 5.0 to 6.0
Chapter/ 
Section 
Number
Chapter/Section Title
Change
Throughout the protocol, where applica-
ble
Minor grammatical, editorial, and/or administrative changes have 
been made to improve the readability and/or clarity of the protocol.
Synopsis
Panel 1
Added:
The extension of the OLE period was added to the study design fig-
ure. 
Synopsis
Panel 3
Added:
The table was updated to include visits from Week 48E onwards.
Synopsis, 
Section 3.1
Study Methodology, 
Overview of the Study 
Design
Updated: 
The study duration from the Screening Visit to the Safety Follow-
up Visit is between 70 to 94 weeks for patients not entering the
optional OLE period and between 118 166 to 142 190 weeks for
patients continuing in the OLE.
The individual DBP will vary from 48 weeks up to 72 weeks.
Once the last patient will reach Week 48, this visit will be the
EoTDBP Visit for that patient. Patients who have not completed
visit at Week 72 at the time of Last Patient reaches End of
Treatment (EoT) The remaining patients in the DBP will have
their next scheduled visit converted to an EoTDBP Visit with
assessments as listed for Visit 24, according to Panel 2.
AfterIn the EoTDBP/End of Open Label Treatment/OLE, patients
will receive Lu AF82422 until Visit 24E (Week 92E) and complete
the EoTOLE at Visit 25E (Week 96E).
Patients who withdraw, except for those who withdraw their
consent, will be scheduled for a Withdrawal Visit to undergo
clinical and safety assessments as soon as possible and a Safety
Follow up Visit 20 weeks after last dose of IMP.
All patients (except the ones withdrawing consent) will be
scheduled for a Safety Follow-up Visit 20 weeks after their last
IMP dose, regardless if they received their last dose in the DBP or
OLE, or if they withdrew.
Synopsis, 
Section 3.1, 
Study Methodology, 
Panel 3, Overview of 
the Study Design
Added:
Visit 13E should occur at Week 48E, 4 weeks after Visit 12E. How-
ever, in the exceptional cases where sites have not yet received In-
stitutional Review Board/Ethics Committee approval for Protocol 
Edition 6.0, Visit 13E can be delayed until approval is in place but 
no later than 5 months after Visit 12E.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 3 of 131
Chapter/ 
Section 
Number
Chapter/Section Title
Change
Synopsis, 
Section 3.1, 
Section 8.1
Study Methodology, 
Overview of the Study 
Design, Overview
Updated:
The study includes the following periods:
Screening Period (4 weeks)
Randomization Period (2 weeks)
DBP (48 weeks up to 72 weeks)
Optional OLE (96 weeks)
Safety Follow-up Period (20 weeks after last investigational 
medicinal product [IMP] administration)
Synopsis, 
Section 3.1, 
Section 6.2
Study Methodology, 
Overview of the Study 
Design, IMP(s), 
Formulation(s), and 
Strength(s)
Updated:
Patients will be monitored after IMP administration for immediate 
drug reactions for a minimum of 2 hours with vital signs taken every 
30 minutes ±5 minutes from the end of the saline flush or until sta-
ble, whichever is later (only applicable through Visit 12E). Begin-
ning at Visit 13E, blood pressure and pulse will only be measured 
immediately prior to and immediately after IMP administration, in-
clusive of the saline flush (±5 minutes).
Synopsis, 
Section 9.6.3
Panel 3, Vital Signs
Updated: 
Blood pressure and pulse will be measured immediately prior to 
IMP administration and patients will be monitored immediately after 
IMP administration inclusive of saline flush (±5 minutes) for imme-
diate drug reactions for a minimum of 2 hours with vital signs taken 
every 30 minutes (±5 minutes) from the end of the saline flush or 
until stable, whichever is later (applicable only through Visit 12E).
Added:
Beginning at Visit 13E, blood pressure and pulse will only be 
measured immediately prior to and immediately after IMP 
administration, inclusive of the saline flush (±5 minutes).
Synopsis, 
Section 16.9.7
Statistical Methods, 
Analysis of Secondary 
Endpoints(s)
Updated:
In addition, an exploratory MMRM will be applied to the changes 
from the original DBP baseline visit to the extract time specific 
estimates, which will be presented graphically. No formal testing 
will be applied.
Updated:
In addition, an exploratory MMRM as described above will be 
applied to the changes from the original DBP baseline visit to 
extract time-specific estimates which will be presented graphically. 
No formal testing will be applied.
Section 3.1
Overview of the Study 
Design
Removed:
Patients who enter the OLE will receive the first open label dose 
(Visit 1E) at the same day as the EoTDBP or as soon as possible 
hereafter, but not later than 5 months after EoT Visit of the DBP and 
will be enrolled to OLE no later than end of Q1 2024.
Section 3.1
Overview of the Study 
Design
Updated:
The study design is presented in Panel 1 and the scheduled study 
procedures and assessments for the DBP are summarized in Panel 2 
and for OLE assessments are summarized in Panel 3.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 4 of 131
Chapter/ 
Section 
Number
Chapter/Section Title
Change
Section 3.2
Rationale for the Study 
Design
Updated:
The treatment duration of 48 to 72 weeks for patients not entering 
the optional OLE periods, between 118 to 142 166 to 190 weeks for 
patients continuing in the OLE, is considered a reasonable time 
window to investigate the natural progression of disease.
Since there are currently no available treatments for MSA, 
Lundbeck wishes to offer patients to continue with, or for patients 
initially receiving placebo, to receive Lu AF82422 for 48 up to 
96 weeks in the optional OLE.
Section 5.4
Withdrawal Criteria
Added:
The patient can no longer attend trial visits due to MSA disease 
progression.
Section 6.1.2
Treatment Regimen 
Open-label Extension 
Periods
Updated:
All In the OLE, all patients will receive open-label treatment with 
Lu AF82422 starting at Visit 1E until Visit 12 24E (Week 44 92E) 
(see Panel 3). 
During the OLE period, any deviation from the Q4W ±3 days 
dosing schedule must be discussed and agreed with the medical 
monitor and documented as a protocol deviation. IMP dosing must 
not take place if less than 2 weeks until the next scheduled IMP 
infusion. 
After Visit 13 25E, or if prematurely discontinued, patients will be 
scheduled for a Safety Follow-up Visit 20 weeks after the last IMP 
dose, as scheduled in Panel 3.
Section 3.1, 
Section 8.5
Overview of the Study 
Design, Optional 
Open-label Extension 
Period
Updated:
If a Safety Follow-up Visit for the DBP is due before the OLE is 
implemented, it should be completed per Panel 2. The patient could 
afterwards enter the OLE and treatment could continue for a 
planned period of 48 96 weeks.
Section 8.5.1
End-of-Treatment Visit 
– Optional Open-label 
Extension Periods
Updated:
Patients who enter the OLE will receive the first open-label dose of 
Lu AF82422 (Visit 1E) on the same day as the EoTDBP or as soon 
as possible thereafter and the last dose on Visit 12E 24E (Week 44), 
92E); EoT in the 48 96-week OLE is on 13E at Visit 25E (Week 48
96E).
Section 8.6
Withdrawal Visit
Updated: 
Patients who withdraw from the study prior to the respective EoT 
Visit for the treatment period (ie, EoTDBP or EoTOLE) will be 
asked to attend a Withdrawal Visit and Safety Follow-up Visit, if at 
all possible.
Section 9.2.1.5 Clinical Global 
Impression-Severity of 
Illness (CGI-S)
Updated: 
The rating is based upon observed and reported symptoms, behav-
iour, and function in the past seven days. Symptoms and behaviour 
may fluctuate over a week; the score should therefore reflect the av
erage severity level across the seven days. The CGI at the time of 
assessment. 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 5 of 131
Chapter/ 
Section 
Number
Chapter/Section Title
Change
Section 9.6.2
Panel 5
Updated:
Count and % of total leucocytes. If any abnormalities are noted in 
the complete blood count and/or differential counts, additional 
workup (ancillary tests) will be performed.  
Section 9.8.2, 
Section 9.8.3, 
Section 9.8.4, 
Section 9.8.5
Blood Sampling for 
Gene Expression 
Profiling (RNA), Blood 
Sampling for 
Metabolomics and/or 
Proteomics, Blood 
Sampling for 
Pharmacogenetics, 
Blood Sampling for 
Anti-drug Antibody
Updated:
Brooks Azenta Life Sciences, Indianapolis, IN, US  
Section 10.2
Pregnancy
Updated:
The investigator must follow-up on the outcome of the pregnancy 
and report it on a Pregnancy Outcome Form (paper). The follow-up 
must include information on the neonate at least up until the age of 
1 month.
If the partner of a man participating in the study becomes pregnant, 
the pregnancy should be reported on the Pregnancy Reporting 
Form (paper) and the outcome of the pregnancy should be followed 
and reported (Pregnancy Outcome Form) if the partner agrees. The 
partner must sign a pregnant partner Informed Consent Form to al-
low the investigator to collect information to report to Lundbeck.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 6 of 131
Table of Contents
Major Changes Since Last Edition...............................................................................................2
List of Panels.................................................................................................................................11
List of Abbreviations and Definitions of Terms ........................................................................12
1
Synopsis – Study 18331A ....................................................................................................16
2
Introduction .........................................................................................................................38
2.1
Background................................................................................................................38
2.1.1
Overview....................................................................................................38
2.1.2
Nonclinical Data.........................................................................................39
2.1.3
Clinical Data...............................................................................................39
2.2
Rationale for the Study ..............................................................................................40
2.3
Benefit – Risk Assessment ........................................................................................41
2.3.1
Overall Benefit – Risk Conclusion.............................................................41
2.3.2
COVID-19 Related Risk Assessment and Mitigation................................42
3
Objectives and Endpoints ...................................................................................................43
4
Study Design.........................................................................................................................48
4.1
Overview of the Study Design...................................................................................48
4.2
Rationale for the Study Design..................................................................................50
5
Ethics ....................................................................................................................................52
5.1
Ethical Rationale........................................................................................................52
5.2
Informed Consent ......................................................................................................53
5.3
Personal Data Protection............................................................................................55
5.4
Ethics Committee(s) and Institutional Review Board(s) ...........................................55
6
Study Population .................................................................................................................55
6.1
Number of Patients and Countries.............................................................................55
6.2
Patient Recruitment ...................................................................................................56
6.3
Selection Criteria .......................................................................................................56
6.4
Withdrawal Criteria ...................................................................................................60
7
Investigational Medicinal Product.....................................................................................61
7.1
Treatment Regimen ...................................................................................................61
7.1.1
Treatment Regimen Double-blind Period ..................................................61
7.1.2
Treatment Regimen Open-label Extension Period.....................................61
7.2
IMP(s), Formulation(s), and Strength(s)....................................................................62
7.3
Manufacturing, Packaging, Labelling, and Storage of IMP ......................................63
7.4
Method of Assigning Patients to Treatment ..............................................................63
7.5
IMP Accountability ...................................................................................................64
7.6
Unblinding Procedures ..............................................................................................64
7.7
Post-study Access to IMP(s)......................................................................................64
8
Concomitant Medication.....................................................................................................65
8.1
Concomitant Medication ...........................................................................................65
8.2
COVID-19 Vaccination.............................................................................................65
9
Study Visit Plan ...................................................................................................................66
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 7 of 131
9.1
Overview ...................................................................................................................66
9.2
Screening Period........................................................................................................66
9.2.1
Screening Visit (Visit 1, -6 Week) .............................................................66
9.2.1.1
Patient Identification Card.........................................................67
9.2.1.2
Re-screening ..............................................................................67
9.3
Randomization Period ...............................................................................................67
9.4
Double-blind Period...................................................................................................68
9.4.1
Baseline Visit (Visit 3, Week 0).................................................................68
9.4.2
General Outline of Visits During Double-blind Period..............................68
9.4.3
End-of-Treatment Visit – Double-blind Period..........................................68
9.4.4
Safety Follow-up Visit 20 Weeks After Last Dose of IMP – Double-blind 
Period .........................................................................................................68
9.5
Optional Open-label Extension Period ......................................................................69
9.5.1
End-of-Treatment Visit – Optional Open-label Extension Period .............69
9.5.2
Safety Follow-up Visit Open-label Extension Period 20 Weeks After Last 
Dose of IMP ...............................................................................................69
9.6
Withdrawal Visit........................................................................................................70
9.7
Unscheduled Visit......................................................................................................71
9.8
End-of-study Definition.............................................................................................71
10
Assessments..........................................................................................................................72
10.1
Screening and Baseline Procedures and Assessments...............................................72
10.1.1
Randomization Visit (Visit 2, Week -2).....................................................72
10.1.2
Demographics and Baseline Characteristics ..............................................72
10.1.2.1
Montreal Cognitive Assessment (MoCA)..................................73
10.1.3
Diagnostic Assessments .............................................................................73
10.2
Efficacy Assessments ................................................................................................73
10.2.1
Clinical Outcome Assessments (COA) ......................................................73
10.2.1.1
Use of COA Tools .....................................................................73
10.2.1.2
Unified Multiple System Atrophy Rating Scale (UMSARS) ....74
10.2.1.3
Composite Autonomic Symptom Scale – Select and Select 
Change (COMPASS-S/SC) .......................................................75
10.2.1.4
Schwab and England Activities of Daily Living (SE-ADL)......76
10.2.1.5
Clinical Global Impression-Severity of Illness (CGI-S)............76
10.2.1.6
Patient Global Impression – Severity of Illness (PGI-S) ...........76
10.2.1.7
Observer-reported Global Impression – Severity of Illness (OGI-
S)................................................................................................76
10.2.1.8
MSA Fall Diary .........................................................................76
10.2.1.9
FeetMe® .....................................................................................77
10.2.1.10 PAMSys.....................................................................................78
10.2.1.11 Rater Qualification.....................................................................78
10.2.1.12 External COA Monitoring Oversight.........................................79
10.2.2
Imaging Assessments .................................................................................79
10.2.2.1
Imaging Procedures ...................................................................79
10.2.3
Biomarker Assessments .............................................................................80
10.2.3.1
NfL and t-tau Analysis...............................................................80
10.3
Quality of Life Assessments......................................................................................81
10.3.1
EuroQol 5-Dimensions, 5 Levels (EQ-5D-5L) ..........................................81
10.4
Pharmacokinetic Assessments...................................................................................81
10.5
Target Engagement Assessments...............................................................................82
10.6
Safety Assessments....................................................................................................82
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 8 of 131
10.6.1
Adverse Events...........................................................................................82
10.6.2
Clinical Safety Laboratory Tests................................................................82
10.6.3
Vital Signs..................................................................................................84
10.6.4
Height and Weight .....................................................................................85
10.6.5
Electrocardiograms.....................................................................................85
10.6.6
Physical and Neurological Examinations...................................................85
10.6.7
Columbia-Suicide Severity Rating Scale ...................................................86
10.6.8
Anti-drug Antibody Assessments...............................................................86
10.6.9
Other Safety Assessments ..........................................................................87
10.7
Other Assessments.....................................................................................................87
10.7.1
Exit Interviews ...........................................................................................87
10.7.2
Study Experience Interviews......................................................................88
10.8
Biobanking.................................................................................................................88
10.8.1
General Considerations ..............................................................................88
10.8.2
Blood Sampling for Gene Expression Profiling (RNA).............................89
10.8.3
Blood Sampling for Metabolomics and/or Proteomics ..............................89
10.8.4
Blood Sampling for Pharmacogenetics ......................................................89
10.8.5
Blood Sampling for Anti-drug Antibody ...................................................90
10.8.6
CSF Sampling for Proteomics and Genomics............................................90
10.9
Order of Assessments ................................................................................................90
10.10 Total Volume of Blood Drawn and Destruction of Biological Material ...................90
10.11 Treatment Compliance...............................................................................................91
11
Adverse Events.....................................................................................................................91
11.1
Definitions .................................................................................................................91
11.1.1
Adverse Event Definitions .........................................................................91
11.1.2
Adverse Event Assessment Definitions .....................................................93
11.1.3
Study-specific Adverse Event Definitions – Adverse Events Requiring 
Additional Data Collection.........................................................................94
11.1.4
Management of Reactions to Study Drug ..................................................95
11.2
Pregnancy ..................................................................................................................95
11.3
Recording Adverse Events ........................................................................................95
11.4
Reporting Serious Adverse Events ............................................................................96
11.5
Treatment and Follow-up of Adverse Events............................................................96
11.6
Study Monitoring Committee(s)................................................................................97
11.6.1
Independent Data Monitoring Committee..................................................97
12
Data Handling and Record Keeping..................................................................................98
12.1
Data Collection..........................................................................................................98
12.1.1
Electronic Case Report Forms....................................................................98
12.1.1.1
Serious Adverse Event Fallback Forms.....................................98
12.1.2
External Data..............................................................................................98
12.2
Retention of Study Documents at the Site.................................................................99
12.2.1
eCRF Data..................................................................................................99
12.2.2
Other Study Documents .............................................................................99
13
Monitoring Procedures .....................................................................................................100
14
Audits and Inspections......................................................................................................101
15
Protocol Compliance .........................................................................................................101
16
Study Termination.............................................................................................................101
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 9 of 131
17
Statistical Methodology.....................................................................................................102
17.1
Study Primary Estimand..........................................................................................102
17.2
Responsibilities........................................................................................................103
17.3
Analysis Sets............................................................................................................103
17.4
Descriptive Statistics ...............................................................................................103
17.5
Patient Disposition...................................................................................................104
17.6
Demographics and Baseline Characteristics............................................................104
17.7
Recent and Concomitant Medication.......................................................................104
17.8
Exposure and Compliance .......................................................................................104
17.9
Efficacy Analyses ....................................................................................................104
17.9.1
General Efficacy Analysis Methodology .................................................104
17.9.2
Primary Analysis of the Primary Endpoint(s) ..........................................105
17.9.3
Sensitivity Analyses of the Primary Endpoint(s) .....................................106
17.9.4
Testing Strategy........................................................................................106
17.9.5
Analysis of the Key Secondary Endpoint.................................................106
17.9.6
Analysis of the Secondary Endpoint(s)....................................................106
17.9.7
Analysis of the Exploratory Endpoint(s)..................................................108
17.9.8
Analysis of Subgroups .............................................................................108
17.10 Safety Analyses .......................................................................................................109
17.10.1
Analysis of Adverse Events .....................................................................109
17.10.2
Analysis of Other Safety Endpoints .........................................................110
17.11 Interim Analyses......................................................................................................110
17.12 Sample Size and Power ...........................................................................................110
17.13 Statistical Analysis Plan ..........................................................................................111
18
Clinical Study Report and Publications ..........................................................................111
18.1
Data Ownership .......................................................................................................111
18.2
Clinical Study Report ..............................................................................................111
18.3
Summary of Clinical Study Results.........................................................................111
18.4
Publications..............................................................................................................111
19
Indemnity and Insurance..................................................................................................111
20
Finance................................................................................................................................112
20.1
Site Agreements.......................................................................................................112
20.2
Financial Disclosure ................................................................................................112
20.3
Equipment................................................................................................................112
Reference.....................................................................................................................................113
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 10 of 131
Appendices
Appendix I
Clinical Study Protocol  Authentication and Authorization.............................115
Appendix II
Recent and Concomitant Medication Disallowed  or Allowed with Restrictions
..........................................................................................................................117
Appendix III
Guidance for Key Clinical Features of Hypersensitivity  Related Reactions ..119
Appendix IV
Hypersensitivity Form......................................................................................123
Appendix V
Gilman Criteria ................................................................................................128
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 11 of 131
List of Panels
Panel 1
Study Design............................................................................................................. 29
Panel 2
Study Procedures and Assessments - Double-blind Period ...................................... 30
Panel 3
Optional Open-label Extension Period ..................................................................... 35
Panel 4
Objectives and Endpoints ......................................................................................... 43
Panel 5
Clinical Safety Laboratory Tests .............................................................................. 83
Panel 6
Published UMSARS Progression ........................................................................... 110
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 12 of 131
List of Abbreviations and Definitions of Terms
ADA
anti-drug antibodies 
AE
adverse event
ALT
alanine aminotransferase
APRS
all-patients-randomized set
APTS
all-patients-treated set
APTS-FU
all-patients-treated set follow-up
ARDS
acute respiratory distress syndrome
ASL
arterial spin labelling
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
aUMSARS
abbreviated Unified Multiple System Atrophy Rating Scale 
BL
baseline
BMI
body mass index
Bpm
beats per minute
CBF
cerebral blood flow
CGI-S
Clinical Global Impression – Severity 
CNS
central nervous system 
CNVs
copy number variations 
COA
clinical outcome assessment
COMPASS S 
Composite Autonomic Symptom Scale Select score
COMPASS SC
Composite Autonomic Symptom Scale Select Change score
COVID-19
coronavirus disease 2019 
CRA
clinical research associate
CRO
clinical research organization 
CRS
Cytokine Release Syndrome
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale 
DBP
Double-blind Period 
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
DTI
diffusion-tensor imaging 
EC
ethics committee
ECG
electrocardiogram
eCOA
electronic COA 
eCRF
electronic case report form
EDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 13 of 131
EIS
Exit Interview subset 
EMSA
European Multiple System Atrophy Registry 
EOI
end of infusion 
EoT
end-of-treatment
EoTDBP
end-of-treatment of Double-blind Period
EoTOLE
end-of-treatment of the Open-label Extension Period
ePRO
electronic patient-reported outcome 
EQ-5D-5L
EuroQol 5-dimension, 5-level
EU
European Union
FAS
full-analysis set
FDA
Food and Drug Administration (United States)
FDG
fluorodeoxyglucose
FIH 
first-in-human
GCI
glial cytoplasmic inclusions
GMP
Good Manufacturing Practice 
GRE
gradient-recalled echo 
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iDMC
Independent Data Monitoring Committee
IEs
intercurrent events
IEC
Independent Ethics Committee
IgE
immunoglobulin E 
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
IV
Intravenously
LEDD
levodopa equivalent daily dose
Lu
Lundbeck
mAb
monoclonal antibody 
MAO-B
monoamine oxidase B
MCID
minimal clinically important difference
MM-QAP
Mixed Methods Qualitative Analysis Plan
MMRM
mixed model for repeated measurements
MoCA
Montreal Cognitive Assessment
MRI
magnetic resonance imaging
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 14 of 131
mRNA
messenger ribonucleic acid
MSA
multiple system atrophy 
MSA-C
multiple system atrophy cerebellar type 
MSA-P
multiple system atrophy parkinsonian type 
mUMSARS
modified Unified Multiple System Atrophy Rating Scale
NfL
neurofilament light chain
NOAEL
no observed adverse effect level
OGI-S
Observer-reported Global Impression - Severity of Illness 
OLE
Open-label Extension 
OLES
Open-label Treatment Extension Set
PAE
potential adverse events
PCR
polymerase chain reaction
PCS
potentially clinically significant
PD
Progressive disease
PET
positron emission tomography
PGI-S
Patient Global Impression – Severity
PK
pharmacokinetic(s)
PKS
PK set
PR
specific ECG interval describing atrioventricular conduction 
PRO
patient-reported outcome
Q4W
every 4 weeks
QAP
Qualitative Analysis Plan
QP
qualified person
qPCR
quantitative polymerase chain reaction
QRS
specific ECG interval describing ventricular depolarization
QT
specific ECG interval describing ventricular depolarization/repolarization
QTc
heart rate corrected QT interval
QTcF
heart rate corrected QT interval using Fridericia’s correction formula
RCT
randomized controlled trial
RNA
ribonucleic acid (micro [miRNA], circular [circRNA] RNA)
ROI
regions-of-interest
RR
specific ECG interval describing the ventricular depolarization/repolarization 
cycle
SAD
single ascending dose 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
statistical software package from the SAS® Institute
SBS
Sensor-based subset
SE-ADL
Schwab and England Activities of Daily Living scale
SEIS
Study Experience Interview subset
SFU-E
Safety Follow-up Extension
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 15 of 131
SNP
single nucleotide polymorphism
SOC
standard of care
t½
apparent elimination half-life
TE
target engagement
TEAE
treatment-emergent adverse event
TMF
trial master file
UMSARS
Unified Multiple System Atrophy Rating Scale 
UMSARS TS
Unified Multiple System Atrophy Rating Scale Total Score
US
United States
VAS
visual analogue scale
vMRI
volumetric MRI 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 16 of 131
1
Synopsis – Study 18331A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Lu AF82422
Study Title
Interventional, randomized, double-blind, parallel-group, placebo-controlled, multi-centre study to assess the 
efficacy, safety and tolerability of Lu AF82422 in patients with Multiple System Atrophy
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of Lu AF82422 
on disease progression in patients with 
Multiple System Atrophy (MSA) during 
the Double-blind Period (DBP)
Disease progression
Primary endpoint:
• Disease progression, as assessed by longitudinal changes from 
baseline in the Unified Multiple System Atrophy Rating Scale 
(UMSARS) Part I and Part II Total score (UMSARS TS) up to 
End-of-Treatment of the DBP (EoTDBP)
Key secondary endpoint:
• Disease progression, as assessed by longitudinal changes from 
baseline in modified UMSARS Part I (mUMSARS) score up 
to EoTDBP
Secondary endpoints:
•
Disease progression, as assessed by longitudinal changes 
from baseline in the UMSARS Part I and UMSARS Part II 
scores up to EoTDBP
•
Change from baseline up to Week 48 in the DBP in 
UMSARS TS, UMSARS Part I, mUMSARS and UMSARS 
Part II scores
Exploratory endpoint:
•
Disease progression, as assessed by longitudinal changes 
from baseline in the abbreviated UMSARS (aUMSARS) up 
to EoTDBP
Secondary Objectives
To evaluate the efficacy of Lu AF82422 
on:
• Function
• Global impression, severity of illness 
during the DBP
Function
Secondary endpoint:
•
Change from baseline to Week 48 in the DBP in Schwab 
and England Activities of Daily Living (SE-ADL) score
Global impression
Secondary endpoints:
•
Change from baseline to Week 48 in the DBP in Clinical 
Global Impression – Severity of Illness (CGI-S) score
•
Change from baseline to Week 48 in the DBP in Patient 
Global Impression – Severity of Illness (PGI-S) score
•
Change from baseline to Week 48 in the DBP in 
Observer-reported Global Impression – Severity of Illness 
(OGI-S) score
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 17 of 131
Secondary Objectives (continued)
To evaluate the efficacy of Lu AF82422 
on:
•
Autonomic symptoms
•
Global disability
•
Disease milestones
•
Health-related quality of life during 
the DBP
To evaluate the efficacy of Lu AF82422 
on disease progression, as measured by 
brain Magnetic Resonance Imaging 
(MRI)
Endpoints (continued)
Autonomic symptoms
Secondary endpoint:
• Change from baseline to Week 48 in the DBP in Composite 
Autonomic Symptom Score Select Change (COMPASS Select 
Change) score
Exploratory endpoint:
• Change from baseline to Week 48 in the DBP in heart rate, 
blood pressure, and orthostatic symptoms, as assessed in 
UMSARS Part III
Global disability
Secondary endpoint:
• Change from baseline to Week 48 in the DBP in UMSARS 
Part IV score
Disease milestones
Secondary endpoints:
• Change from baseline to Week 48 in the DBP in speech, 
swallowing, falls and walking, as assessed by the UMSARS 
Part I item scores
• Change from baseline to Week 48 in the DBP in frequency, 
cause and consequence of falls, as assessed by the fall diary 
periods
Exploratory endpoints:
• Time to wheelchair use
• Change from baseline to Week 48 in the DBP in frequency of 
falls, as assessed by PAMSys (subset)
• Change from baseline to Week 48 in the DBP in gait 
parameters, as assessed by FeetMe® (subset)
Health-related quality of life
Secondary endpoint:
• Change from baseline to Week 48 in the DBP in EuroQol 
5-dimension, 5-level (EQ-5D-5L) score
MRI biomarkers
Secondary endpoint:
• Percentage change from baseline to Week 48 in the DBP in 
brain volume in brain regions-of-interest (ROIs); primary 
ROIs: pons and cerebellum; secondary ROIs: caudate nucleus, 
putamen, brain stem and total grey matter, as measured by 
volumetric MRI (vMRI)
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 18 of 131
Secondary Objectives (continued)
Endpoints (continued)
Exploratory endpoints:
• Percentage change from baseline to Week 48 in the DBP in 
tissue integrity in ROIs; primary ROIs: putamen, cerebellar 
cortex and white matter; secondary ROIs: caudate nucleus, 
globus pallidus and middle cerebellar peduncle, as measured 
by diffusion-tensor imaging (DTI) MRI
• Percent change from baseline to Week 48 in the DBP in 
cerebral blood flow (CBF) in ROIs; putamen and cerebellum, 
as measured by arterial spin labelling (ASL) MRI
To evaluate the efficacy of Lu AF82422 
on biofluid biomarkers of disease 
progression during the DBP
To evaluate the pharmacokinetics of 
Lu AF82422
Biofluid biomarkers
Secondary endpoint:
•
Blood biomarkers: Change from baseline up to Week 48 in 
the DBP in neurofilament light chain (NfL) concentrations
Exploratory endpoints:
•
Cerebrospinal fluid (CSF) biomarkers: Change from 
baseline up to Week 48 in the DBP in t-tau and NfL 
concentrations
Pharmacokinetics
Secondary endpoints:
•
Lu AF82422 plasma concentration during treatment and 
Safety Follow-up
•
Lu AF82422 CSF concentrations and the CSF/plasma 
concentration ratios at Week 48 in the DBP
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 19 of 131
Exploratory Objectives
To explore the target engagement (TE) of 
Lu AF82422 to α-synuclein during the 
DBP
To explore the TE of Lu AF82422 to 
pathological species of α-synuclein 
during the DBP
To explore the relationship between 
UMSARS, MRI parameters and NfL 
during the DBP
To explore the effect of long-term 
treatment with Lu AF82422 during the 
open-label extension (OLE)
Endpoints (Exploratory)
Blood:
•
Plasma concentrations of “free” and “total” α-synuclein 
during treatment and Safety Follow-up
CSF:
•
Concentrations of “free” and “total” α-synuclein at baseline 
and Week 48 in the DBP
CSF biomarkers:
•
Changes from baseline up to Week 48 in the DBP in 
pathological species of α-synuclein
Relationship between:
•
Change from baseline to Week 48 in the DBP in 
UMSARS TS, Part I and Part II scores,
•
Percentage change from baseline to Week 48 in the DBP in 
brain volume and tissue integrity in brain ROIs as measured 
by MRI, and
•
Change from baseline up to Week 48 in the DBP in NfL 
concentrations.
Effect of long-term treatment:
• Change from baseline of the DBP and baseline of the OLE to 
End-of-Treatment of the OLE (EoTOLE) in UMSARS TS and 
mUMSARS score
• Change from baseline of the DBP and baseline of the OLE to 
EoTOLE in CGI-S score
• Change from baseline of the DBP and baseline of the OLE to 
EoTOLE in PGI-S score
• Change from baseline of the DBP and baseline of the OLE to 
EoTOLE in SE-ADL score
• Change from baseline of the DBP and baseline of the OLE to 
EoTOLE in health-related quality of life, as assessed using 
EuroQol 5-dimension, 5-level (EQ-5D-5L) score
• Percentage change from baseline of the DBP and baseline of 
the OLE to EoTOLE in brain atrophy in ROIs, as measured 
using vMRI
• Change from baseline of the DBP and baseline of the OLE to 
EoTOLE in blood NfL concentrations
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 20 of 131
Exploratory Objectives
To explore the efficacy of Lu AF82422 
for up to 72 weeks of treatment on 
clinical scales and biomarkers during the 
DBP
To collect patient experience with 
impaired functions due to MSA to 
support the interpretation of change 
during the study (Exit Interview subset) 
during the DBP
To collect patient experience with study 
participation (Study Experience Interview 
subset) during the DBP
Endpoints (Exploratory)
Clinical scales:
• Change from baseline to EoTDBP in UMSARS Part I items 1, 
2, 7 and 8, Part III and Part IV, and SE-ADL, CGI-S, PGI-S, 
OGI-S, COMPASS Select Change and EQ-5D-5L scores
Blood biomarkers:
• Change from baseline to EoTDBP in NfL concentrations
MRI biomarkers:
• Change from baseline to EoTDBP in vMRI, DTI and ASL 
measures
Describe patient experience data and meaningful change (for 
example, symptoms, function, quality of life and disease 
manifestations) from the patient’s and caregiver’s perspective, as 
assessed by the Exit interviews
Describe patient experience data (for example, study experience, 
operational considerations, satisfaction with study experience, 
suggestions) from the patient’s and caregiver’s perspective, as 
assessed by the Study Experience interviews
Safety Objective
To evaluate the safety and tolerability of 
Lu AF82422 in patients with MSA in the 
DBP
To evaluate safety and tolerability of 
Lu AF82422 in patients with MSA in the 
Open-label Extension Period
Safety Endpoints
Double-blind Period
• Treatment-emergent adverse events
• Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, weight, and 
electrocardiogram (ECG) parameter values
• Development of specific anti-drug antibodies (ADAs)
• Findings on MRI during the DBP, as specified in the Imaging 
Charter
• Columbia-Suicide Severity Rating Scale (C-SSRS) score
Open-label Extension
• Treatment-emergent adverse events
• Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, and weight parameter values
• Development of specific ADAs
• C-SSRS score
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
Study Methodology
 7KLVLVDSKDVH,,LQWHUYHQWLRQDOUDQGRPL]HGGRXEOHEOLQGSDUDOOHOJURXS SODFHERFRQWUROOHGLQFOXGLQJDQ
RSWLRQDORSHQODEHOH[WHQVLRQ2/( PXOWLFHQWUHVWXG\RIWKHHIILFDF\VORZLQJGLVHDVHSURJUHVVLRQVDIHW\
DQGWROHUDELOLW\RI/X $)LQSDWLHQWVZLWK06$7KHHIILFDF\RI/X $)LVDVVHVVHGXVLQJWKH
806$5676VXSSRUWLYHDVVHVVPHQWVLQFOXGHHYDOXDWLRQRIIXQFWLRQJOREDOLPSUHVVLRQRIVHYHULW\RILOOQHVV
DXWRQRPLFV\PSWRPVGLVDELOLW\KHDOWKUHODWHGTXDOLW\RIOLIHELRIOXLGELRPDUNHUVDQGLPDJLQJ
 7KHWDUJHWSRSXODWLRQIRUWKLVVWXG\LVSDWLHQWVZLWKSRVVLEOHRUSUREDEOH06$DVGHILQHGE\WKHFXUUHQW
FRQVHQVXVGLDJQRVWLFFULWHULD7KHVWXG\ZLOOUHFUXLWSDWLHQWVZLWKHYLGHQFHRISDUNLQVRQLVP06$3DQGRU
FHUHEHOODUV\QGURPH06$&3DWLHQWVZLOOEHDOORZHGVWDEOHWUHDWPHQWIRUPDQDJLQJWKHLUV\PSWRPVRI
06$GXULQJWKHVWXG\
 7KHSDWLHQWVZLOOEHUDQGRPL]HGWR/X $)
RUSODFHERYLDDFHQWUDOL]HGUDQGRPL]DWLRQV\VWHP
,QWHUDFWLYH5HVSRQVH7HFKQRORJ\>,57@7ZRVWUDWDYDULDEOHVZLOOEHDSSOLHGWRHQVXUHDEDODQFHGWUHDWPHQW
DOORFDWLRQRI/X $)DQGSODFHER
DQG5HJLRQ8QLWHG
6WDWHV>86@-DSDQZLWKDPD[LPXPRIRISDWLHQWVIURP-DSDQ$OOSDWLHQWVHQWHULQJWKH2/(ZLOO
UHFHLYH/X $)
GXULQJWKH2/(
 7KHVWXG\GXUDWLRQIURPWKH6FUHHQLQJ9LVLWWRWKH6DIHW\)ROORZXS9LVLWLVEHWZHHQWR ZHHNVIRUSD
WLHQWVQRWHQWHULQJWKHRSWLRQDO2/(SHULRGDQG EHWZHHQ WR ZHHNVIRUSDWLHQWVFRQWLQXLQJLQWKH2/(
 7KHVWXG\LQFOXGHVWKHIROORZLQJSHULRGV
 6FUHHQLQJ3HULRG ZHHNV
 5DQGRPL]DWLRQ3HULRG ZHHNV
 '%3  ZHHNVXSWR ZHHNV
 2SWLRQDO2/(WUHDWPHQWSHULRG  ZHHNV
 6DIHW\)ROORZXS3HULRG ZHHNVDIWHUODVWLQYHVWLJDWLRQDOPHGLFLQDOSURGXFW>,03@DGPLQLVWUDWLRQ
 3DWLHQWVZKRGRQRWFRQVHQWWRWKHRSWLRQDO2/( ZLOOHQWHUWKH6DIHW\)ROORZXS3HULRGDIWHUWKH(R7'%3
9LVLW
 7KHLQGLYLGXDO'%3ZLOOYDU\IURP ZHHNVXSWR ZHHNV2QFHWKHODVWSDWLHQWZLOOUHDFK:HHN WKLV
YLVLWZLOOEHWKH(R7'%39LVLWIRUWKDWSDWLHQW7KHUHPDLQLQJSDWLHQWVLQWKH'%3ZLOOKDYHWKHLUQH[W
VFKHGXOHGYLVLWFRQYHUWHGWRDQ(R7'%39LVLWZLWKDVVHVVPHQWVDVOLVWHGIRU9LVLW DFFRUGLQJWR3DQHO
'XULQJWKH'%3SDWLHQWVZLOODWWHQG,039LVLWVWRIROORZDGRVLQJVFKHGXOHZLWKHLWKHU/X $)RU
SODFHERHYHU\ ZHHNV4:
 3DWLHQWVZKRHQWHUWKH2/( ZLOOUHFHLYHWKHILUVWRSHQODEHOGRVH9LVLW(RQ WKHVDPHGD\DVWKH(R7'%3
RUDVVRRQDVSRVVLEOHWKHUHDIWHUEXWQRODWHUWKDQ PRQWKVDIWHUWKH(R7'%39LVLWDQGZLOOEHHQUROOHGWR
2/( QRODWHUWKDQWKHHQGRI4
 ,QWKH2/(SDWLHQWVZLOOUHFHLYH/X $)XQWLO9LVLW (:HHN (DQGFRPSOHWHWKH(R72/(DW
9LVLW (:HHN (9LVLW (VKRXOGRFFXUDW:HHN ( ZHHNVDIWHU9LVLW ( +RZHYHULQWKH
H[FHSWLRQDOFDVHVZKHUHVLWHVKDYHQRW\HWUHFHLYHG,QVWLWXWLRQDO5HYLHZ%RDUG(WKLFV&RPPLWWHHDSSURYDO
IRU3URWRFRO(GLWLRQ9LVLW (FDQEHGHOD\HGXQWLODSSURYDOLVLQSODFHEXWQRODWHUWKDQ PRQWKVDIWHU
9LVLW (
 3DWLHQWVZKRZLWKGUDZH[FHSWIRUWKRVHZKRZLWKGUDZWKHLUFRQVHQWZLOOEHVFKHGXOHGIRUD:LWKGUDZDO
9LVLWWRXQGHUJRFOLQLFDODQGVDIHW\DVVHVVPHQWVDVVRRQDVSRVVLEOH
 $OOSDWLHQWVH[FHSWWKHRQHVZLWKGUDZLQJFRQVHQWZLOOEHVFKHGXOHGIRUD6DIHW\)ROORZXS9LVLW ZHHNV
DIWHUWKHLUODVW,03GRVHUHJDUGOHVVLIWKH\UHFHLYHGWKHLUODVWGRVHLQWKH'%3RU 2/(RULIWKH\ZLWKGUHZ
 3DWLHQWVZLOOEHPRQLWRUHGDIWHU,03DGPLQLVWUDWLRQIRULPPHGLDWHGUXJUHDFWLRQVIRUDPLQLPXPRI KRXUV
ZLWKYLWDOVLJQVWDNHQHYHU\PLQXWHVPLQXWHVIURPWKHHQGRIWKHVDOLQHIOXVK RUXQWLOVWDEOHZKLFKHYHU
LVODWHU RQO\DSSOLFDEOHWKURXJK9LVLW (%HJLQQLQJDW9LVLW (EORRGSUHVVXUHDQGSXOVHZLOORQO\EH
PHDVXUHGLPPHGLDWHO\SULRUWRDQGLPPHGLDWHO\DIWHU,03DGPLQLVWUDWLRQLQFOXVLYHRIWKHVDOLQHIOXVK
 PLQXWHV
 &6)DVVHVVPHQWVIRUHYDOXDWLRQRISKDUPDFRNLQHWLFV3.7(DQGELRPDUNHUVDWEDVHOLQHDQGDIWHULQLWLDWLRQ
RIWUHDWPHQWZLOOEHFROOHFWHGDFFRUGLQJWR3DQHO&6)VDPSOLQJLVQRWDSSOLFDEOHIRUSDWLHQWVZLWK
FRQWUDLQGLFDWLRQVRIOXPEDUSXQFWXUHKLVWRU\RIVHYHUHSRVWOXPEDUSXQFWXUHKHDGDFKHRQJRLQJVNLQ
LQIHFWLRQDWWKHOXPEDUSXQFWXUHLQMHFWLRQVLWHRUGRFXPHQWHGKLVWRU\RIYHUWHEUDOGHIRUPLWLHVPDMRUOXPEDU
CCI
CCI
CCI
Y 
&/,B

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
Study Methodology (continued)
EDFNVXUJHU\FOLQLFDOO\VLJQLILFDQWEDFNSDLQFOLQLFDOO\VLJQLILFDQWDEQRUPDO;UD\DQGRULQMXU\WKDWLQWKH
RSLQLRQRIWKHLQYHVWLJDWRUZRXOGSUHFOXGH&6)FROOHFWLRQ
 3DWLHQWVPXVWYLVLWGHVLJQDWHGLPDJLQJIDFLOLWLHVIRU05,VFDQVIRUHOLJLELOLW\VDIHW\DQGHIILFDF\7KH
SUHVHQFHRI05,DEQRUPDOLWLHVVXSSRUWLQJWKHGLDJQRVLVRI06$ZLOODOVREHUHFRUGHG7KHVFDQVZLOOEH
HYDOXDWHGE\DFHQWUDOUHDGHUDVSUHVSHFLILHGLQWKHVWXG\VSHFLILFImaging Charter
$W DOOWKH86VLWHVDGGLWLRQDODVVHVVPHQWVREMHFWLYHVHQVRUEDVHGDVVHVVPHQWVDQGTXDOLWDWLYH([LW
LQWHUYLHZVZLOOEHSHUIRUPHGKHUHDIWHUUHIHUUHGWRDVWKH³6HQVRUVXEVHW´DQG³([LW,QWHUYLHZVXEVHW´
3DUWLFLSDWLRQLQWKH([LW,QWHUYLHZVXEVHWLVPDQGDWRU\IRUSDWLHQWVDQGFDUHJLYHUVZKLOHSDUWLFLSDWLRQLQWKH
6HQVRUVXEVHWLVRSWLRQDO3DWLHQWVZKRZLVKWRSDUWLFLSDWHLQWKH6HQVRUVXEVHWPXVWSURYLGHVSHFLILFFRQVHQW
WRRQHRUERWKGHYLFHVDVSDUWRIWKHPDLQInformed Consent Form3DWLHQWVFDQZLWKGUDZIURPWKHVH
DGGLWLRQDODVVHVVPHQWVZLWKRXWKDYLQJWRZLWKGUDZIURPWKHPDLQVWXG\$GGLWLRQDOO\DW86VLWHVDVXEVHWRI
SDWLHQWVDQGFDUHJLYHUVPD\EHFRQWDFWHGDERXWDQRSSRUWXQLW\WRSDUWLFLSDWHLQD6WXG\([SHULHQFHLQWHUYLHZ
³6WXG\([SHULHQFH,QWHUYLHZVXEVHW´
 $QLQGHSHQGHQW'DWD0RQLWRULQJ&RPPLWWHHL'0&ZLOOUHJXODUO\PRQLWRUWKHSDWLHQWV¶VDIHW\GDWD
DFFRUGLQJWRWKHData Monitoring Committee (DMC) Charter GXULQJWKH '%3.
 7KHVWXG\GHVLJQLVSUHVHQWHGLQ3DQHO DQGWKHVFKHGXOHGVWXG\SURFHGXUHVDQGDVVHVVPHQWVIRU'%3DUH
VXPPDUL]HGLQ3DQHO DQG IRU2/(DVVHVVPHQWVDUHVXPPDUL]HGLQ3DQHO
Number of Patients Planned
 SDWLHQWVUHFUXLWHGIURPVSHFLDOLVWFHQWUHVDUHSODQQHGIRUUDQGRPL]DWLRQLQWKH/X $)
JURXS
DQGLQWKHSODFHERJURXS
Target Patient Population
Main Inclusion Criteria
 'LDJQRVLVRISRVVLEOHRUSUREDEOH06$3RU06$&DFFRUGLQJWRWKHGilman criteria DWWKH6FUHHQLQJ9LVLW
 /HVVWKDQ \HDUVIURPWKHWLPHRIRQVHWRIPRWRU06$V\PSWRPVDWWKH6FUHHQLQJ9LVLWLQWKHMXGJHPHQWRI
WKHLQYHVWLJDWRU
 $QWLFLSDWHGVXUYLYDORIDWOHDVW \HDUVLQWKHRSLQLRQRIWKHLQYHVWLJDWRUDWWKH6FUHHQLQJ9LVLW
 $Q806$563DUW,VFRUHRPLWWLQJLWHPRQVH[XDOIXQFWLRQDWWKH6FUHHQLQJ9LVLW
 &RJQLWLYHSHUIRUPDQFHHYDOXDWHGE\WKH0RQWUHDO&RJQLWLYH$VVHVVPHQW0R&$ZLWKDVFRUHDW WKH
6FUHHQLQJ9LVLW
 7KHSDWLHQWKDVDNQRZOHGJHDEOHDQGUHOLDEOHFDUHJLYHUZKRZLOOEHDYDLODEOHWKURXJKRXWWKHVWXG\ZKHQ
FDUHUREVHUYHUUHSRUWHGRXWFRPHVDUHSHUIRUPHG$FDUHJLYHULVGHILQHGDVDSHUVRQZKRVSHQGV
DSSUR[LPDWHO\ KRXUVRUPRUHZLWKWKH SDWLHQWSHUZHHNDQGFDQLQIRUPRQOHYHORIIXQFWLRQRIWKHSDWLHQW
 $JHGDQG \HDUVDWWKH6FUHHQLQJ9LVLW
Open-label Extension Entry Criteria
 7KHSDWLHQWKDVFRPSOHWHGWKH(R7'%39LVLWDQGGLGQRWZLWKGUDZLQWKH'%3
 7KHSDWLHQWKDVFRQVHQWHGWRSDUWLFLSDWHLQWKH2/(
 7KHSDWLHQWKDVFRPSOHWHGWKH(R7'%3ZLWKLQWKHODVW PRQWKVDQGZLOOEHHQUROOHGLQWRWKH2/( QRODWHU
WKDQHQGRI4
 7KHSDWLHQWLVLQWKHLQYHVWLJDWRU¶VRSLQLRQOLNHO\WRFRPSO\ZLWKWKHSURWRFRO
 7KHSDWLHQWKDVQRWUHFHLYHGDQ\RWKHULQYHVWLJDWLRQDOSURGXFWVLQFHWKH(R7'%39LVLW
Main Exclusion Criteria
 7UHDWPHQWZLWKDQDQWLĮV\QXFOHLQPRQRFORQDODQWLERG\P$ERUDQLQKLELWRURIĮV\QXFOHLQDJJUHJDWLRQ
ZLWKLQWKHODVW PRQWKV
 $Q\SDVWRUFXUUHQWWUHDWPHQWZLWKDQDFWLYHYDFFLQHWDUJHWLQJĮV\QXFOHLQ
 7KHSDWLHQWKDVWZRRUPRUHEORRGUHODWLYHVZLWKDKLVWRU\RI06$
 (YLGHQFHFOLQLFDOO\RURQ05,DQGRUKLVWRU\RIDQ\VHULRXVQHXURORJLFDOGLVRUGHURWKHULQWUDFUDQLDORUV\V
WHPLFGLVHDVHVRUFRQGLWLRQVUHVXOWLQJLQDGLDJQRVLVRWKHUWKDQ06$
 &XUUHQWGLDJQRVLVRIPRYHPHQWGLVRUGHUVWKDWFRXOGPLPLF06$IRUH[DPSOH3DUNLQVRQ¶VGLVHDVHGHPHQWLD
CCI
Y 
&/,B

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
Target Patient Population (continued)
Main Exclusion Criteria (continued)
ZLWK/HZ\ERGLHVHVVHQWLDOWUHPRUSURJUHVVLYHVXSUDQXFOHDUSDOV\VSLQRFHUHEHOODUDWD[LDVSDVWLF
SDUDSDUHVLVFRUWLFREDVDOGHJHQHUDWLRQRUYDVFXODUSKDUPDFRORJLFDORUSRVWHQFHSKDOLWLFSDUNLQVRQLVPSHU
LQYHVWLJDWRUGLVFUHWLRQ3DWLHQWVZKRKDYHSUHYLRXVO\EHHQGLDJQRVHGZLWK3DUNLQVRQ¶VGLVHDVHZLOOQRWEH
H[FOXGHG
 +LVWRU\RIVHYHUHGUXJDOOHUJ\DQDSK\OD[LVRUK\SHUVHQVLWLYLW\RUNQRZQK\SHUVHQVLWLYLW\RULQWROHUDQFHWRWKH
,03RULWVH[FLSLHQWV
 +LVWRU\RIQHXURVXUJLFDOSURFHGXUHVLQFOXGLQJGHHSEUDLQVWLPXODWLRQWKDWFRXOGLQWKHLQYHVWLJDWRU¶VRSLQLRQ
LQWHUIHUHZLWKWKHDVVHVVPHQWVRIVDIHW\RUHIILFDF\
 &RQWUDLQGLFDWLRQVIRU05,
 $WWHPSWHGVXLFLGHZLWKLQWKHSDVW PRQWKVRULVDWVLJQLILFDQWULVNRIVXLFLGHHLWKHULQWKHRSLQLRQRIWKH
LQYHVWLJDWRURUGHILQHGDVD³\HV´WRVXLFLGDOLGHDWLRQTXHVWLRQVRURUDQVZHULQJ³\HV´WRVXLFLGDO
EHKDYLRXURQWKH&6656ZLWKLQWKHSDVW PRQWKV
 7KHIROORZLQJUHFHQWDQGFRQFRPLWDQWPHGLFDWLRQVDUHGLVDOORZHGRUDOORZHGZLWKUHVWULFWLRQVZLWKUHVSHFWWR
WKHLUXVHSULRUWRRUGXULQJWKHVWXG\WKHOLVWLVQRWFRPSUHKHQVLYH
 DisallowedDQ\LQYHVWLJDWLRQDOSURGXFWVZLWKLQ GD\VEHIRUHWKH6FUHHQLQJ9LVLWWUHDWPHQWWDUJHWLQJ
ĮV\QXFOHLQDQGRU06$GLVHDVHSURJUHVVLRQ
 Allowed with restrictionVWDEOHGRVHIRUDWOHDVW ZHHNVSULRUWRUDQGRPL]DWLRQRIGUXJVDFWLQJDJDLQVWSDU
NLQVRQLVPIRUH[DPSOH/HYRGRSD'RSDPLQH$JRQLVWV$PDQWDGLQHDQG0RQRDPLQHR[LGDVHE>0$2%@
LQKLELWRUVDQGRUGUXJVDFWLQJDJDLQVWDXWRQRPLFG\VIXQFWLRQIRUH[DPSOHHSKHGULQHGUR[LGRSDPLGR
GULQHIOXGURFRUWLVRQHRFWUHRWLGHGHVPRSUHVVLQR[\EXW\QLQDQGDQWLFLSDWHGVWDEOHGXULQJWKH'%3,I
PHGLFDOO\QHFHVVDU\LQLWLDWLRQRIRUFKDQJHRIGRVHRIFRQFRPLWDQWPHGLFDWLRQLVDOORZHGSHULQYHVWLJDWRU
GLVFUHWLRQ
Investigational Medicinal Product, Doses and Modes of Administration
/X $)LVDKXPDQUHFRPELQDQWPRQRFORQDODQWLERG\RIWKHLPPXQRJOREXOLQ*,J*LVRW\SHWKDW
UHFRJQL]HVDOOPDMRUVSHFLHVRIĮV\QXFOHLQROLJRPHUDQGILEULOODUIRUPV1 RU&WHUPLQDOWUXQFDWHGIRUPV
/X $)WDUJHWVH[WUDFHOOXODUĮV\QXFOHLQDQGLQKLELWVVHHGLQJDQGVSUHDGLQJRISDWKRORJLFDOIRUPVRI
ĮV\QXFOHLQLQin vitro DQGin vivo PRGHOV
'RVDJHIRUP
 /X $)VROXWLRQIRULQIXVLRQPJP/GRVH
 3ODFHERWR/X $)VROXWLRQIRULQIXVLRQ
5RXWHRIDGPLQLVWUDWLRQLQWUDYHQRXVLQIXVLRQRYHUPLQXWHVPLQXWHVRQFHHYHU\ ZHHNV
Assessment Details/Biomarker Methodology
7KHDVVHVVPHQWVDUHVXPPDUL]HGLQ3DQHO DQG 3DQHO'HWDLOVIRUVHOHFWHGDVVHVVPHQWVDUHSURYLGHGEHORZ
%ORRGDQG&6)DVVHVVPHQWVZLOOEHFRQGXFWHGXVLQJYDOLGDWHGELRDQDO\WLFDOPHWKRGVDVVSHFLILHGLQWKH
Laboratory Specification Manual,PDJLQJDVVHVVPHQWVZLOOEHFRQGXFWHGDFFRUGLQJWRWKHVWXG\VSHFLILF
Imaging Manual7KHVFDQVZLOOEHHYDOXDWHGE\DFHQWUDOUHDGHUDVSUHVSHFLILHGLQWKHVWXG\VSHFLILFImaging 
Charter
Efficacy Assessments
 7KH806$56LVDFRPELQHGFOLQLFLDQDQGSDWLHQWFDUHJLYHUUHSRUWHGVFDOHWRDVVHVVGLVHDVHSURJUHVVLRQLQ
SDWLHQWVZLWK06$7KHP806$56VFRUHZLOOFRQVLVWRI806$563DUWZKHUHWKHUHVSRQVHRSWLRQVFRUHV
RIDQGZLOOEHFROODSVHGWRRQHFDWHJRU\LQWKHDQDO\VLV7KHD806$56VFRUHLVGHULYHGIURPD VXEVHWRI
LWHPVIURP806$563DUW,DQG3DUW,,VKRZQWREHSDWLHQWFHQWULFDQGVHQVLWLYHWRSURJUHVVLRQLQ06$
7KXVWKH806$56ZLOOEHDGPLQLVWHUHGRQO\RQFHWRWKHSDWLHQWDFFRUGLQJWRVWDQGDUGSURFHGXUHVDWWKH
FOLQLFYLVLWWRGHULYHWKH806$5676P806$56DQGD806$56VFRUHV7KHDGPLQLVWUDWLRQRI806$56
3DUW,DQG3DUW,,ZLOOEHYLGHRUHFRUGHGIRUFHQWUDOUHDGLQJ
 7KH&203$666HOHFW&KDQJHLVGHULYHGIURPWKHRULJLQDO&203$66VFDOHDSSO\LQJDFRPSXWHUL]HG
DOJRULWKP'DWDZLOOEHVXEPLWWHGWR0D\R&OLQLFIRUFDOFXODWLRQV
 05,VFDQIRUHYDOXDWLRQRIELRPDUNHUVRIGLVHDVHSURJUHVVLRQ
CCI
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 24 of 131
Assessment Details/Biomarker Methodology (continued)
Efficacy Assessments (continued)
• vMRI for quantification of atrophy measures in brain ROIs; primary ROIs: pons and cerebellum; secondary 
ROIs: caudate nucleus, putamen, brain stem and total grey matter
• DTI in the DBP for quantification of diffusivity measures in brain ROIs; primary ROIs: putamen, cerebellar 
cortex and white matter; secondary ROIs: caudate nucleus, globus pallidus and middle cerebellar peduncle
• ASL in the DBP for quantification of CBF in selected brain regions (for example, putamen and cerebellum)
Blood sampling for biomarkers of disease progression; for quantification of NfL
CSF sampling for biomarkers of disease progression; for quantification of t-tau and NfL
Fall diary; assessment of Date/Time of fall; Context of fall; Causes of the fall; Consequences of the fall. 
Patients will receive diary training at the Randomization Visit and then start the diary data entries.
FeetMe® sensor-based device; consists of a pair of digital insoles to be placed in patients’ shoes for remote 
and continuous assessment of gait, which will be self-administered in the remote environment (Sensor 
subset).
PAMSys sensor-based device; consists of a wearable sensor worn as a pendant on the chest and an electronic 
diary for a remote monitoring of falls and mobility, which will be self-administered in the remote 
environment (Sensor subset).
• Data from the fall diary and the Sensor subset will be collected during the Randomization period, and then 
for four pre-defined periods during the study according to Panel 2. The fall diary and devices will be 
handed out and returned at standard in-clinic visits. This does not apply to a patient who scores 4 on 
UMSARS Part I item 7 (walking) or if the patient is wheelchair bound for unrelated disorders. This needs 
to be evaluated at each visit, where the fall diary and the sensors are to be dispensed.
Pharmacokinetic Assessments
Blood sampling; for quantification of “free” (that is, not bound to α-synuclein) Lu AF82422 in plasma
CSF sampling; for quantification of “free” (that is, not bound to α-synuclein) Lu AF82422 in CSF
Target Engagement Assessments
Blood sampling for α-synuclein; for quantification of “free” and “total” α-synuclein in plasma
CSF sampling for α-synuclein; for quantification of “free” and “total” α-synuclein
CSF sampling for pathological species of α-synuclein (for example, aggregated and truncated species)
Safety Assessments
MRI for safety during the DBP; for evaluation of clinically important findings for example, oedema, 
microhaemorrhages, infarcts and meningoencephalitis
Blood Sampling for ADA analysis; plasma samples to determine presence or absence of ADAs. Samples 
confirmed positive for ADA will be evaluated for clearing ADAs by evaluation of exposure and TE.
Adverse events requiring additional data collection: hypersensitivity reactions
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
Statistical Methodology (continued)
 7(RI/X $)WRĮV\QXFOHLQLQ&6) ZLOOEHSUHVHQWHGGHVFULSWLYHO\DV³IUHH´V\QXFOHLQ³WRWDO´
ĮV\QXFOHLQDQGUDWLRRI³IUHH´WR³WRWDO´ĮV\QXFOHLQ
 7KHUHODWLRQVKLSEHWZHHQFKDQJHVLQVHOHFWHGEORRG&6)ELRPDUNHUVWKDWLV1I/WWDXDQGFKDQJHVLQ05,
SDUDPHWHUVDQGFKDQJHVLQPDLQFOLQLFDORXWFRPHWKDWLV806$56VFRUHVZLOOEHH[SORUHGJUDSKLFDOO\
DQGXVLQJSDUWLDOFRUUHODWLRQFRHIILFLHQWV
 *DLWDQGEDODQFHSDUDPHWHUVGHULYHGIURPWKHVHQVRUEDVHG)HHW0H GHYLFHZLOOSULPDULO\EHDQDO\]HGGH
VFULSWLYHO\IRUWKH6%6,IDSSURSULDWHD0050PRGHOOLNHWKHRQHGHVFULEHGDERYHIRUFRQWLQXRXVVHF
RQGDU\DQGH[SORUDWRU\HQGSRLQWVZLOOEHDSSOLHG&RUUHODWLRQWRWKHNH\SURJUHVVLRQPDUNHUVZKLFKLVWKH
806$56VFRUHVDQG05,SDUDPHWHUVZLOOEHH[SORUHGJUDSKLFDOO\
 7KHSRWHQWLDOLQIOXHQFHRIFRYDULDWHVLQDGGLWLRQWR
DQGUHJLRQZLOOEHLQYHVWL
JDWHGXVLQJDIUHTXHQWLVWUHSHDWHGPHDVXUHVDQDO\VLVZLWKIL[HGHIIHFWV$PRQJWKHFRYDULDWHVWREHLQYHVWL
JDWHGDUHDJHJHQGHUFRXQWU\UDFHWLPHVLQFHGLDJQRVLVGRVHRI3DUNLQVRQ¶VGLVHDVHPHGLFDWLRQH[
SUHVVHGDVOHYRGRSDHTXLYDOHQWGDLO\GRVH>/(''@EDVHOLQH05,VLJQDODQGEDVHOLQHSODVPD&6)ĮV\QX
FOHLQDQG1I/OHYHOV
 7KHDQDO\VLVRIVHPLVWUXFWXUHG([LWLQWHUYLHZVDQG6WXG\([SHULHQFHLQWHUYLHZVZLOOEHSUHVSHFLILHGLQD
VSHFLILF 4XDOLWDWLYH$QDO\VLV3ODQ 4$3
$QDO\VLVRI2/(HIILFDF\GDWD
 $QDO\VLVRIH[SORUDWRU\HIILFDF\GDWDFROOHFWHGLQWKH2/(ZLOOEHEDVHGRQWKH2/(6ZKHUHWKHRULJLQDO
SODFHERSDWLHQWVZLOOEHKDQGOHGDVDVHSDUDWHJURXS
 $OOFRQWLQXRXVHQGSRLQWVIROORZLQJWUHDWPHQWH[WHQVLRQ ZLOOSULPDULO\EHDQDO\]HGGHVFULSWLYHO\,QDGGLWLRQ
DQH[SORUDWRU\0050ZLOOEHDSSOLHGWRWKHFKDQJHVIURPWKH'%3 EDVHOLQH YLVLW 1RIRUPDOWHVWLQJZLOOEH
DSSOLHG)XUWKHUGHWDLOVRQWKHPRGHOZLOOEHRXWOLQHGLQWKH6WDWLVWLFDO$QDO\VLV3ODQ6$3
$VWXG\VSHFLILF6$3ZLOOEHGHYHORSHGIRUWKLVVWXG\WRGHVFULEHIXUWKHUGHWDLOVRQWKHSURSRVHGDQDO\VHV,Q
DGGLWLRQWKHUHZLOOEHDVHSDUDWHPsychometric SAP ZKLFKZLOOLQFOXGHWKHGHVFULSWLRQRIWKHPHWKRGVDQG
DQDO\WLFDOSULQFLSOHVWRSUHOLPLQDULO\H[SORUHLQWKLVVWXG\WKHSV\FKRPHWULFSURSHUWLHVDQGWKHPHDQLQJIXO
ZLWKLQSDWLHQWFKDQJHRIWKH806$5676P806$56DQGD806$56
 3DWLHQWGLVSRVLWLRQDQGGHPRJUDSKLFVZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFV
 5HDVRQIRUZLWKGUDZDOZLOOEHLQYHVWLJDWHGDQGFRPSDUHGEHWZHHQ/X $)DQGSODFHER
 7KHXVHRIFRQFRPLWDQWPHGLFDWLRQZLOOEHDQDO\]HGGHVFULSWLYHO\
 $QDO\VLVRIVDIHW\HQGSRLQWV
 7KHVDIHW\DQDO\VHVZLOOEHEDVHGRQWKH$376DQGWKH2/(6
7UHDWPHQWHPHUJHQWDGYHUVHHYHQWVFOLQLFDOVDIHW\ODERUDWRU\WHVWVYLWDOVLJQVZHLJKWERG\PDVVLQGH[%0,
(&*SDUDPHWHUV&665605,ILQGLQJVDQGSUHVHQFHRI$'$VZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYH
VWDWLVWLFV
Testing Strategy
$WHVWLQJVWUDWHJ\ZLOOEHDSSOLHGLQFOXGLQJWKHSULPDU\HQGSRLQWWKDWLV806$5676DQGWKHNH\VHFRQGDU\
HQGSRLQWWKDWLVP806$56WRSURWHFWWKHW\SH,HUURUIRUWKHVHHQGSRLQWVLQDKLHUDUFKLFDOPDQQHU
CCI
Y 
&/,B

v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 30 of 131
Panel 2
Study Procedures and Assessments - Double-blind Period
Visit Name
Screening
Randomization
Baseline + IMP
Telephone Visit
IMP
Site Visit
IMP
Telephone Visit
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
EoTDBP/WDb
SFUc
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Weekd
-6
-2
0
2
4
6
8
10 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 88
Visit Windowe (days 
relative to nominal visit)

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

7
Screening/Randomization Procedures and Assessments
Signed informed consent 

Demographics (age, sex, 
race)

MSA diagnostic criteria: 
Possible or probable, 
MSA-P or MSA-C 

MSA History

MoCA

Relevant medical history 
(for example, psychiatric, 
neurological)

Recent and on-going 
medication

Height

Blood sampling for 
pregnancy test 

MRI scan for eligibilityf

Inclusion/exclusion criteria


Signs and symptoms 
present at SCR, 
Randomization and/or BL 
(before IMP 
administration; recorded on 
an Adverse Event Form)



Randomization

Efficacy Assessments
UMSARS








SE-ADL




COMPASS Select

COMPASS Select Change



CGI-S







PGI-S







OGI-S







Fall diary, daily recording
g h
g
h
g h
g h
g h
FeetMe® (subset) optionali
j k
j
k
j k
j k
j k
PAMSys (subset) optionali
j k
j
k
j k
j k
j k
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 31 of 131
Visit Name
Screening
Randomization
Baseline + IMP
Telephone Visit
IMP
Site Visit
IMP
Telephone Visit
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
EoTDBP/WDb
SFUc
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Weekd
-6
-2
0
2
4
6
8
10 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 88
Visit Windowe (days 
relative to nominal visit)

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

7
MRI scan: vMRI, DTI and 
ASL measuresl,m




n
CSF samplingo for NfL and 
t-tau


p
Blood sampling for NfL







Quality of Life Assessments
EQ-5D-5L




Pharmacokinetic Assessments
Blood sampling for IMP 
quantificationq
q



q

q




CSF samplingo for IMP 
quantification


p
Target Engagement Assessments
CSF samplingo for 
α-synuclein and 
pathological species of 
α-synuclein


p
Blood sampling for 
α-synucleinq
q



q

q




Safety Assessments
AEs






















Follow-up of adverse 
events on-going at 
EoTDBP or withdrawal, 
and new AEs and SAEs

Blood and urine sampling 
for clinical safety 
laboratory tests 












Blood sampling for ADAs











Vital signsr





















Weight







Examinations (physical, 
neurological)s









ECG






MRI scan for safetym




n
C-SSRSt






















v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 32 of 131
Visit Name
Screening
Randomization
Baseline + IMP
Telephone Visit
IMP
Site Visit
IMP
Telephone Visit
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
IMP/EoTDBPa
EoTDBP/WDb
SFUc
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Weekd
-6
-2
0
2
4
6
8
10 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 88
Visit Windowe (days 
relative to nominal visit)

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

3

7
Biobanking
Blood sampling for gene 
expression profiling 
(RNA)u



Blood sampling for 
metabolomics/proteomics 
(plasma)u



Blood sampling for 
pharmacogenetics (DNA) 
(optional)v

Blood sampling for ADA











CSF samplingo


p
Other Study Procedures and Assessments
IMP administrationr


















Concomitant medication 
(prescription and 
non-prescription)

























Pregnancy test, urine 
dipstickw





















Exit interview (subset)x

ADA = anti-drug antibody; AE = adverse event; ASL = arterial spin labelling; BL = baseline; CGI-S = Clinical Global 
Impression – Severity of Illness; CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Rating Scale; 
COMPASS = Composite Autonomic System Score; DBP = Double-blind Period; DNA = deoxyribonucleic acid; 
DTI = diffusion-tensor imaging; ECG = electrocardiogram; EOI = end of infusion; EoT = End-of-Treatment; 
EoTDBP = End-of-Treatment DBP; EQ-5D-5L = EuroQol 5-Dimensions, 5-Levels; IMP = investigational medicinal 
product; IRT = Interactive Response Technology; MoCA = Montreal Cognitive Assessment; MRI = magnetic resonance 
imaging; MSA = Multiple System Atrophy; MSA-C = MSA with predominant cerebellar features; MSA-P = MSA with 
predominant parkinsonism; NfL = neurofilament light chain; OGI-S = Observer-rated Global Impression – Severity of 
Illness; OLE = Open-label Extension Period; PGI-S = Patient Global Impression – Severity of Illness;
PK = pharmacokinetics; RNA = ribonucleid acid; SAE = serious adverse event; SCR = screening; SE-ADL = Schwab & 
England Activities of Daily Living; SFU = Safety Follow-up of DBP; T-tau = total tau; UMSARS = Unified Multiple 
System Atrophy Rating Scale; US = United States; vMRI = volumetric magnetic resonance imaging; WD = withdrawal
a. When the last patient randomized reaches Visit 18/Week 48, the remaining patients in the DBP will have 
their next scheduled visit converted to an EoTDBP Visit (assessments as listed for Visit 24, no IMP 
administration).
b. Patients who withdraw, except for those who withdraw their consent, will be asked to attend a Withdrawal 
Visit as soon as possible.
c. The Safety Follow-up Visit will take place 20 weeks after last IMP administration. This will apply only to 
patients who do not enter the OLE or if timing of the Safety Follow-up Visit will be before their first visit in 
the OLE.
d. All assessments may be completed over a maximum of 2 consecutive days (except for MRI, see footnote m); 
if so, the first day is considered the “visit” day according to the schedule and at IMP Visits, IMP must be 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 33 of 131
registered in IRT and administered on the second day. The Screening Visit can be performed over 2 days 
during the first week of the Screening Period.
e. If the date of a visit does not conform to the schedule, subsequent visits should be planned to maintain the 
visit schedule relative to screening for Visit 2 and Visit 3 and relative to baseline for visits after baseline.
f.
MRI scan for eligibility can be performed between Visit 1 and Visit 2. The MRI scan should be uploaded for 
central reading no later than 10 calendar days before the Randomization Visit.
g. Dispense fall diary. This does not apply to a patient who scores 4 on UMSARS Part I item 7 (walking) or if 
the patient is wheelchair bound for unrelated disorders. This needs to be evaluated at each visit, where the fall 
diary is dispensed.
h. Return of the fall diary. Patients who withdraw during a period with fall diary entries must return the diary at 
the Withdrawal Visit.
i.
Participation in FeetMe® and PAMSys subsets are optional, but informed consent for these are part of the 
main informed consent. The use of the sensors does not apply to a patient who scores 4 on UMSARS Part I 
item 7 (walking) or if the patient is wheelchair bound for unrelated disorders. This needs to be evaluated at 
each visit, where the sensors are to be dispensed.
j.
Sensor subset: at the US sites, the patients can participate in an optional objective sensor-based assessments 
subset. The patients undergoing the additional objective sensor-based assessments must provide specific 
consent as part of the main Informed Consent Form. The patient does not have to consent to both objective 
sensor-based assessments to participate. The sensor(s) will be applied during the clinic visit. The use of the 
sensors does not apply to a patient who scores 4 on UMSARS Part I item 7 (walking) or if the patient is 
wheelchair bound for unrelated disorders. This needs to be evaluated at each visit, where the sensors are 
dispensed.
k. Return of the sensor(s). Patients who withdraw during a period with objective sensor-based assessments must 
return the sensor(s) at the Withdrawal Visit.
l.
DTI and ASL measures where available. If Visit 3 MRI scanning is performed without DTI and/or ASL 
sequences and these sequences are implemented in the scanner at a later stage, DTI and ASL should not be 
performed at subsequent visits with MRI measurements.
m. MRI scan can be performed any day within the Visit Window, except for Visit 3 where it must be performed 
before IMP administration. Date of MRI scan will not define Day 1 or Day 2 of a visit and will not be 
regarded as a separate visit.
n. MRI scanning only to be performed as EoT/withdrawal procedure if not performed within the last 8 weeks.
o. CSF sampling not applicable for patients with contraindications of lumbar puncture, history of severe 
post-lumbar puncture headache, on-going skin infection at the lumbar puncture injection site or documented 
history of vertebral deformities, major lumbar back surgery, clinically significant back pain, clinically 
significant abnormal X-ray, and/or injury that, in the opinion of the investigator, would preclude CSF 
collection. CSF sampling, when performed at baseline, should be completed prior to IMP administration.
p. CSF sampling only to be performed as withdrawal procedure in case of withdrawal prior to Visit 18/Week 48 
and for patients with EoTDBP at Visit 18/Week 48. Patients with EoTDBP after Visit 18/Week 48 will not 
undergo CSF sampling as part of the EoTDBP procedures.
q. Multiple samples to be taken relative to IMP infusion: before infusion (at the same time as sampling for 
clinical safety laboratory tests), immediately after the EOI, 1 and 2 hours after EOI at baseline, Week 12 and 
Week 36. At all other visits with blood PK and α-synuclein sampling, samples will be taken before infusion.
r.
Blood pressure and pulse will be measured immediately prior to IMP administration and patients will be 
monitored after IMP administration for immediate drug reactions for a minimum of 2 hours with vital signs 
taken every 30 minutes (±5 minutes) or until stable, whichever is later.
s. Including recording of use of feeding tube and/or wheelchair.
t.
Different versions will be used: “Baseline/Screening” version at Visit 1 and at Visit 3 and “Since last visit” 
version at subsequent visits.
u. Exploratory gene expression profiling (RNA) and metabolomics/proteomics are an integrated part of the 
study and are covered by the main Informed Consent Form.
v. Sampling for pharmacogenetics is optional and a separate signed Informed Consent Form must be in place to 
cover this analysis.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 34 of 131
w. Only for women of childbearing potential. If positive, confirm with serum pregnancy test.
x. Exit interview subset: at the US sites, the patients and caregivers will undergo the Exit interviews via 
telephone or web conferencing platform (for example, Microsoft Teams). The Exit interview will be 
conducted within 3 weeks after the EoTDBP Visit or within 3 weeks after the Withdrawal Visit for patients 
who reach a 48-week treatment period but withdraw prior to the EoTDBP Visit. Study Experience Interview 
subset: at US sites, a subset of patients and caregivers may be contacted to participate in a Study Experience 
interview by telephone or web conferencing platform (for example, Microsoft Teams). The Study Experience 
interview will be conducted within 6 weeks after the completed Exit interview for patients who consent.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 35 of 131
Panel 3
Optional Open-label Extension Period
Visit Name
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP 
EoTOLE
Withdrawala
SFU-Eb
Visit Number
Baseline
1
E
2E
3E
4E
5E
6E
7E
8E
9E
10E
11E
12E
WD
Weekc
0
E
4E
8E
12E
16E
20E
24E
28E
32E
36E
40E
44E
Visit Number
13Ed
14E
15E
16E
17E
18E
19E
20E
21E
22E
23E
24E
25E
26E
Weekc
48E
52E
56E
60E
64E
68E
72E
76E
80E
84E
88E
92E
96E
112
E
Visit Windowe (days 
relative to nominal visit)
3
3
3
3
3
3
3
3
3
3
3
3
7
Signed informed consent 

Efficacy Assessments 
UMSARS
f





CGI-S
f





PGI-S
f





SE-ADL
f



EQ-5D-5L
f



MRI scans: vMRIg
f,h


Blood sampling for NfL




Pharmacokinetic Assessments 
Blood sampling for IMP 
quantification 
f




Pharmacodynamic Assessments
Blood sampling for 
α-synuclein
f




Safety Assessments 
AEs















Blood and urine sampling 
for clinical safety 
laboratory tests 
f



Blood sampling for ADA
f




Vital signsi














Examinationsj (physical, 
neurological)
f



C-SSRS since last visit
f














v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 36 of 131
Visit Name
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP
IMP 
EoTOLE
Withdrawala
SFU-Eb
Visit Number
Baseline
1
E
2E
3E
4E
5E
6E
7E
8E
9E
10E
11E
12E
WD
Weekc
0
E
4E
8E
12E
16E
20E
24E
28E
32E
36E
40E
44E
Visit Number
13Ed
14E
15E
16E
17E
18E
19E
20E
21E
22E
23E
24E
25E
26E
Weekc
48E
52E
56E
60E
64E
68E
72E
76E
80E
84E
88E
92E
96E
112
E
Visit Windowe (days 
relative to nominal visit)
3
3
3
3
3
3
3
3
3
3
3
3
7
Biobanking
Blood sampling for ADA
f




Other Study Procedures and Assessments
IMP administrationi












Concomitant medication 















Urine pregnancy testk
f













ADA = anti-drug antibody; AE = adverse event; CGI-S = Clinical Global Impression – Severity of Illness; 
C-SSRS = Columbia-Suicide Severity Rating Scale; EoTDBP = End-of-Treatment Double-blind Period; EoTOLE = End-
of-treatment of OLE; EQ-5D-5L = EuroQol 5-Dimensions, 5-Levels; IMP = investigational medicinal product; 
IRT = Interactive Response Technology; MRI = magnetic resonance imaging; NfL = neurofilament light chain; 
OLE = Open-label Extension Period; PGI-S = Patient Global Impression-Severity of Illness; SAE = serious adverse event; 
SE-ADL = Schwab & England Activities of Daily Living; SFU-E = Safety Follow-up Extension; UMSARS = Unified 
Multiple System Atrophy Rating Scale; vMRI = volumetric magnetic resonance imaging; WD = withdrawal
a. Participants who withdraw, except for those who withdraw their consent, will be asked to attend a With-
drawal Visit as soon as possible.
b. The SFU-E Visit will take place 16 weeks after Visit 25E/20 weeks after last IMP administration in case of 
withdrawal (follow-up of adverse events on-going at EoTOLE or withdrawal, and new adverse events and 
SAEs).
c. All assessments may be completed over a maximum of 2 days (except for MRI, see footnote g); if so, the first 
day is considered the “visit” day according to the schedule and at IMP visits, IMP must be registered in IRT 
and administered on the second day.
d. Visit 13E should occur at Week 48E, 4 weeks after Visit 12E. However, in the exceptional cases where sites 
have not yet received IRB/EC approval for Protocol Edition 6.0, Visit 13E can be delayed until approval is in 
place but no later than 5 months after Visit 12E.
e. If the date of a visit does not conform to the schedule, subsequent visits should be planned to maintain the 
visit schedule relative to Visit 1E.
f.
Only applicable for patients who enter the OLE more than 1 week after the EoTDBP Visit.
g. MRI scan can be performed any day within the Visit Window. Date of MRI scan will not define Day 1 or 
Day 2 of a visit and will not be regarded as a separate visit.
h. MRI scanning only to be performed at Visit 1E if not performed within the last 8 weeks.
i.
Blood pressure and pulse will be measured immediately prior to IMP administration and patients will be 
monitored immediately after IMP administration inclusive of saline flush (±5 minutes) for immediate drug 
reactions for a minimum of 2 hours with vital signs taken every 30 minutes (±5 minutes) from the end of the 
saline flush or until stable, whichever is later (applicable only through Visit 12E). Beginning at Visit 13E, 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 37 of 131
blood pressure and pulse will only be measured immediately prior to and immediately after IMP administra-
tion, inclusive of the saline flush (±5 minutes).
j.
Including recording of use of feeding tube and/or wheelchair.
k. Only for women of childbearing potential. If positive, confirm with serum pregnancy test.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 38 of 131
2
Introduction
2.1
Background
2.1.1
Overview
Multiple system atrophy (MSA) is a sporadic, rapidly progressing neurodegenerative disorder 
characterized by autonomic failure, parkinsonism and/or cerebellar symptoms (multiple 
system atrophy parkinsonian type [MSA-P] and multiple system atrophy cerebellar type 
[MSA-C], respectively). Most patients are diagnosed with MSA between 50 to 60 years of 
age and the mean survival from onset of symptoms is 6 to 10 years, with few surviving more 
than 15 years.1,2
The pathogenesis of MSA is linked to the misfolding of α-synuclein monomers and its 
pathological hallmark is the presence of inclusions of misfolded α-synuclein (glial 
cytoplasmic inclusions [GCIs]) in oligodendroglia cells. The glial cells survive, while there is 
a loss of neurons in several brain areas, particularly in the putamen, substantia nigra, pons, 
inferior olive, and cerebellum. Neuronal inclusions also occur in MSA, most frequently in the 
putamen, pontine nuclei, and inferior olivary nucleus. Oligodendrocytes express little 
α˗synuclein messenger ribonucleic acid (mRNA), either normally or in MSA, supporting the 
neuronal origin of α-synuclein seeds spreading the pathology. Animal models support cellular 
release and uptake as the mechanism of progression and spreading of the pathology.
MSA is an orphan disease. The prevalence ranges from 2 to 5 per 100,000 in the United 
States (US) and European Union (EU)3 and from 7 to 20 per 100,000 in Japan.4 MSA-P 
constitutes approximately 70% of the cases in the US and EU, while this ratio is inverted in 
Japan with MSA-C constituting approximately 70% of the cases in Japan.
There is a sigmoid progression of clinical impairment and deficits over time. A preclinical 
stage without apparent functional impairment or clinical features might be a phase when 
pathological changes are starting to accumulate without apparent deficits. This phase is 
followed by a stage of evolving early disease, which is clinically non-specific and escapes 
current consensus criteria. A phase with steep progression follows; captured by current 
consensus criteria, this phase represents patients diagnosed at an early stage who fulfil the 
possible or probable MSA criteria by having a low Unified Multiple System Atrophy Rating 
Scale (UMSARS) score. Finally, patients reach a late plateau phase that almost invariably 
meets the consensus criteria for probable MSA.5
No disease-modifying therapies are currently available. The management of the disease 
involves purely symptomatic treatments, that is, medications to stabilize and raise blood 
pressure and medications, such as levodopa, to reduce Parkinson’s disease-like signs and 
symptoms. However, only a subset of MSA patients benefit from levodopa. 
Dopamine-agonists are not considered a therapeutic option due to poor efficacy and risk of 
worsening orthostatic hypotension.6 There are no therapies that can slow down disease 
progression by inhibiting the neurodegenerative processes leading to neuronal cell loss. Thus, 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 39 of 131
due to the fatality and lack of effective treatments, there is an unmet need for a treatment that 
can delay the progression in MSA.
2.1.2
Nonclinical Data
Lu AF82422 is an anti-α-synuclein human immunoglobulin G1 monoclonal antibody (mAb), 
which was identified from screening hybridomas derived from transgenic mice that express 
human antibodies (BMS/Medarex HumAb mice). A panel of in vitro and in vivo studies were 
performed to select Lu AF82422 that met the following desired criteria (more details are 
provided in the Investigators Brochure [IB]7):

Binds to recombinant α-synuclein and α-synuclein isolated from disease brain tissue

Does not cross-react with the nearest homologous, beta- and gamma-synuclein

Recognizes all major species of α-synuclein oligomers and fibrillar forms and N˗ or 
C-terminal truncated forms of the protein

Inhibits C-terminal proteolytic cleavage of α-synuclein

Binds to rodent, cynomolgus, and human α-synuclein

Inhibits seeding and aggregation of α-synuclein in cellular and animal models
Safety pharmacology assessments revealed no Lu AF82422-related adverse effects on central 
nervous system (CNS) (rats and monkeys), cardiovascular (monkeys), or respiratory function 
(monkeys).
The 4-week repeat-dose toxicity studies in rats and cynomolgus monkeys showed that 
Lu AF82422 was well tolerated when administered intravenously (IV) every 10 days, with no 
treatment-related observations or adverse findings and no observed adverse effect level 
(NOAEL) at the highest dose tested; 600 mg/kg/10 days.
The nonclinical immunotoxicity assessment, with focus on blood cells and neurons, did not 
suggest Lu AF82422-related risks of immunotoxicity.
2.1.3
Clinical Data
A first-in-human (FIH) study (Study 17699A) with Lu AF82422 in healthy subjects and 
patients with progressive disease (PD) has been conducted. As of Nov 2021, the Clinical 
Study Report is not yet final, and the results are considered preliminary. Fifty-eight healthy 
subjects and 15 patients with Parkinson’s disease were exposed to Lu AF82422 or placebo 
(Part A, Cohorts A1-A6 in healthy subjects + Part B, Cohort B1-B2 in patients with PD) with 
a single dose of 75 mg (Cohort A1) to 9000 mg (Cohort A6) and 2250 mg (Cohort B1) and 
9000 mg (Cohort B2). Cohort A4 to A6 included 50% Japanese healthy subjects, giving a 
total of 17 Japanese subjects dosed.
Target engagement (TE) of Lu AF82422 binding to α-synuclein was measured by the 
percentage of free α-synuclein in plasma (not bound to Lu AF82422). The data from Part A 
showed a good correlation between plasma concentrations of % free α-synuclein and 
Lu AF82422 plasma concentrations. The IC50 was close to that observed from in vitro
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 40 of 131
binding. Data demonstrated TE in plasma and pharmacokinetic (PK) properties as expected 
for a human IgG1, with an apparent elimination half-life (t½) of approximately 30 days.
The treatment-emergent adverse events (TEAEs) were all non-serious, mainly mild, and did 
not reveal any safety concerns; Lu AF82422 was safe and well tolerated.
No safety concerns have been raised regarding infusion-related reactions, immunotoxicity, or 
platelet function based on the data from the FIH single ascending dose (SAD) study 17699A.
The outcome of the FIH SAD study was used to support a potential approach for Lu AF82422
to treat other α-synucleinopathies, and specifically MSA.
2.2
Rationale for the Study
MSA is a progressive, fatal disorder characterized by autonomic failure and parkinsonism 
and/or cerebellar involvement. Neuropathologically, MSA is characterized by 
oligo-dendroglial inclusions of abnormally aggregated α-synuclein. No disease-modifying 
therapies are currently available; symptomatic treatment options are limited, and the 
therapeutic benefit of these therapies is often only transient. Thus, there is a critical unmet 
need for a treatment that can delay the progression in MSA. α-synuclein is considered a valid 
target for immunotherapies that aim to neutralize and/or clear toxic α-synuclein species, 
Lu AF82422 is a human IgG1 mAb that recognizes all major species of α-synuclein and is 
being developed as a treatment for delaying of disease progression in idiopathic PD and/or 
MSA.
Nonclinical and clinical data of Lu AF82422 supports its potential as a safe and well tolerated 
treatment to reduce or inhibit seeding of pathological form(s) of α-synuclein, and potentially 
delay disease progression in MSA.
A FIH SAD study was conducted in healthy non-Japanese and Japanese subjects and in 
patients with Parkinson’s disease. The main objectives of the FIH SAD study were to evaluate 
the safety and tolerability of Lu AF82422, to investigate the PK properties of Lu AF82422, to 
investigate the cerebrospinal fluid (CSF)/plasma ratio of Lu AF82422, and to evaluate the 
immunogenicity of Lu AF82422 following single ascending doses. 73 subjects/patients were 
administered a single IV infusion of Lu AF82422. The dose range was 75 to 9000 mg. Data 
demonstrated TE in plasma and PK properties as expected for a human IgG1, with a t½ of 
approximately 30 days and no treatment-related serious adverse events (SAEs). The outcome 
of the FIH SAD study was used to support a potential approach for Lu AF82422 to treat other 
α-synucleinopathies, and specifically MSA.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 41 of 131
2.3
Benefit – Risk Assessment
2.3.1
Overall Benefit – Risk Conclusion
Benefit
There are no therapies that can slow down disease progression by inhibiting the 
neurodegenerative processes leading to neuronal cell loss. Thus, due to the fatality and lack of 
effective treatments, there is a high unmet need for a treatment that can delay the disease 
progression in MSA. α-synuclein is considered a valid target for therapies that aim to 
neutralize and/or clear toxic α‑synuclein species, thus potentially providing a beneficial 
outcome on the disease course.
Risks and Risk Mitigations
In general, toxicity results obtained from nonclinical studies with Lu AF82422 do not reveal 
any potential risk for humans and have not identified specific safety issues. In an FIH SAD 
study, safety data with Lu AF82422 had not raised any clinical safety concerns at doses up to 
9000 mg, supporting that Lu AF82422 is considered safe and well tolerated.
The target, α-synuclein, is primarily expressed in blood cells and neurons in the CNS and the 
peripheral nervous system. Therefore, the following will be closely monitored: 
immunogenicity and major CNS-related effects. As for all mAbs, there is a potential risk of 
infusion-related reactions, including systemic hypersensitivity reactions, which is why 
Lu AF82422 is administered in a clinical facility at the study site under medical supervision 
with appropriate measures for adequate treatment in place. Per protocol, patients are required 
to be closely monitored during the infusion and with regular vital sign measurements for at 
least 2 hours from end of infusion (EOI). Patients will be requested to stay longer should the 
investigator determine this is clinically warranted.
In addition to the above, the following risk mitigations are also taken for hypersensitivity 
reactions;

History of severe drug allergy, anaphylaxis or hypersensitivity or known hypersensitivity 
or intolerance to the investigational medicinal product (IMP) or its excipients is an 
exclusion criterion.

Severe and/or serious systemic hypersensitivity reaction to IMP infusion or any 
anaphylactic reaction, confirmed by a clinically relevant increase of serum total tryptase 
from baseline level is a withdrawal criterion.
To monitor patient safety, blinded safety data will be reviewed regularly by internal medical 
monitoring and safety review and by the Lundbeck Lu AF82422 Safety Committee to ensure 
that prompt action can be taken. In addition, an independent Data Monitoring Committee 
(iDMC) will regularly review/analyze the unblinded patients’ safety data according to the 
iDMC Charter in the double-blind period (DBP).
The risks associated with this study are considered adequately elucidated in the nonclinical 
studies and in the FIH SAD study, well controlled by cautionary measures in the study design, 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 42 of 131
and well balanced with the potential benefits of the treatment; a potentially effective treatment 
to delay disease progression in MSA.
Lundbeck considers the benefit/risk profile of this study (18331A) to be acceptable based on 
the available nonclinical and clinical data for Lu AF82422.
2.3.2
COVID-19 Related Risk Assessment and Mitigation
Appropriate risk assessment has been performed and mitigations to be done in case of 
restrictions due to coronavirus disease 2019 (COVID-19) are described in detail in a separate 
“COVID-19 Mitigation Plan”.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 43 of 131
3
Objectives and Endpoints
The study objectives and endpoints are summarized in Panel 4.
Panel 4
Objectives and Endpoints
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of 
Lu AF82422 on disease 
progression in patients with 
Multiple System Atrophy 
(MSA) during the 
Double-blind Period (DBP)
Disease progression
Primary endpoint:
• Disease progression, as assessed by longitudinal changes from baseline in 
the Unified Multiple System Atrophy Rating Scale (UMSARS) Part I and 
Part II Total score (UMSARS TS) up to End-of-Treatment of the DBP 
(EoTDBP)
Key secondary endpoint:
• Disease progression, as assessed by longitudinal changes from baseline in 
modified UMSARS Part I (mUMSARS) score up to EoTDBP
Secondary endpoints:
• Disease progression, as assessed by longitudinal changes from baseline in 
the UMSARS Part I and UMSARS Part II scores up to EoTDBP
• Change from baseline up to Week 48 in the DBP in UMSARS TS, 
UMSARS Part I, mUMSARS and UMSARS Part II scores
Exploratory endpoint:
• Disease progression, as assessed by longitudinal changes from baseline in 
the abbreviated UMSARS (aUMSARS) up to EoTDBP
Secondary Objectives
To evaluate the efficacy of 
Lu AF82422 on:
• Function
• Global impression, sever-
ity of illness during the 
DBP
Function
Secondary endpoint:
• Change from baseline to Week 48 in the DBP in Schwab and England Ac-
tivities of Daily Living (SE-ADL) score
Global impression
Secondary endpoints:
• Change from baseline to Week 48 in the DBP in Clinical Global Impres-
sion – Severity of Illness (CGI-S) score
• Change from baseline to Week 48 in the DBP in Patient Global Impression 
– Severity of Illness (PGI-S) score
• Change from baseline to Week 48 in the DBP in Observer-reported Global 
Impression – Severity of Illness (OGI-S) score
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 44 of 131
Objectives and Endpoints
Objectives
Endpoints
Secondary Objectives 
(continued)
To evaluate the efficacy of 
Lu AF82422 on:
• Autonomic symptoms
• Global disability
• Disease milestones
• Health-related quality of 
life during the DBP
To evaluate the efficacy of 
Lu AF82422 on disease 
progression, as measured by 
brain magnetic resonance 
imaging (MRI)
Endpoints (continued)
Autonomic symptoms
• Secondary endpoint:
• Change from baseline to Week 48 in the DBP in Composite Autonomic 
Symptom Scale Select Change (COMPASS Select Change) score
• Exploratory endpoint:
• Change from baseline to Week 48 in the DBP in heart rate, blood pressure, 
and orthostatic symptoms, as assessed in UMSARS Part III
Global disability
• Secondary endpoint:
• Change from baseline to Week 48 in the DBP in UMSARS Part IV score
Disease milestones
• Secondary endpoints:
• Change from baseline to Week 48 in the DBP in speech, swallowing, falls 
and walking, as assessed by the UMSARS Part I item scores
• Change from baseline to Week 48 in the DBP in frequency, cause and con-
sequence of falls, as assessed by the fall diary periods
• Exploratory endpoints:
• Time to wheelchair use
• Change from baseline to Week 48 in the DBP in frequency of falls, as as-
sessed by PAMSys (subset)
• Change from baseline to Week 48 in the DBP in gait parameters, as as-
sessed by FeetMe® (subset)
Health-related quality of life
• Secondary endpoint:
• Change from baseline to Week 48 in the DBP in EuroQol 5-dimension, 
5-level (EQ-5D-5L) score
MRI biomarkers
Secondary endpoint:
• Percentage change from baseline to Week 48 in the DBP in brain volume 
in brain regions-of-interest (ROIs); primary ROIs: pons and cerebellum; 
secondary ROIs: caudate nucleus, putamen, brain stem and total grey mat-
ter, as measured by volumetric MRI (vMRI)
Exploratory endpoints:
• Percentage change from baseline to Week 48 in the DBP in tissue integrity 
in ROIs; primary ROIs: putamen, cerebellar cortex and white matter; sec-
ondary ROIs: caudate nucleus, globus pallidus and middle cerebellar pe-
duncle, as measured by diffusion-tensor imaging (DTI) MRI
• Percent change from baseline to Week 48 in the DBP in cerebral blood 
flow (CBF) in ROIs; putamen and cerebellum, as measured by arterial spin 
labelling (ASL) MRI
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 45 of 131
Objectives and Endpoints
Objectives
Endpoints
Secondary Objectives 
(continued)
To evaluate the efficacy of 
Lu AF82422 on biofluid 
biomarkers of disease 
progression during the DBP
To evaluate the 
pharmacokinetics of 
Lu AF82422
Endpoints (continued)
Biofluid biomarkers
Secondary endpoint:
• Blood biomarkers: Change from baseline up to Week 48 in the DBP in 
neurofilament light chain (NfL) concentrations
Exploratory endpoints:
• Cerebrospinal fluid (CSF) biomarkers: Change from baseline up to 
Week 48 in the DBP in t-tau and NfL concentrations
Pharmacokinetics
Secondary endpoints:
• Lu AF82422 plasma concentration during treatment and Safety Follow-up
• Lu AF82422 CSF concentrations and the CSF/plasma concentration ratios 
at Week 48 in the DBP
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 46 of 131
Objectives and Endpoints
Objectives
Endpoints
Exploratory Objectives
To explore the target en-
gagement (TE) of 
Lu AF82422 to α-synuclein 
during the DBP
To explore the TE of 
Lu AF82422 to pathological 
species of α-synuclein dur-
ing the DBP
To explore the relationship 
between UMSARS, MRI pa-
rameters and NfL during the 
DBP
To explore the effect of 
long-term treatment with 
Lu AF82422 during the 
open-label extension (OLE)
Endpoints (Exploratory)
Blood:
• Plasma concentrations of “free” and “total” α-synuclein during treatment 
and Safety Follow-up
CSF:
• Concentrations of “free” and “total” α-synuclein at baseline and Week 48 
in the DBP
CSF biomarkers:
• Changes from baseline up to Week 48 in the DBP in pathological species 
of α-synuclein
Relationship between:
• Change from baseline to Week 48 in the DBP in UMSARS TS, Part I and 
Part II scores,
• Percentage change from baseline to Week 48 in the DBP in brain volume 
and tissue integrity in brain ROIs as measured by MRI, and
• Change from baseline up to Week 48 in the DBP in NfL concentrations.
Effect of long-term treatment:
• Change from baseline of the DBP and baseline of the OLE to 
End-of-Treatment of the OLE (EoTOLE) in UMSARS TS and mUMSARS 
score
• Change from baseline of the DBP and baseline of the OLE to EoTOLE in 
CGI-S score
• Change from baseline of the DBP and baseline of the OLE to EoTOLE in 
PGI-S score
• Change from baseline of the DBP and baseline of the OLE to EoTOLE in 
SE-ADL score
• Change from baseline of the DBP and baseline of the OLE to EoTOLE in 
health-related quality of life, as assessed using EQ-5D-5L score
• Percentage change from baseline of the DBP and baseline of the OLE to 
EoTOLE in brain atrophy in ROIs, as measured using vMRI
• Change from baseline of the DBP and baseline of the OLE to EoTOLE in 
blood NfL concentrations
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 47 of 131
Objectives and Endpoints
Objectives
Endpoints
Exploratory Objectives
To explore the efficacy of 
Lu AF82422 for up to 
72 weeks of treatment on 
clinical scales and 
biomarkers during the DBP
To collect patient experience 
with impaired functions due 
to MSA to support the 
interpretation of change 
during the study (Exit 
Interview subset) during the 
DBP
To collect patient experience 
with study participation 
(Study Experience Interview 
subset) during the DBP
Endpoints (Exploratory)
Clinical scales:
• Change from baseline to EoTDBP in UMSARS Part I items 1, 2, 7 and 8, 
Part III and Part IV, and SE-ADL, CGI-S, PGI-S, OGI-S, COMPASS Se-
lect Change and EQ-5D-5L
Blood biomarkers:
• Change from baseline to EoTDBP in NfL concentrations
MRI biomarkers:
• Change from baseline to EoTDBP in vMRI, DTI and ASL measures
Describe patient experience data and meaningful change (for example,
symptoms, function, quality of life and disease manifestations) from the 
patient’s and caregiver’s perspective, as assessed by the Exit interviews
Describe patient experience data (for example, study experience, operational 
considerations, satisfaction with study experience, suggestions) from the 
patient’s and caregiver’s perspective, as assessed by the Study Experience 
interviews
Safety Objective
To evaluate the safety and 
tolerability of Lu AF82422 in 
patients with MSA in the DBP
To evaluate safety and 
tolerability of Lu AF82422 in 
patients with MSA in the 
OLE
Safety Endpoints
Double-blind Period
• Treatment-emergent adverse events
• Absolute values and changes from baseline in clinical safety laboratory test 
values, vital signs, weight, and electrocardiogram (ECG) parameter values
• Development of specific anti-drug antibodies (ADAs)
• Findings on MRI, as specified in the Imaging Charter
• Columbia-Suicide Severity Rating Scale (C-SSRS) score
Open-label Extension Period
• Treatment-emergent adverse events
• Absolute values and changes from baseline in clinical safety laboratory test 
values, vital signs, and weight parameter values
• Development of ADAs 
• C-SSRS score
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
4
Study Design
4.1
Overview of the Study Design
7KLVVWXG\KDVEHHQGHVLJQHGLQDFFRUGDQFHZLWKWKHDeclaration of Helsinki.
7KLVLVDSKDVH,,LQWHUYHQWLRQDOUDQGRPL]HGGRXEOHEOLQGSDUDOOHOJURXS
SODFHERFRQWUROOHGLQFOXGLQJDQRSWLRQDORSHQODEHOH[WHQVLRQ2/( PXOWLFHQWUHVWXG\RI
WKHHIILFDF\VORZLQJGLVHDVHSURJUHVVLRQVDIHW\DQGWROHUDELOLW\RI/X $) LQSDWLHQWV
ZLWK06$7KHHIILFDF\RI/X $) LVDVVHVVHGXVLQJWKH8QLILHG0XOWLSOH6\VWHP
$WURSK\5DWLQJ6FDOH7RWDO6FRUH806$5676VXSSRUWLYHDVVHVVPHQWVLQFOXGHHYDOXDWLRQ
RIIXQFWLRQJOREDOLPSUHVVLRQRIVHYHULW\RILOOQHVVDXWRQRPLFV\PSWRPVGLVDELOLW\
KHDOWKUHODWHGTXDOLW\RIOLIHELRIOXLGELRPDUNHUVDQGLPDJLQJ
7KHVWXG\GHVLJQLVSUHVHQWHGLQ3DQHO DQGWKHVFKHGXOHGVWXG\SURFHGXUHVDQGDVVHVVPHQWV
IRUWKH'%3DUHVXPPDUL]HGLQ3DQHO DQG IRU2/(DVVHVVPHQWVDUHVXPPDUL]HGLQ3DQHO
7KLVVWXG\ ZLOO EHFRQGXFWHGLQFRPSOLDQFHZLWKWKHSURWRFROGood Clinical Practice DQG
DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV
SDWLHQWVUHFUXLWHGIURPVSHFLDOLVWFHQWUHVDUHSODQQHGIRUUDQGRPL]DWLRQ SDWLHQWVLQWKH
/X $)
JURXSDQG SDWLHQWVLQWKHSODFHERJURXS
7KHWDUJHWSRSXODWLRQIRUWKLVVWXG\DUH SDWLHQWVZLWKSRVVLEOHRUSUREDEOH06$DVGHILQHGE\
WKHFXUUHQWFRQVHQVXVGLDJQRVWLFFULWHULD VHH$SSHQGL[ 97KHVWXG\ZLOOUHFUXLWSDWLHQWV
ZLWKHYLGHQFHRISDUNLQVRQLVP06$3DQGRUFHUHEHOODUV\QGURPH06$&3DWLHQWVZLOO
EHDOORZHGVWDEOHWUHDWPHQWIRUPDQDJLQJWKHLUV\PSWRPVRI06$GXULQJWKHVWXG\
,QWKH'%3 SDWLHQWVZLOOEHUDQGRPL]HGWR/X $)
RUSODFHERYLDD
FHQWUDOL]HGUDQGRPL]DWLRQV\VWHP,QWHUDFWLYH5HVSRQVH7HFKQRORJ\>,57@7RHQVXUHD
EDODQFHGWUHDWPHQWDOORFDWLRQVWUDWLILFDWLRQZLOOEHDSSOLHGDFFRUGLQJWRWZRIDFWRUVWKDWLV
DQG
5HJLRQ86-DSDQZLWKDPD[LPXPRIRISDWLHQWVIURP-DSDQ3DWLHQWVZLWKDPLVVLQJ
ZLOOEHVWUDWLILHGWRDVHSDUDWHJURXSODEHOOHG³PLVVLQJ´
7KHVWXG\GXUDWLRQIURPWKH6FUHHQLQJ9LVLWWRWKH6DIHW\)ROORZXS9LVLWLVEHWZHHQWR
 ZHHNV IRUSDWLHQWVQRWHQWHULQJWKHRSWLRQDO2/(SHULRGDQG EHWZHHQ WR ZHHNV IRU
SDWLHQWVFRQWLQXLQJLQWKH 2/(7KHVWXG\ LQFOXGHVWKHIROORZLQJSHULRGV

6FUHHQLQJ3HULRG ZHHNV

5DQGRPL]DWLRQ3HULRG ZHHNV

'%3  ZHHNV XSWR ZHHNV

2SWLRQDO2/(  ZHHNV

6DIHW\)ROORZXS3HULRG ZHHNV DIWHUODVW,03 DGPLQLVWUDWLRQ
$OOSDWLHQWVHQWHULQJWKH2/(ZLOOUHFHLYH/X $)
GXULQJWKH2/(3DWLHQWVZKR
HQWHUWKH2/( ZLOOUHFHLYHWKHILUVWRSHQODEHOGRVH9LVLW (RQ WKHVDPHGD\DVWKH
(QGRI7UHDWPHQW9LVLWIRUWKH'%3(R7'%3 RUDVVRRQDVSRVVLEOHWKHUHDIWHUEXWQRODWHU
CCI
CCI
CCI
CCI
CCI
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 49 of 131
than 5 months after the EoTDBP Visit, and will be enrolled into OLE no later than the end of 
Q1 2024. If a Safety Follow-up Visit for the DBP is due before the OLE is implemented, it 
should be completed per Panel 2. The patient could afterwards enter the OLE and treatment 
could continue for a planned period of 96 weeks. OLE procedures will be performed as 
presented in Panel 3.
In the OLE, patients will receive Lu AF82422 until Visit 24E (Week 92E) and complete the 
EoTOLE at Visit 25E (Week 96E). Visit 13E should occur at Week 48, 4 weeks after 
Visit 12E. However, in the exceptional cases where sites have not yet received Institutional 
Review Board (IRB)/Ethics Committee (EC) approval for Protocol Edition 6.0, Visit 13E can 
be delayed until approval is in place but no later than 5 months after Visit 12E.
Patients who do not consent to the optional OLE will enter the Safety Follow-up Period after
the EoTDBP.
The individual DBP will vary from 48 weeks up to 72 weeks. Once the last patient will reach 
Week 48, this visit will be the EoTDBP Visit for that patient. The remaining patients in the 
DBP will have their next scheduled visit converted to an EoTDBP Visit with assessments as 
listed for Visit 24, as according to Panel 2.
During the DBP, patients will attend IMP Visits to follow a dosing schedule with either 
Lu AF82422 or placebo every 4 weeks (Q4W).
Patients who withdraw, except for those who withdraw their consent, will be scheduled for a 
Withdrawal Visit to undergo clinical and safety assessments as soon as possible.
All patients (except the ones withdrawing consent) will be scheduled for a Safety Follow-up 
Visit 20 weeks after their last IMP dose, regardless if they received their last dose in the DBP 
or OLE, or if they withdrew.
Patients will be monitored after IMP administration for immediate drug reactions for a mini-
mum of 2 hours with vital signs taken every 30 minutes ±5 minutes from the end of the saline 
flush or until stable, whichever is later (applicable only through Visit 12E).
Beginning at Visit 13E, blood pressure and pulse will only be measured immediately prior to 
and immediately after IMP administration, inclusive of the saline flush (±5 minutes).
CSF assessments for evaluation of PK, TE, and biomarkers at baseline and after initiation of 
treatment will be collected according to Panel 2. CSF sampling is not applicable for patients 
with contraindications of lumbar puncture, history of severe post-lumbar puncture headache, 
on-going skin infection at the lumbar puncture injection site, or documented history of 
vertebral deformities, major lumbar back surgery, clinically significant back pain, clinically 
significant abnormal X-ray, and/or injury, that in the opinion of the investigator, would 
preclude CSF collection.
At all the US sites, additional assessments (objective sensor-based assessments and qualitative 
interviews) will be performed (hereafter referred to as the “Sensor subset” and “Exit Interview 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 50 of 131
subset”). Participation in the Exit Interview subset is mandatory for patients and caregivers, 
while participation in the Sensor subset is optional. Patients who wish to participate in the 
Sensor subset must provide specific consent to one or both devices as part of the main 
Informed Consent Form. Patients can withdraw from these additional assessments without 
having to withdraw from the main study. Additionally, at US sites, a subset of patients and 
caregivers may be contacted about an opportunity to participate in an additional interview 
about study experience (“Study Experience Interview subset”).

Patients from the Sensor subset will be subject to additional objective sensor-based 
assessments using the PAMSys and/or FeetMe® devices. These devices will collect data on
the patient’s gait and events of fall (sections 10.2.1.9 and 10.2.1.10). The devices will 
passively collect data in the remote environment starting from the Randomization Visit 
until the Baseline Visit, and then for four pre-defined periods during the DBP according to 
Panel 2. The devices will be handed out to patients and returned by patients at standard 
in-clinic visits.

Patients and caregivers from the Exit Interview subset will participate in an Exit interview 
via web conferencing platform (for example, Microsoft Teams) or telephone. The Exit 
interviews will take place approximately 3 weeks after the EoTDBP Visit or Withdrawal 
Visit. For patients withdrawing from the study, the Exit interview will only be performed if 
they have been in the DBP for at least 48 weeks. The content of the Exit interviews may 
reveal potential adverse events (PAEs) that occurred between EoTDBP/Withdrawal Visit 
and the conduct of the interview (section 10.7.1).

A subset of patients and caregivers at US sites may be contacted to participate in a Study 
Experience interview. The interview will focus on the overall Study Experience from the 
perspective of the patient and caregiver, including topics such as logistical considerations, 
satisfaction with participation in the study, and suggestions for improvement for future 
studies. The interviews will follow a separate interview protocol and will be conducted by 
ICON. The content of the Study Experience interviews may reveal PAEs that occurred 
between and the conduct of the Exit interview and the Study Experience interview 
(section 10.7.2).
An iDMC will regularly monitor the patients’ unblinded safety data according to the DMC 
Charter during the DBP (more information is provided in section 11.6).
4.2
Rationale for the Study Design
In preparation for this study, Lundbeck conducted a qualitative patient insight research to 
understand MSA patients’ needs and collect feedback on a preliminary visit schedule. A total 
of 10 MSA patients and 5 caregivers in the US, United Kingdom, and Germany were 
interviewed to gain patient insights. These patient insights and concerns were considered 
when planning procedures and the design of the current study. In these interviews, patients 
understood the need for a tight study schedule and were interested in a close monitoring of 
their disease. Overall, these efforts are in consideration of MSA patients’ needs and 
challenges, ultimately supporting patient centric study design and protocol.
This protocol is targeting an early population of MSA patients, allowing patients with either 
MSA-P or MSA-C and including only patients with an UMSARS Part I score ≤16 (omitting 
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 52 of 131
of a clear link between biomarker and clinical endpoints. Exit interviews will facilitate 
interpretation of meaningful change from a patient and caregiver perspective.
The study is designed in accordance with regulatory guidance.
5
Ethics
In general, toxicity results obtained from nonclinical studies with Lu AF82422 do not reveal 
any potential risk for humans and have not identified specific issues. Safety data with 
Lu AF82422 have not raised any clinical safety concerns following a single dose up to 
9000 mg in healthy volunteers and patients with Parkinson’s disease from the completed FIH 
SAD study, supporting that Lu AF82422 can be safely used in the proposed clinical phase II 
study in patients with MSA.
The target, α-synuclein, is primarily expressed in blood cells and neurons in the CNS and the 
peripheral nervous system, therefore the following will be closely monitored: immunogenicity 
and major CNS-related effects. As for all mAbs, there is a potential risk of infusion-related 
reactions, including acute systemic hypersensitivity reactions, which is why close monitoring 
of patients with regular vital sign measurements for 2 hours post-dose will take place.
The risks associated with this study are considered adequately elucidated in the nonclinical 
studies and in the FIH SAD study, well controlled by cautionary measures in the study design, 
and well balanced with the potential benefits of the treatment; a potentially effective treatment 
to delay disease progression in MSA.
5.1
Ethical Rationale
The ethical rationales for this study are the following:

There is an unmet medical need for a treatment that can delay the progression in MSA, 
addressed by this study

The justification of the study design is provided in section 4.2

Establishing an iDMC because:
MSA is a new indication, and in the FIH SAD study only a few patients with another 
type of α-synucleinopathy (Parkinson’s disease) were exposed to Lu AF82422. No
MSA patients have previously been exposed to Lu AF82422.
Use of a mAb, a new therapeutic, where other entities of the class had effects on the 
CNS.
Limited safety data overall are available on Lu AF82422 (low number of subjects 
exposed to a single dose of Lu AF82422).
The patient will be fully informed about the study including the risks and benefit of his/her 
participation in the study.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 53 of 131
The patient may withdraw from the study at any time, for any reason, specified or 
unspecified, and without penalty or loss of benefits to which the patient is otherwise entitled.
Information on race will be collected to support future filing claims in the US according to 
Food and Drug Administration (FDA) guidance document12 and ICH E17 guideline on 
general principles for planning and design of multi-regional clinical trials.13
In accordance with Good Clinical Practice,9 qualified medical personnel at Lundbeck or 
designated clinical research organization (CRO) will be readily available to advise on 
study-related medical questions. Medical monitoring and safety review will be performed 
throughout the study. In addition, safety data will be reviewed regularly by the Lundbeck 
Lu AF82422 Safety Committee to ensure that prompt action is taken, if needed.
In accordance with Good Clinical Practice,9 the investigator will be responsible for all 
study-related medical decisions.
5.2
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the patient and the caregiver. An 
informed consent is required for patients in the optional OLE.
Informed Consent for the Patient: The patient Informed Consent Form will explain the 
purpose, benefits and risks of the study, the details of their involvements, services and 
compensations. In the US, the main informed consent will in addition include participation in 
the Exit Interview subset for patients, optional participation in the PAMSys and FeetMe®
assessments as well as the optional exploratory laboratory assessments detailed below.
Informed Consent for the Caregiver: The caregiver Informed Consent Form will explain the 
purpose, benefits and risks of the study, the details of their involvements, services and 
compensations. It will also describe the treatment of confidential information. In the US, the 
caregiver informed consent will also include participation in the Exit Interview subset for 
patient and caregivers. In case the caregiver drops out before the study ends, a new caregiver 
should be identified. The new caregiver should participate in the Exit interview. However, the 
patient can remain in study if no new caregiver can be identified.
In case of pregnancy, please refer to section 11.2.
It is the responsibility of the investigator or person designated by the investigator to obtain 
written informed consent from the patient and the caregiver(s). If the informed consent 
process may be delegated, the requirements for the delegates must be documented prior to the 
start of the study. National laws must always be adhered to when allowing potential 
delegation. Any delegation must be documented in the site delegation log.
The investigator must identify vulnerable patients, that is, patients whose willingness to 
participate in this study might be unduly influenced by the expectation, regardless of whether 
it is justified, of benefits associated with participation, or of a retaliatory response from senior 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 54 of 131
members of a hierarchy in case of refusal to participate. Patients thus identified must be 
excluded from participation in the study.
Prior to obtaining written informed consent, the investigator or a designee must explain to the 
patients and the caregiver(s) the aims and methods of the study and any reasonably expected 
benefits and foreseeable risks or inconveniences to the patients.
The patients must be informed:

that their participation in the study is voluntary and that they are free to withdraw from the 
study at any time without justifying their decision

of the possibility of withdrawing consent (section 6.4)

of their right to request a copy of their personal data from the study via the investigator

of their right to be informed by the investigator, after the study has been reported, about 
which treatment they received

of their right to receive information about the study results from the investigator on the 
patient’s own initiative; the results will be available approximately 1 year after the end of 
the study
The patients must be informed that persons authorized by Lundbeck and authorized personnel 
from certain authorities (domestic, foreign, data protection agencies, or ECs or IRBs) may 
view their medical records. The patients must also be informed that de-personalized copies of 
parts of their medical records may be requested by authorized personnel from certain 
authorities (domestic, foreign, data protection agencies, or ECs or IRBs) for verification of 
study procedures and/or data. The confidentiality of the patients will, in all cases, be 
respected.
The patients must be given ample time and opportunity to inquire about the details of the 
study prior to deciding whether to participate in the study.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the patients prior to allowing a patient to participate in the 
study, an Informed Consent Form must be signed and dated (by the patient and signed and 
dated by the investigator or a designee on the same day). The patient must be given a copy of 
the written information (Patient Information Sheet) as well as a copy of the signed Informed 
Consent Form.
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ECs.
As the blood sampling for the exploratory analyses (gene expression profiling [ribonucleic 
acid that is RNA] and metabolomics/proteomics) is an integral part of this study, the main 
Informed Consent Form covers these analyses. Conversely, the blood sampling for potential 
future genetic biomarker analysis is optional and a separate Informed Consent Form covers 
this analysis.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 55 of 131
The blood and CSF samples for potential future exploratory biomarker analysis, or the data 
derived from these blood samples, may be shared with academic and public institutions and 
other companies. However, Lundbeck will retain full control of the samples and their use in 
accordance with the information in the Informed Consent Form.
A patient may, at any time and without stating a reason, specifically request the destruction of 
the patient’s deoxyribonucleic acid (DNA) sample, irrespective of the patient’s continued 
participation in the study. The investigator must send a written request on behalf of the patient 
to the Lundbeck international study manager. The investigator will receive written 
confirmation from Lundbeck when the DNA sample has been destroyed.
5.3
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and the applicable laws of the US and Japan to 
ensure that requirements regarding personal data protection are met. If an external 
organization will process data on behalf of Lundbeck, a contractual procedure will be signed 
between Lundbeck or delegate and the external organization to ensure compliance with the 
above-mentioned legislation.
5.4
Ethics Committee(s) and Institutional Review Board(s)
This study will be conducted only after Lundbeck has received confirmation that the 
regulatory authorities have approved or confirmed notification of the study and that written 
approval of the protocol has been granted by the appropriate EC or IRB.
The investigator must not allow any patients to participate in the study before receiving 
confirmation from Lundbeck or the CRO that the required approvals and/or notifications have 
been received.
The EC or IRB must be informed when specific types of protocol amendments have been 
made and written approval must be obtained before implementation of each amendment, if 
required by local law.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
EC or IRB by the investigator at intervals stipulated in its guidelines.
6
Study Population
6.1
Number of Patients and Countries
Overall, a minimum of 60 patients, recruited from specialist centres, are planned for 
randomization.
Planned regions include: North America (US) and Asia (Japan).
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 56 of 131
6.2
Patient Recruitment
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients are randomized within the 
planned recruitment period.
The investigators will be notified immediately when the recruitment period comes to an end.
6.3
Selection Criteria
Patient selection is based on the inclusion and exclusion criteria listed below.
Patients who meet each of the inclusion criteria and none of the exclusion criteria at the 
Screening Visit as well as Randomization Visit are eligible to participate in this study.
Inclusion Criteria
1.
The patient is capable of communicating with the site personnel
2.
The patient is able to read and understand the Informed Consent Form
3.
The patient’s caregiver is able to read and understand the Caregiver’s Informed Consent 
Form
4.
The patient has signed the Informed Consent Form
5.
The patient’s caregiver has signed the Caregiver’s Informed Consent Form
6.
The patient is aged ≥40 and ≤75 years at the Screening Visit
7.
The patient has suitable peripheral venous access for IMP administration and blood 
sampling
8.
The patient is diagnosed with possible or probable MSA of the MSA-P or MSA-C 
sub-type according to the Gilman criteria14 at the Screening Visit (see Appendix V)
9.
The patient had onset of motor and/or autonomic (orthostatic or urinary) MSA symptoms 
within 5 years prior to the Screening Visit in the judgement of the investigator (applicable 
to patients enrolled before Protocol Version 4.0)
a.
The patient had onset of motor MSA symptoms within 5 years prior to the Screening 
Visit in the judgement of the investigator (applicable to patients enrolled under
Protocol Version 4.0)
10. The patient has an anticipated survival of at least 3 years, in the opinion of the 
investigator, at the Screening Visit
11. The patient has an UMSARS Part I score ≤16 (omitting item 11 on sexual function) at the 
Screening Visit
12. The patient has a cognitive performance evaluated by the Montreal Cognitive Assessment 
(MoCA) with a score ≥22 at the Screening Visit. Add 1 point for an individual who has 
12 years or fewer of formal education
13. The patient has a knowledgeable and reliable caregiver who will be available throughout 
the study to complete a caregiver observer questionnaires (at site visit or in a remote 
setting) when carer/observer-reported outcomes are performed. A caregiver is defined as 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 57 of 131
a person who spends approximately 3 hours or more with the patient per week and can 
inform on the patient’s level of functioning
14. The patient, if a woman, must:
have had her last natural menstruation ≥12 months prior to the Screening Visit, OR
have been surgically sterilized prior to the Screening Visit, OR
have had a hysterectomy prior to the Screening Visit, OR
agree not to try to become pregnant during the study, AND accept to follow one of the 
following contraceptive methods:
o
Combined (oestrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation for example, oral (in combination with a 
double barrier methods [either a condom in combination with a spermicide or a 
diaphragm in combination with a spermicide]), intravaginal or transdermal 
hormonal contraception
o
Progesterone only hormonal contraception associated with inhibition of 
ovulation for example, oral (in combination with a spermicide or a diaphragm in 
combination with spermicide), injectable or implantable hormonal contraception
o
Intrauterine hormone-releasing system
o
Intrauterine devices
o
Vasectomized partner
o
Sexual abstinence
o
Engaging in same-sex relationships
The contraception must be used from Screening Visit and until ≥5 months after the last 
dose of IMP
15. The patient, if a man, must:
use two methods of contraception in combination if his female partner is of childbearing 
potential; this combination of contraceptive methods must be used from the Baseline 
Visit until ≥5 months after the last dose of IMP, OR
have been surgically sterilized prior to the Screening Visit
Exclusion Criteria
1.
The patient has previously been enrolled in this study
2.
The patient has participated in a clinical study with last dose of an IMP <30 days or 
5 plasma half-lives (whichever is longer) prior to the Screening Visit
3.
The patient is a member of the study personnel or of their immediate families or is a 
subordinate (or immediate family member of a subordinate) to any of the study personnel
4.
The patient is pregnant or breastfeeding
5.
The patient has a history of severe drug allergy, anaphylaxis or hypersensitivity or known 
hypersensitivity or intolerance to the IMP or its excipients
6.
The patient has any other disorder for which the treatment takes priority over treatment of 
MSA or is likely to interfere with the study treatment or impair treatment compliance
7.
The patient has been treated with an anti-α-synuclein monoclonal antibody, mesenchymal 
stem cells or an inhibitor of α-synuclein aggregation within the last 12 months
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 58 of 131
8.
The patient has any past or current treatment with an active vaccine targeting α-synuclein
9.
The patient has two or more blood relatives with a history of MSA
10. The patient meets any of the following criteria at the Screening Visit, which suggests 
advanced disease (only applicable to patients enrolled before Protocol Version 4.0 and 
not applicable for patients enrolled under Protocol Version 4.0):
Speech impairment, as assessed by a score of ≥3 on UMSARS Part I, item 1
Swallowing impairment, as assessed by a score of ≥3 on UMSARS Part I, item 2
Impairment in ambulation, as assessed by a score of ≥3 on UMSARS Part I, item 7
Falling more frequently than once per week, as assessed by a score of ≥3 on UMSARS 
Part I, item 8
11. The patient has evidence (clinically or on MRI) and/or history of any clinically 
significant disease or condition other than MSA, for example, serious neurological 
disorder, other intracranial or systemic disease. Abnormalities (space-occupying lesions, 
vascular lesions, tumours, stroke, etc.) on MRI are to be discussed with the Lundbeck 
medical expert or the CRO medical monitor before the patient is enrolled
12. The patient has a current diagnosis of movement disorders that could mimic MSA; for 
example, Parkinson’s disease, dementia with Lewy bodies, essential tremor, progressive 
supranuclear palsy, spinocerebellar ataxia, spastic paraparesis, corticobasal degeneration, 
or vascular, pharmacological or post-encephalitic parkinsonism, per investigator 
discretion. Patients who have previously been incorrectly diagnosed with Parkinson’s 
disease will not be excluded
13. The patient has a history of moderate or severe head trauma or other neurological 
disorder or systemic medical disease that is, in the investigator’s opinion, likely to affect 
CNS functioning
14. The patient has a history of neurosurgical procedures including deep brain stimulation 
that could, in the investigator’s opinion, interfere with the assessments of safety or 
efficacy
15. The patient has contraindications for MRI
16. The patient has attempted suicide within the last 6 months or is at significant risk of 
suicide (either in the opinion of the investigator or defined as a “yes” to suicidal ideation 
questions 4 or 5 or answering “yes” to suicidal behaviour on the Columbia-Suicide 
Severity Rating Scale [C-SSRS] within the past 6 months)
17. The patient has a history of cancer, other than basal cell, Stage 1 squamous cell 
carcinoma of the skin or cured gastric or cervical carcinoma in situ, that has not been in 
remission for >5 years prior to the first dose of IMP
18. The patient takes or has taken recent or concomitant medication that is disallowed or 
allowed with restrictions (specified in Appendix II) or it is anticipated that the patient will 
require treatment with at least one of these medications during the study:
Disallowed: any investigational products within 30 days before the Screening Visit, 
treatment targeting α-synuclein and/or MSA disease progression
Allowed with restriction: stable dose for at least 8 weeks prior to randomization of drugs 
acting against parkinsonism (for example, Levodopa, Dopamine-Agonists, Amantadine 
and Monoamine oxidase B [MAO-B]-inhibitors) and/or drugs acting against autonomic 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 59 of 131
dysfunction (for example, ephedrine, droxidopa, midodrine, fludrocortisone, octreotide, 
desmopressin, oxybutynin) and anticipated stable during the DBP. If medically 
necessary, initiation of or change of dose of concomitant medication is allowed per 
investigator discretion.
19. The patient has previously tested positive for hepatitis B surface antigen (HBsAg), 
anti-hepatitis virus C (HCV) or human immunodeficiency virus (HIV)
20. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit:
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >2 times the upper limit of the reference range. If the 
patient is diagnosed or suspected of having Gilbert’s syndrome, the patient can be 
discussed with the medical monitor
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
21. The patient has, at the Screening Visit:
an abnormal electrocardiogram (ECG) that is, in the investigator’s opinion, clinically 
significant AND/OR
a PR interval >225 ms OR
a QRS interval ≥150 ms OR
a QTcF interval >450 ms (for men) or >470 ms (for women) (based on the Fridericia 
correction where QTcF = QT/RR0.33)
or a QTcF interval >440 ms (for men) or >460 ms (for women) if the patient has a heart 
rate <60 bpm (beats per minute)
22. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
23. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is un-
suitable for any reason.
Open-label Extension Entry Criteria
1.
The patient has completed the EoTDBP Visit and did not withdraw in the DBP
2.
The patient has consented to participate in the OLE
3.
The patient has completed the EoTDBP within the last 5 months and will be enrolled into 
the OLE no later than end of Q1 2024
4.
The patient is, in the investigator’s opinion, likely to comply with the protocol
5.
The patient has not received any other investigational product since the EoTDBP Visit
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 60 of 131
6.4
Withdrawal Criteria
A patient must be withdrawn from the study if:

The patient withdraws consent (defined as a patient explicitly takes back his or her 
consent); section 9.6 states how the patient’s data will be handled

The patient has been randomized in error and has not been administered IMP

Withdrawal of patients enrolled in error and who have received the IMP should be based 
on a case-by-case evaluation of the individual risk/benefit. The decision about the 
administration of more doses of Lu AF82422 will be based on an individual risk/benefit 
assessment as judged by the investigator

The patient can no longer attend study visits due to MSA disease progression.

The patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient])
A patient must be withdrawn from treatment if:

The patient experiences any systemic hypersensitivity reaction to IMP infusion which are 
confirmed as anaphylactic reaction by a clinically relevant increase of serum total tryptase 
from baseline level (see section 11.1.3)

The patient experiences any severe and/or serious systemic hypersensitivity reactions even 
though the serum total tryptase does not confirm an anaphylactic reaction

The patient experiences an adverse event that, in the opinion of the investigator or 
sponsor’s medical expert, contraindicates further dosing

The investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interests of the patient that he or she be withdrawn from treatment

Any site personnel breaks the randomization code for that patient

The patient becomes pregnant

The patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range

The patient has a serum ALT or AST value >5 times the upper limit of the reference range 
that is confirmed by testing <2 weeks later

The patient has a QTcF interval >500 ms confirmed on repeat, if the repeat is done within 
72 hours; the decision to withdraw the patient may be postponed until a repeat ECG is 
taken, if it is taken within 72 hours during the DBP.

A patient may be withdrawn from the study if:
The patient fails to comply with study procedures
Patients who withdraw will not be replaced.
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
7
Investigational Medicinal Product
/X $) LVDKXPDQ,J*PRQRFORQDODQWLERG\WKDWUHFRJQL]HVDOOPDMRUVSHFLHVRI
ĮV\QXFOHLQ
7.1
Treatment Regimen
7.1.1
Treatment Regimen Double-blind Period
3DWLHQWVZLOOEHUDQGRPO\DOORFDWHGYLDDFHQWUDOL]HGUDQGRPL]DWLRQV\VWHP,57WRRQHRI
WZRWUHDWPHQWJURXSV

/X $)

SODFHER
3DWLHQWVZLOOEHUDQGRPO\DOORFDWHGLQUDWLR/X $)
DQGSODFHER
3DWLHQWVZLOOUHFHLYH,03VWDUWLQJIURPWKH%DVHOLQH9LVLWWRIROORZD4:GRVLQJVFKHGXOH
ZLWKHLWKHU/X $) RUSODFHERE\,9LQIXVLRQ$Q\GHYLDWLRQIURPWKH4: ± GD\V
GRVLQJVFKHGXOHPXVWEHGLVFXVVHGDQGDJUHHGZLWKWKHPHGLFDOPRQLWRUDQGGRFXPHQWHGDVD
SURWRFROGHYLDWLRQ,03GRVLQJPXVWQRWWDNHSODFHLIOHVVWKDQ ZHHNV XQWLOWKHQH[W
VFKHGXOHG,03LQIXVLRQ
$OOSDWLHQWVZLOOUHFHLYHGRXEOHEOLQGWUHDWPHQWZLWK,03VWDUWLQJDWEDVHOLQH:HHN XQWLO
9LVLW :HHN KRZHYHUVRPHSDWLHQWVZLOOFRQWLQXHWRUHFHLYHWUHDWPHQWXSWR9LVLW 
:HHN 7KHLQGLYLGXDOWUHDWPHQWSHULRGZLOOYDU\IURP ZHHNV XSWR ZHHNV EDVHGRQ
WKHWLPLQJRIWKHODVWSDWLHQWUDQGRPL]HG2QFHWKHODVWSDWLHQWUHDFKHV:HHN WKLVYLVLWZLOO
EHWKH(R7'%3 9LVLW IRUWKDWSDWLHQW3DWLHQWVZKRKDYHQRWFRPSOHWHGWKHYLVLWDW:HHN DW
WKHWLPHRI/DVW3DWLHQW(R7'%3 9LVLWZLOOKDYHWKHLUQH[WYLVLWFRQYHUWHGWRDQ(R7'%3
9LVLWZLWKDVVHVVPHQWVDVOLVWHGIRU9LVLW DFFRUGLQJWR3DQHO'XULQJWKH'%3SDWLHQWV
ZLOODWWHQG,039LVLWVWRIROORZDGRVLQJVFKHGXOHZLWKHLWKHU/X $) RUSODFHER4:
3DWLHQWVZKRGRQRWFRQVHQWWRWKHRSWLRQDO2/( ZLOOHQWHUWKH6DIHW\)ROORZXS3HULRGDIWHU
WKH(R7'%3 9LVLW
7.1.2
Treatment Regimen Open-label Extension Period
3DWLHQWVZLOOUHFHLYH/X $)

,QWKH2/(DOOSDWLHQWVZLOOUHFHLYHRSHQODEHOWUHDWPHQWZLWK/X $) VWDUWLQJDW
9LVLW (XQWLO9LVLW (:HHN (VHH3DQHO
'XULQJWKH2/(SHULRG DQ\GHYLDWLRQIURPWKH4:± GD\V GRVLQJVFKHGXOHPXVWEH
GLVFXVVHGDQGDJUHHGZLWKWKHPHGLFDOPRQLWRUDQGGRFXPHQWHGDVDSURWRFROGHYLDWLRQ,03
GRVLQJPXVWQRWWDNHSODFHLIOHVVWKDQ ZHHNV XQWLOWKHQH[WVFKHGXOHG,03LQIXVLRQ
$IWHU9LVLW (RULISUHPDWXUHO\GLVFRQWLQXHGSDWLHQWVZLOOEHVFKHGXOHGIRUD6DIHW\
)ROORZXS9LVLW  ZHHNVDIWHUWKHODVW,03GRVHDVVFKHGXOHGLQ3DQHO
CCI
CCI
CCI
Y 
&/,B

v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
,IDQDQDSK\ODFWLFUHDFWLRQ RUDV\VWHPLF K\SHUVHQVLWLYLW\UHDFWLRQ RFFXUVDEORRGVDPSOHZLOO
EHGUDZQIURPWKHSDWLHQWDVVRRQDVSRVVLEOHDIWHUWKHHYHQW )RUGHWDLOVVHHVHFWLRQ
7.3
Manufacturing, Packaging, Labelling, and Storage of IMP
7KH,03VZLOOEHPDQXIDFWXUHGSDFNDJHGODEHOOHGUHOHDVHGE\DTXDOLILHGSHUVRQ>43@
DQGGLVWULEXWHGLQDFFRUGDQFHZLWKWKHSULQFLSOHVRIGood Manufacturing Practice *03)
XQGHUWKHUHVSRQVLELOLW\RI/XQGEHFN
7KH,03VZLOOEHSURYLGHGLQVLQJOHGRVHYLDOVRI P/HDFKDVVROXWLRQIRULQIXVLRQ
7KHZRUGLQJRQWKHODEHOVZLOOEHLQDFFRUGDQFHZLWK*03UHJDUGLQJODEHOOLQJDQGQDWLRQDO
DQGRUORFDOUHJXODWRU\UHTXLUHPHQWV,IDGGLWLRQDOLQIRUPDWLRQLVWREHDGGHGZKHQWKH,03LV
GLVSHQVHGWRWKHSDWLHQWVWKLVZLOOEHFOHDUO\VWDWHGRQWKHODEHOVDQGWKHLQYHVWLJDWRUZLOOEH
LQVWUXFWHGWRGRVR
1RPDQLSXODWLRQUHSDFNDJLQJRUUHODEHOLQJ RI,03LVSHUPLWWHGDIWHU43UHOHDVHE\
/XQGEHFNXQOHVVDUHSDFNDJLQJUHODEHOLQJ DJUHHPHQWH[LVWVDQGWKHGRFXPHQWDWLRQLV
DYDLODEOHWR&OLQLFDO6XSSO\/XQGEHFNDQGZKHUHQHFHVVDU\QHZ43UHOHDVHVDUHPDGH
7KH,03VZLOOEHLGHQWLILHGXVLQJDXQLTXHPHGLFDWLRQQXPEHU
7KH,03VPXVWEHVWRUHGLQDVDIHDQGVHFXUHORFDWLRQDQGLQDFFRUGDQFHZLWKWKHVWRUDJH
FRQGLWLRQVVSHFLILHGRQWKHODEHOV
7.4
Method of Assigning Patients to Treatment
,57ZLOOEHXVHGLQWKLVVWXG\(DFKSDWLHQWZLOOEHDVVLJQHGDVFUHHQLQJQXPEHUE\WKH,57
DQGWKDWQXPEHUZLOOEHXVHGWRLGHQWLI\WKHSDWLHQWWKURXJKRXWWKHVWXG\:KHQDSDWLHQWLVWR
EHUDQGRPL]HGWKHLQYHVWLJDWRURUDGHVLJQDWHGXQEOLQGHGVLWHVWDIIZLOOXVHWKH,577KH,57
DOORFDWHVWKHSDWLHQWWRDWUHDWPHQWJURXSDQGDVVLJQVWKHSDWLHQWDUDQGRPL]DWLRQQXPEHULQ
DFFRUGDQFHZLWKWKHVSHFLILFDWLRQVIURP%LRVWDWLVWLFV/XQGEHFN
5DQGRPL]DWLRQZLOOWDNHSODFHDW9LVLW DIWHUFRQILUPDWLRQWKDWWKHSDUWLFLSDQWFRQWLQXHVWR
PHHWWKHLQFOXVLRQH[FOXVLRQFULWHULD3DWLHQWVZLOOEHUDQGRPL]HGWRUHFHLYHHLWKHUVWXG\
GUXJRUSODFHER
6WUDWLILFDWLRQZLOOEHSHUIRUPHGDFFRUGLQJWRWZRIDFWRUVWKDWLV
DQG5HJLRQ86-DSDQZLWKDPD[LPXPRIRISDWLHQWVIURP-DSDQ
3DWLHQWVZLWKQRDYDLODEOH
ZLOOEHUDQGRPL]HGLQWRDWKLUGJURXS
ODEHOOHG³PLVVLQJ´
,QWKHRSWLRQDO2/(SHULRGDOOSDWLHQWVZLOOUHFHLYH/X $)
CCI
CCI
CCI
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 64 of 131
7.5
IMP Accountability
IMP accountability is documented in the IRT and using IMP forms.
The investigator and the designated, unblinded site staff must agree to only dispense IMP to 
patients randomized in the study. The designated, unblinded site staff must maintain an 
adequate record of the receipt and distribution of the IMP(s). This record must be available 
for inspection at any time.
7.6
Unblinding Procedures
Global Patient Safety, H. Lundbeck A/S, and the designated, unblinded site staff will have 
access to the unblinded information for the double-blind treatment for each patient. Access to 
these details will be via IRT.
Lu AF82422 is eliminated through proteolytic degradation and not metabolized through 
CYP P450 enzymes, thus no drug-drug interactions are expected and treatment with 
Lu AF82422 would not prevent any acute medical or surgical intervention.
The investigator may only break the code for a patient if knowledge of the IMP is necessary 
to provide optimal treatment to the patient in an emergency situation. If possible, if the 
investigator needs medical guidance, the investigator should consult the clinical research 
associate (CRA) and/or in some cases the medical monitor before breaking the code. The 
investigator must record the date and reason for breaking the code. If the emergency situation 
was an adverse event, it must be recorded on an Adverse Event Form. The CRA and the 
medical monitor must be notified immediately. The IRT will capture the date and time of the 
code break call. Information on the allocated treatment will be provided during the call and by 
email. When the code is broken for a patient, the patient must be immediately withdrawn from 
the study. If this occurs during a visit, the investigator must complete the visit as a 
Withdrawal Visit; otherwise, the patient will be asked to attend a Withdrawal Visit.
7.7
Post-study Access to IMP(s)
Post-study access to the IMP will not be available. Patients in the study will have access to 
appropriate medical care after they complete or withdraw from the study.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 65 of 131
8
Concomitant Medication
8.1
Concomitant Medication
Concomitant medication is any medication other than the IMP that is taken during the study, 
from 3 months prior to Screening Visit up until the Safety Follow-up Visit.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarized in Appendix II.
Details of all concomitant medications (prescription and over-the-counter) taken <3 month(s) 
prior to the Screening Visit must be recorded in the eCRF at the first visit. Any changes 
(including reason for changes) in concomitant medication must be recorded at each 
subsequent visit. If medically necessary, initiation of or change of dose of concomitant 
medication is allowed per investigator discretion.
Any new concomitant treatment should not be initiated the same day as a visit with IMP 
infusion, unless for immediate treatment of a drug reaction or in case of an emergency.
For any concomitant medication for which the dose was increased due to worsening of a 
concurrent disorder after enrolment in the study, the worsening of the disorder must be 
recorded as an adverse event (see section 11.1.1).
For any concomitant medication initiated due to a new disorder after enrolment in the study, 
the disorder must be recorded as an adverse event.
8.2
COVID-19 Vaccination
There is currently no data indicating that Lu AF82422 may interact with or impair the body’s 
immunological response to the COVID-19 vaccines. Hence, there are no indications for safety 
concerns of concomitant use of the COVID-19 vaccines with Lu AF82422. As such, 
COVID-19 vaccination is allowed during this study with the guidance measures as described 
below.
The patient should not receive a COVID-19 vaccination (or any concomitant medication, see 
section 8.1) the same day as an IMP infusion. If the patient has recently received a COVID-19 
vaccine, the investigator should judge if the patient can be administered the IMP infusion at 
the scheduled visit based upon the patient´s individual response to the COVID-19 vaccine.
In the current study, if a patient is administered a COVID-19 vaccine, this should be captured 
as concomitant medication in the eCRF, including the date that the vaccine was given. The 
name of the manufacturer and, if applicable, whether it was the “first, second or booster, etc.” 
vaccination should also be added, in a bracket.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 66 of 131
All adverse events, including those judged by the investigator to be related to the COVID-19 
vaccine must be captured in the eCRF on the Adverse Event Form. A causality assessment, 
including an alternative causality as relevant, must be provided on the Adverse Event Form.
9
Study Visit Plan
9.1
Overview
The study concept components are presented in Panel 1 and the patient flow is also presented 
in Panel 1. An overview of the procedures and assessments to be conducted during the study 
and their timing is presented in Panel 2and Panel 3. Further details are in section 10.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
The study includes the following periods:

Screening Period (4 weeks)

Randomization Period (2 weeks)

DBP (48 weeks to 72 weeks)

Optional OLE (96 weeks)

Safety Follow-up Period (20 weeks after last IMP administration)
9.2
Screening Period
9.2.1
Screening Visit (Visit 1, -6 Week)
Informed consent must be obtained before any study-related procedures are initiated, 
including washout of disallowed medications. At the US sites, the patients undergoing the 
additional objective censor-based assessments must provide specific consent as part of the 
main Informed Consent Form. The patient does not have to consent to both objective 
sensor-based assessments to participate. The Screening Period will occur up to 4 weeks prior 
to randomization at Visit 2 and have a duration of approximately 4 weeks.
The main procedures performed at screening include signing the informed consent, 
demographics, diagnosis of MSA-P or MSA-C according to the Gilman criteria, MoCA, 
relevant history (medical, psychiatric, neurological, family history of MSA), concomitant
medication MRI scan for eligibility and, in addition, evidence of MRI abnormalities 
supporting the diagnosis of MSA, physical and neurological examination, checking 
inclusion/exclusion criteria, UMSARS score, safety laboratory and other safety assessments. 
The Screening Visit can be performed over 2 days during the first week of the Screening 
Period. The MRI scan should be uploaded for central reading no later than 10 calendar days 
before the Randomization Visit.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 67 of 131
All screening procedures are summarized in Panel 2. Assessments are described in detail in 
section 10.
9.2.1.1
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, and the investigator’s 
name and contact information.
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
9.2.1.2
Re-screening
Re-screening is only allowed for patients who screen fail for administrative reasons, or who 
screen fail due to a change in concomitant medication allowed with restrictions within 
8 weeks prior to randomization or have previously screen failed due to an eligibility criterion 
that has since been revised or removed. The patients must otherwise be eligible for the study 
at the time of screen failure. Re-screened patients will receive a new screening number.
Authorization for re-screening may only be granted by the sponsor’s medical expert (or the 
CRO’s medical monitor) after a thorough review of all data from the original Screening Visit.
At the new Screening Visit, the patient and caregiver must sign a new Informed Consent 
Form. At the new Screening Visit, the patient will be assigned a new screening number. A 
re-screened patient must have an entirely new Screening Visit with all screening procedures 
and assessments performed again, except for the screening MRI scan if performed within the 
last 3 months. All the eligibility criteria must be re-assessed at the new Screening Visit.
The following information will also be recorded in the eCRF at the new Screening Visit:

that the patient has previously been screened for the study

that re-screening has been authorized (by the sponsor’s medical expert OR state who)

the screening number that was assigned to the patient at the original Screening Visit
If a patient is re-screened, no data from the original Screening Visit will be used except for 
the original screening MRI if not repeated.
A patient may only be re-screened once.
9.3
Randomization Period
See section 10.1.1.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 68 of 131
9.4
Double-blind Period
9.4.1
Baseline Visit (Visit 3, Week 0)
Important procedures at baseline include MRI scan for volumetric and diffusivity measures, 
application of IMP PK measurement of IMP in blood and CSF, biobanking samples and 
pregnancy test. The full list of assessments at the Baseline Visit are summarized in Panel 2.
9.4.2
General Outline of Visits During Double-blind Period
During the DBP, site visits will be every 4 weeks ±3 days with the possibility of completing 
the assessments over a maximum of 2 consecutive days for a given visit; and if so, then the 
first day is considered the “Visit” day according to the schedule and at IMP Visits, the visit 
must be registered in IRT and IMP administered to the patient on the second day. In addition, 
two telephone visits (Visits 4 and 8) will be conducted during the DBP to record adverse 
events and concomitant medication.
9.4.3
End-of-Treatment Visit – Double-blind Period
The individual DBP will vary from 48 weeks up to 72 weeks. Once the last patient reaches 
Week 48, this visit will be the EoTDBP Visit for that patient. Patients who have not 
completed the visit at Week 72 at the time of Last Patient EoT Visit will have their next 
scheduled visit converted to an EoTDBP Visit with assessments as listed for Visit 24, as 
according to Panel 2.
At US sites, a subset of patients and caregivers may be contacted to participate in a Study 
Experience interview by telephone or web conferencing platform (for example, Microsoft 
Teams). The Study Experience interview will be conducted within 6 weeks after the 
completed Exit interview for patients who consent.
Patients who do not consent to the optional OLE will enter the Safety Follow-up Period after 
the EoTDBP Visit.
9.4.4
Safety Follow-up Visit 20 Weeks After Last Dose of IMP – Double-blind Period
A Safety Follow-up is conducted to capture new adverse events that occur during the Safety 
Follow-up Period as well as to follow-up on the outcome of adverse events on-going at the 
end of the treatment period. In addition, the following will be collected; blood and urine 
samples for clinical safety laboratory tests, blood sampling for IMP quantification and 
anti-drug antibodies (ADAs), vital signs, physical and neurological examination, ECG, 
C-SSRS assessment, concomitant medication and pregnancy test. The Safety Follow-up Visit 
must be conducted as a visit to the site. The Safety Follow-up Visit is scheduled 20 weeks
after the last dose of IMP.
For adverse events that were on-going at the EoTDBP or Withdrawal Visit and that resolved 
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 69 of 131
events still on-going at the Safety Follow-up Visit, the On-going Adverse Event checkbox on 
the Adverse Event Form must be ticked. SAEs must be followed until resolution, or the 
outcome is known.
For details of assessments to be conducted at the Safety Follow-up Visit see Panel 2.
9.5
Optional Open-label Extension Period
Patients who consent to the optional OLE will enter the OLE under the circumstances defined 
in section 6.3.
Treatment with Lu AF82422 will continue on the first visit of the OLE (Visit 1E) which will 
take place at the same day as the EoTDBP Visit, or as soon as possible thereafter, but no later 
than 5 months after the EoTDBP Visit, and will be enrolled into the OLE no later than the end 
of Q1 2024. If a Safety Follow-up Visit for the DBP is due before the OLE is implemented, it 
should be completed per Panel 2. The patient could afterwards enter the OLE and treatment 
could continue for a planned period of 96 weeks. OLE procedures will be performed as 
presented in Panel 3.
For patients who enter the OLE and have the first visit of the OLE at the same day of the 
EoTDBP visit, clinical assessments would not have to be repeated. In that case, data will 
automatically be transferred. However, in case of >7 days in between the EoTDBP visit and 
the first visit of the OLE, clinical assessments would have to be re-performed.
9.5.1
End-of-Treatment Visit – Optional Open-label Extension Period
Patients who enter the OLE will receive the first open-label dose of Lu AF82422 (Visit 1E) 
on the same day as the EoTDBP or as soon as possible thereafter and the last dose on 
Visit 24E (Week 92E); EoT in the 96-week OLE is at Visit 25E (Week 96E).
9.5.2
Safety Follow-up Visit Open-label Extension Period 20 Weeks After Last Dose 
of IMP
A Safety Follow-up Visit of the extension period (SFU-E) is conducted to capture new 
adverse events that occur during the Safety Follow-up Period as well as to follow-up on the 
outcome of adverse events on-going at the end of the treatment period. In addition, the 
following will be collected; blood and urine samples for clinical safety laboratory tests, blood 
sampling for IMP quantification and ADA, vital signs, physical and neurological 
examination, C-SSRS assessment, concomitant medication and pregnancy test. The Safety 
Follow-up must be conducted as a visit to the site. The Safety Follow-up Visit is scheduled 
20 weeks after the last dose of IMP.
For adverse events that were on-going at the EoTOLE, or Withdrawal Visit and that resolved 
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
events still on-going at the Safety Follow-up Visit, the On-going Adverse Event checkbox on 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 70 of 131
the Adverse Event Form must be ticked. SAEs must be followed until resolution, or the 
outcome is known.
The Safety Follow-up Visit for patients who withdraw consent must be performed, if at all 
possible; any information collected will only be recorded in the patients’ medical records.
For details of assessments to be conducted at the Safety Follow-up Visit, see Panel 3.
9.6
Withdrawal Visit
Patients who withdraw from the study prior to the respective EoT Visit for the treatment 
period (ie, EoTDBP or EoTOLE) will be asked to attend a Withdrawal Visit and Safety 
Follow-up Visit, if at all possible. If the patient cannot attend the site physically for the 
Withdrawal Visit, and the visit would then not be performed, the visit should be performed as 
a remote or Telemedicine visit with assessments performed as described in the “COVID-19 
Mitigation Plan”, if possible. The Withdrawal Visit must be scheduled as soon as possible 
after withdrawal.
No new information will be collected from patients who withdraw from the study, except 
information collected in relation to the scheduled Withdrawal Visit and the Safety Follow-up 
Visit 20 weeks after last dose of IMP or needed for the follow-up of adverse events 
(section 11.5).
MRI scanning is only to be performed as an EoT/withdrawal procedure if it was not 
performed within the last 8 weeks.
Patients who withdraw during a period with fall diary entries must return the diary at the 
Withdrawal Visit.
Patients who withdraw during a period with objective sensor-based assessments must return 
the sensor(s) at the Withdrawal Visit.
The Exit interview will be conducted within 3 weeks after the Withdrawal Visit for patients 
who have been in the DBP for at least 48 weeks prior to withdrawal. For patients who 
withdraw from study treatment after Week 48 in the DBP and complete an Exit interview, 
patients may be contacted to participate in a Study Experience interview.
The reason for withdrawal must be recorded in the eCRF.
For a patient who withdraws consent:

if the patient withdraws consent during a visit and then agrees to it being the final visit, the 
investigator will complete the visit as the Withdrawal Visit and all the data collected up to 
and including that visit will be used.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 71 of 131

if the patient withdraws consent during a telephone conversation, the investigator will ask 
the patient if he or she will attend a Withdrawal Visits. If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including these 
visits will be used
refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical records

if the patient explicitly requests that the patient’s data collected from the time of 
withdrawal of consent onwards not be used, this will be respected.
It is planned to conduct the same assessments as for the EoT if the patient is withdrawn 
during the DBP (Visit 18, for list of assessments see Panel 2).
9.7
Unscheduled Visit
If needed, an unscheduled visit can be performed between Randomization and the Safety 
Follow-up Visit for any of the safety assessments:

Blood and urine sampling for clinical safety laboratory tests

Blood sampling for ADA

Vital signs

Weight

Examinations (physical, neurological)

ECG

MRI scan for safety

C-SSRS

Serum total tryptase sample to evaluate baseline tryptase level in the event of an 
anaphylactic reaction or a systemic hypersensitivity reaction
Adverse events must always be collected at an unscheduled visit.
9.8
End-of-study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient on-going in the study.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 72 of 131
10 Assessments
10.1
Screening and Baseline Procedures and Assessments
10.1.1
Randomization Visit (Visit 2, Week -2)
Randomization will be performed at Visit 2 after checking inclusion/exclusion criteria, as well 
as signs and symptoms present. The tablet to record falls (fall diary) and other 
patient-reported outcomes (PROs) will be handed out. All PROs will be administered 
electronically by using a tablet. The patients and their caregivers will be trained on how to use 
the electronic PROs (ePROS) by site staff who have adequate experience with MSA patients 
and have received adequate training on good standards in providing guidance to patients on 
how to use the ePROs.
In exceptional cases, the visit interval between the Screening and Randomization Visits may 
be extended with consent from the Lundbeck medical expert/medical monitor, provided the 
Lundbeck medical expert accepts the rationale provided for the extension. The full list of 
assessments at the Randomization Visit are summarized in Panel 2.
10.1.2
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria. The following will be subject to assessment after the Informed Consent 
Form has been signed:

Diagnosis (see diagnostic assessment in section 10.1.3)

MSA History (onset of motor and/or autonomic MSA symptoms, date of MSA diagnosis, 
blood relatives with diagnosis of MSA)

MoCA

Recent and on-going medication

Medical history

Demographics (age, sex, race)

Height and weight

Signs and symptoms; adverse events

MRI for eligibility and, in addition, presence of MRI abnormalities supporting the 
diagnosis of MSA

UMSARS for eligibility

Blood sampling for NfL
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 73 of 131
Safety at screening

Physical and neurological examination

Vital signs

ECG

C-SSRS

Blood sampling for pregnancy test

Blood and urine sampling for clinical safety laboratory tests (as listed in Panel 2, Panel 3,
and Panel 5)
10.1.2.1
Montreal Cognitive Assessment (MoCA)
MoCA is a cognitive test (available at https://www.mocatest.org) assessing 8 cognitive 
domains: visuospatial/executive, naming, memory, attention, language, abstraction, delayed 
recall, and orientation (place and time). Normal score would be ≥26/30 achievable points. 
Inclusion criterion is ≥22 points at screening.
10.1.3
Diagnostic Assessments
The following diagnostic assessments will be performed:

Diagnosis (possible or probable MSA-P or MSA-C according to the Gilman criteria)

Inclusion/exclusion criteria pertaining to diagnosis and prognosis (see section 6.3)

Relevant history (medical, psychiatric, neurological, family history of MSA)

Physical and neurological examination

MRI scan
10.2
Efficacy Assessments
10.2.1
Clinical Outcome Assessments (COA)
10.2.1.1
Use of COA Tools
The following COA tools will be used for efficacy assessment:

UMSARS – to assess the severity of MSA symptoms, impacts, and disease progression

Composite Autonomic Symptom Scale (COMPASS) Select (Baseline) and COMPASS 
Select Change (subsequent visits) – to assess severity of autonomic symptoms

Schwab and England Activities of Daily Living (SE-ADL) – to assess function, level of 
dependency

Clinical Global Impression – Severity (CGI-S) – to assess clinical global impression of 
MSA severity

Patient Global Impression – Severity (PGI-S) – to assess patient global impression of MSA 
severity
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 74 of 131

Observer-reported Global Impression - Severity of Illness (OGI-S) – to assess caregiver 
observed global impression of MSA severity in the patient

Fall eDiary – to assess fall events and consequences of falls

FeetMe® – to assess gait parameters (in a subset of patients in the US)

PAMSys – to assess frequency of falls (in a subset of patients in the US)
Detailed instructions on how to administer the COA tools and how to score using them will be 
provided to the site in Rater Guideline and Vendor Manuals.
Rater training of electronic COA as well as central review of UMSARS Part I and Part II will 
be provided by MedAvante-Prophase.1 Central review will only be performed during DBP. 
Training materials are available throughout the duration of the study on the training provider’s 
eLearning platform, which can be accessed from any device. Independent Review Guidelines, 
as well as Videography training modules, are part of the training provider’s eLearning 
platform and are accessible the same way as COA training.
The UMSARS, COMPASS-S/SC, SE-ADL, CGI-S, PGI-S, OGI-S, and Fall eDiary will be 
administered in the local language. Only those provided by Lundbeck that have been 
validated in the language to which they have been translated will be used in this study.
The COMPASS-S/SC, PGI-S and Fall eDiary are PROs: guidance will be provided to patients 
on how to complete them and how to use the ePRO device.
The OGI-S is a carer/observer-reported outcome: guidance will be provided to caregivers on 
how to complete the scale and how to use the electronic outcome device.
10.2.1.2
Unified Multiple System Atrophy Rating Scale (UMSARS)
The UMSARS is a combined clinician and patient-reported scale to assess motor impairment 
in MSA patients.10 The UMSARS consists of four parts:
Part I assesses historical information on symptoms and activities of daily living over the past 
2 weeks as reported by patients and caregivers (12 items) rated on a scale ranging from 
0 = not affected to 4 = unable to do the activity (Note; each item uses different anchor 
descriptors as relevant to the question addressed).
Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items) 
rated on a scale ranging from 0 = normal to 4 = marked/severe impairment (Note; each item 
uses different anchor descriptors as relevant to the question addressed).
Part III includes an autonomic examination (4 items), individual measures of systolic and 
diastolic blood pressure, heart rate and orthostatic symptoms (yes/no).
1 MedAvante-Prophase is now part of WCGclinical.com
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 75 of 131
Part IV assesses global disability (1 item) ranging on a scale from 1 = completely independent 
to 5 = totally dependent and helpless/bedridden.
The total UMSARS score (UMSARS TS) is obtained by the sum of the items from Part I and 
Part II. Part I scores range between 0 to 48, and Part II scores range between 0 and 56. A 
higher score indicates greater impairment. An experienced neurologist can use the UMSARS 
after a short training session. It takes approximately 30 to 45 minutes to administer the 
UMSARS. The administration of UMSARS Part I and Part II will be video recorded for 
central reading.
The modified UMSARS (mUMSARS) score will consist of UMSARS Part I where the 
response option scores of 0 and 1 will be collapsed to one category in the analysis.
The abbreviated UMSARS (aUMSARS) score is derived from a subset of items from 
UMSARS Part I and Part II shown to be patient centric and sensitive to progression in MSA. 
Thus, the UMSARS will be administered only once to the patient (according to standard 
procedures) at the clinic visit to derive the UMSARS TS, mUMSARS and abbreviated scores.
The aUMSARS has been developed to be patient centric (relevant to patients) and sensitive to 
detect change in patients diagnosed with possible and probable MSA. The abbreviated 
UMSARS score will be derived by a subset of items from Part I and Part II in the original 
UMSARS scale. The clinician will administer the full original UMSARS to assess MSA signs 
and symptoms and its impact on function. Raters will be kept blinded to the items constituting 
the abbreviated UMSARS to avoid bias during patient examination. Full details on how to 
generate the abbreviated UMSARS score will be described in the 18331A Statistical Analysis 
Plan (SAP).
Central reading of the UMSARS scale during the DBP will be provided by the vendor 
(MedAvante-Prophase).
10.2.1.3
Composite Autonomic Symptom Scale – Select and Select Change 
(COMPASS-S/SC)
The COMPASS Select,15 a patient-reported scale, consists of a subset of 36 items derived 
from the original COMPASS,16 to assess severity of autonomic symptoms in MSA during the 
last year. The COMPASS Select includes 3 domains related to blood pressure control: 
syncope, orthostatic intolerance, and vasomotor symptoms; and 3 domains focused on 
symptoms of disturbed secretomotor, bladder, and sleep function.
The COMPASS Select Change is a derivate of COMPASS Select, consisting of 16 items in 
which patients are asked to score their change in autonomic symptoms since their last visit.
The scoring algorithm of COMPASS is highly complicated and requires computer analysis 
for score generation. A higher score indicates greater autonomic symptom severity. It takes 
approximately 10 to 15 minutes to complete the COMPASS-S and COMPASS-SC.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 76 of 131
10.2.1.4
Schwab and England Activities of Daily Living (SE-ADL)
The SE-ADL is a combined patient- and clinician-reported scale to assess patients physical 
functioning in activities in daily living to grade functional status.11 For the 18331A study only 
the clinician-rated part will be administered. The SE-ADL rates the patient’s function on a 
scale ranging from 0% indicating worst possible function to 100% indicating no impairment. 
Each 10-point increment is accompanied by a description of function. The score is obtained 
by the 10-point response option applicable for the patient. The SE-ADL can be administered 
by an experienced health care professional after a short training. It takes approximately 
5 to 10 minutes to rate the SE-ADL.
10.2.1.5
Clinical Global Impression-Severity of Illness (CGI-S)
The CGI-S is administered by an experienced neurologist familiar with MSA patients to make 
an expert clinical global judgement about the severity of the disease across various time 
points. The neurologist makes a judgement about the total picture of the patient at each visit: 
the disease severity, the patient’s level of distress and other aspects of impairment, and the 
impact of disease on functioning. The rating is based upon observed and reported symptoms, 
behaviour, and function at the time of assessment. The CGI-S is rated on a scale ranging from 
0 to 4 (whereas the 0 = normal, not impaired; 1 = mildly impaired; 2 = moderately impaired; 
3 = severely impaired; 4 = extremely impaired).
10.2.1.6
Patient Global Impression – Severity of Illness (PGI-S)
The PGI-S is a self-reported single item to evaluate all aspects of patients’ MSA symptoms. 
Patients are asked to choose the response that best describes the severity of their MSA 
symptoms over the past week. The question is rated on a 5-point scale ranging from 
0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 4 = very severe). It takes approximately 
1 minute to complete the PGI-S.
10.2.1.7
Observer-reported Global Impression – Severity of Illness (OGI-S)
The OGI-S is a carer/observer-reported outcome to evaluate all aspects of patients’ MSA 
symptoms. Carer/observers are asked to choose the response that best describes the observed 
severity of MSA symptoms in the person they care for over the past week. The question is 
rated on a 5-point scale ranging from 0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 
4 = very severe). It takes approximately 1 minute to complete the OGI-S.
10.2.1.8
MSA Fall Diary
At the Randomization Visit, all patients will be provisioned and trained on an electronic MSA 
Fall Diary. During the study patients will be instructed to record fall events on a daily basis 
using a MSA Fall Diary during 5 distinct intervals; 2 weeks between Randomization Visit and 
Baseline Visit and 4 intervals of 4 weeks during the DBP. Patients are asked to report 
date/time of falls (yes/no), location of the fall (indoors or outdoors, familiar or unfamiliar 
environment), cause of fall (experience of orthostatic symptoms or freezing of gait), action 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 77 of 131
taken, and type of injury sustained (if any). At the end of each week patients will also be 
asked to report any health care professional visits and hospital visits and type of examination 
(for example, X-ray due to the fall etc.). The use of the fall diary does not apply to a patient 
who scores 4 on UMSARS Part I item 7 (walking) or if the patient is wheelchair bound for 
unrelated disorders. This needs to be evaluated at each visit, where the fall diary is to be 
dispensed.
10.2.1.9
FeetMe®
At US sites, additional, objective sensor-based assessments will be performed during 
5 distinct intervals (2 weeks interval between randomization and baseline, then 4 periods of 
4 weeks) on consenting subsets of patients in the US (hereafter referred to as the “Sensor 
subset”). Patients can withdraw from these additional assessments without having to withdraw 
from the main study. Patients may consent to participate in one or both of the objective 
sensor-based assessments. The use of the sensors does not apply to a patient who scores 4 on 
UMSARS Part I item 7 (walking) or if the patient is wheelchair bound for unrelated disorders. 
This needs to be evaluated at each visit, where the sensors are to be dispensed.
FeetMe® solution includes connected insoles FeetMe® Insole, FeetMe® Evaluation mobile 
application and FeetMe® Mobility web platform. FeetMe® Insole combines pressure sensors, 
motion sensors and embedded calculation power, which allow to calculate more than 20 gait 
metrics for every step. The patients receive insoles during scheduled visits and are asked to 
wear the insoles continuously for 10 days in their home environment.
Metrics calculated for every step with FeetMe® Insole:

Stride length

Walking speed

Width motion

Cadence

Stride time

Single support time

Swing time

Double support time

Pressure distribution

Stride length difference

Strides time difference

Distance travelled

Support asymmetry

Trajectory centre of pressure
Detailed instructions on how to administer FeetMe® digital insoles will be provided to the site 
in a Rater Guideline.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 78 of 131
10.2.1.10 PAMSys
At US sites, patients will have the option for undergoing objective sensor-based assessments, 
which will be performed during 5 distinct intervals (2 weeks interval between randomization 
and baseline, then 4 periods of 4 weeks) (hereafter referred to as the “Sensor subset”). Patients 
can withdraw from these additional assessments without having to withdraw from the main 
study. Patients may consent to participate in one or both of the objective sensor-based 
assessments. The use of the sensor does not apply to a patient who scores 4 on UMSARS 
Part I item 7 (walking) or if the patient is wheelchair bound for unrelated disorders. This 
needs to be evaluated at each visit, where the sensor is to be dispensed.
BioSensics’ PAMSys is a system that consists of a wearable motion sensor that is paired to a 
tablet. The wearable sensor is worn as a pendant on the chest for continuous monitoring of 
falls and physical activity. The tablet supports electronic COA technology, which, when a fall 
is detected by a sensor, asks the patient to confirm or deny the occurrence of the detected fall. 
Patients receive the sensor during the scheduled visits and are instructed to wear the sensor 
continuously for 30 days at each interval and bring the sensor back at the next scheduled visit.
The parameters provided by the PAMSys system are: number of detected falls, posture 
classification (sitting, standing, walking and lying down), number of steps, and compliance 
for wearing the sensor.
Detailed instructions on how to administer PAMSys system will be provided to the site in a 
Rater Guideline.
10.2.1.11 Rater Qualification
Rater training and certification will be conducted by the MedAvante-Prophase who will also 
provide training, including the video recording and central review process (as agreed with the 
sponsor). Raters will complete their designated training curriculum based on their initial 
qualification status and assigned role. The training programme will also include instructions 
on general COA administration, quality assurance and management guidance.
The UMSARS and the CGI-S, should only be administered by a rater having adequate 
experience with MSA and administration of semi-structured interviews. The rater should be a 
clinician, such as a neurologist, involved in clinical practice or regularly evaluating MSA 
patients. SE-ADL can be administered by a health care professional with adequate experience 
with MSA and administration of semi-structured interviews. Any exceptions must be 
discussed and approved by Lundbeck and/or its designee. All clinician-reported outcomes will 
be administered electronically by using a site tablet. For each scale, the same rater should 
preferably rate the same patient throughout the study.
All PROs will be administered electronically by using a tablet. The patients will be trained on 
how to use the ePROs by site staff who have adequate experience with MSA patients and 
have received adequate training on good standards in providing guidance to patients on how 
to use the ePROs. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 79 of 131
Only site staff who have received adequate training on good standards in administering the 
COMPASS-S/SC, PGI-S and MSA Fall Diary, and how to use the FeetMe® and PAMSys, 
digital devices will be authorized to train the patients on completion of ePROs and the use of 
digital devices in the study. Documentation of training will be provided to site staff for 
archiving in the investigator trial master file (TMF).
New electronic COA and digital device trainers joining the study must be trained similarly. 
Rater training of electronic COA will be provided by MedAvante-Prophase.
Only raters who qualify on study-specific Rater Certification Programme will be authorized to 
administer and rate the COAs in the study. Documentation of training and certification will be 
provided to raters for archiving in the investigator TMF. No patient must be rated before the 
documentation has been archived.
New raters joining the study will be trained and certified by using the same certification 
process.
For each individual patient, the same certified rater should preferably rate the patient 
throughout the study. In case of unforeseen circumstances, certified back-up raters should be 
available throughout the study.
10.2.1.12 External COA Monitoring Oversight
Lundbeck reserves the right to use external quality oversight methods to ensure eDiary 
compliance and COA data quality (as well as ensure accurate administration of the COAs). 
For this study, the CRO will conduct the external data monitoring (to be agreed with the 
sponsor) which will include the following quality oversight methods:

Compliance check (that is, MSA Fall Diary)

Independent review of source documents

Clinical data analytics review
10.2.2
Imaging Assessments
10.2.2.1
Imaging Procedures
MRI at screening will be performed for eligibility and, in addition, the presence of MRI 
abnormalities supporting the diagnosis of MSA (putaminal atrophy, pontine atrophy, 
cerebellar and middle cerebellar peduncle atrophy, presence of putaminal hyperintense rim, 
putaminal signal hypointensity and/or hot cross bun sign) will also be recorded.
MRI scans will be performed for evaluation of biomarkers of disease progression and safety. 
Patients must visit designated imaging facilities for the MRI scans. The scans will be 
evaluated by a central reader, as pre-specified in the study-specific Imaging Charter. A 
study-specific Imaging Manual, detailing procedures for scan acquisition, will be issued to all 
participating imaging centres.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 80 of 131
The following assessments will be performed for evaluation of disease progression:

Volumetric MRI (vMRI) for quantification of atrophy measures in brain regionsofinterest
(ROIs) (for example, caudate nucleus, putamen, striatum, pons, brain stem, and 
cerebellum)
The following assessment will be performed, where available, for evaluation of disease 
progression in DBP:

Diffusion-tensor imaging (DTI) for quantification of diffusivity measures in brain ROIs 
(for example, caudate nucleus, putamen, globus pallidus, pons, cerebellar white matter, and 
middle cerebellar peduncle)

Arterial spin label (ASL) for quantification of cerebral blood flow (CBF) in selected brain 
regions (for example, putamen and cerebellum)
Additional MRI sequences will be performed for assessment of safety in DBP, including 
2D T2-weighted, 3D T2 FLAIR, diffusion-weighted imaging and gradient-recalled echo 
(GRE) sequence. The last will be used to assess the presence of cerebral microhaemorrhages.
10.2.3
Biomarker Assessments
MRI biomarkers are included as secondary and exploratory endpoints to investigate if the 
delay in clinical progression is supported by a delay in the underlying neuropathological
process (section 10.2.2).
The inclusion of blood and CSF biomarkers as exploratory endpoints will allow the 
understanding of any downstream biomarker effects of potential α-synuclein reduction and 
the establishment of a clear link between biomarker and clinical endpoints (section 10.4).
Blood Biomarkers:

NfL concentrations

plasma concentrations of “free” and “total” α-synuclein
CSF Biomarkers:

t-tau and NfL concentrations

concentrations of “free” and “total” α-synuclein

pathological species of α-synuclein
10.2.3.1
NfL and t-tau Analysis
The blood for the analysis of NfL and CSF for analysis of NfL and t-tau will be drawn in 
accordance with Panel 2 and Panel 3. CSF sampling will not be applicable for patients with 
contraindications of lumbar puncture, on-going skin infection at the lumbar puncture injection 
site or documented history of vertebral deformities, major lumbar back surgery, clinically 
significant back pain, clinically significant abnormal X-ray, and/or injury, in the opinion of 
the investigator that would preclude CSF collection. The blood and CSF sampling and 
handling procedures are described in the Laboratory Specification Manual.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 81 of 131
The analysis will be performed by vendors with a validated assay, under the responsibility of 
H. Lundbeck A/S.
10.3
Quality of Life Assessments
The following COA tools will be used for quality of life assessment:

EuroQol 5-Dimensions, 5 Levels (EQ-5D-5L)
10.3.1
EuroQol 5-Dimensions, 5 Levels (EQ-5D-5L)
The EQ-5D-5L17 is a patient-reported assessment designed to measure the patient’s wellbeing. 
It consists of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and 
depression/anxiety) and a visual analogue scale (VAS) of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems) and a single summary index (from 0 to 1) can be calculated. The VAS ranges from 
0 (worst imaginable health state) to 100 (best imaginable health state). The EQ˗5D-5L can be 
administered by a study nurse after a brief training. It takes approximately 5 minutes to 
complete the EQ-5D-5L.
10.4
Pharmacokinetic Assessments
Blood and CSF sampling for PK evaluation will target quantification of “free” (that is, not 
bound to α-synuclein) Lu AF82422 in plasma and CSF.
PK in plasma: At baseline, Weeks 12 and 36, multiple plasma PK samples are to be taken 
relative to IMP infusion: before infusion, immediately after the EOI, 1 and 2 hours after EOI.
At the other visits with PK sampling, PK samples will be sampled before IMP administration. 
The blood sampling and handling procedures are described in the Laboratory Specification 
Manual. PK assessments will be performed in blood plasma according to the schedule 
depicted in Panel 2 and Panel 3.
PK in CSF: CSF sampling will not be applicable for patients with contraindications of lumbar 
puncture, on-going skin infection at the lumbar puncture injection site or documented history 
of vertebral deformities, major lumbar back surgery, clinically significant back pain, clinically 
significant abnormal X-ray, and/or injury, in the opinion of the investigator that would 
preclude CSF collection. The blood sampling and handling procedures are described in the 
Laboratory Specification Manual. Pharmacokinetic assessments will be performed in CSF 
according to the schedule depicted in Panel 2.
The samples will be analyzed using a validated bioanalytical method by a bioanalytical 
laboratory under the responsibility of sponsor. Analysis method will be defined in a 
Bioanalytical Protocol and be reported in a Bioanalytical Report.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 82 of 131
10.5
Target Engagement Assessments
The following parameters will be assessed:

Blood sampling for α-synuclein; for quantification of “free” and “total” α-synuclein in 
plasma

CSF sampling for α-synuclein; for quantification of “free”, and “total” α-synuclein

CSF sampling for pathological species of α-synuclein; for example, aggregated and 
truncated. The blood and CSF samples for analysis of “free” and “total” α-synuclein as 
well as pathological species in CSF will be drawn as shown in Panel 2 and Panel 3. The 
blood sampling and handling procedures are described in the Laboratory Specification 
Manual.
For the site, all samples will be sent to ICON Central Labs and ICON Central Labs will 
manage the onward distribution to the Special Laboratories. The samples will be analyzed 
using a scientific validated bioanalytical method by a bioanalytical laboratory under the 
responsibility of sponsor. Analysis method and samples analysis will be reported in a separate 
report.
10.6
Safety Assessments
10.6.1
Adverse Events
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit when the 
patient signs the Informed Consent Form. Adverse events (including worsening of concurrent 
disorders, new disorders, and pregnancies) either observed by the investigator or reported 
spontaneously by the patient will be recorded, and the investigator will assess the seriousness 
and the intensity of each adverse event and its relationship to the IMP. Results from relevant 
tests and examinations, such as clinical safety laboratory tests, vital signs, MRI, C-SSRS, and 
ECGs, or their corresponding conditions will also be recorded as adverse events if considered 
by the investigator to be clinically significant.
See section 11 for further information on adverse events.
10.6.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 5.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 83 of 131
Panel 5
Clinical Safety Laboratory Tests
Haematology
Liverb
Urine
B-haemoglobin
B-erythrocyte count
B-total leucocyte count
B-neutrophilsa
B-eosinophilsa
B-basophilsa
B-lymphocytesa
B-monocytesa
B-thrombocyte count
B-haematocrit
P-prothrombin time
S-total tryptased
S-total bilirubin
S-conjugated bilirubin
S-alkaline phosphatase
S-alanine aminotransferase
S-aspartate aminotransferase
S-gamma-glutamyl transferase
U-protein (dipstick)
U-glucose (dipstick)
U-blood (dipstick)
U-leucocytes (dipstick)
U-nitrites (dipstick)
Urine culture
Electrolytesb
Kidneyb
Infection
S-sodium
S-potassium
S-calcium (total)
S-creatinine
S-urea nitrogen
S-C-reactive protein
Endocrine and Metabolicb
Lipidsb
Pregnancyc
S-albumin
B-HbA1c
S-creatine phosphokinase
S-low density lipoprotein
S-high density lipoprotein
S-triglycerides
S-cholesterol (total)
hCG tests
B = blood; hCG = human choriogonadotropin; P = plasma; S = serum; U = urine
a
Count and % of total leucocytes. If any abnormalities are noted in the complete blood count and/or 
differential counts, additional workup (ancillary tests) will be performed
b
Clinical chemistry
c
Only for women of childbearing potential, serum hCG test at screening and urine dipstick at later 
assessments
d
S-total tryptase only to be collected in relation to systemic hypersensitivity reactions (adverse events 
requiring additional data collection), see section 11.1.3
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2
and Panel 3. The blood sampling and handling procedures are described in the study-specific 
Laboratory Specification Manual.
The blood samples will be analyzed at the central laboratory.
The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results. Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up. Tests for clinically significant out-of-range values must be 
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP). A patient with 
a value that is out-of-range at an EoT or Withdrawal Visit and considered clinically 
significant must be followed in accordance with usual clinical practice.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 84 of 131
If the clinically significant out-of-range clinical safety laboratory test value has not 
normalized or stabilized or a diagnosis or a reasonable explanation has not been established 
by the DBP/OLE Safety Follow-up Visit, the investigator must decide whether further 
follow-up visits are required (this may include an additional medical examination and/or 
additional blood sampling). Any out-of-range values followed after the last protocol-specified 
contact with the patient will be documented in the patient’s medical records.
For patients that attend the DBP Safety Follow-up Visit before entering the OLE:
Clinically significant out-of-range clinical safety laboratory test values that have not 
normalized or stabilized or a diagnosis or a reasonable explanation has not been established 
by the DBP Safety Follow-up Visit should be followed-up on in the OLE by the investigator 
in accordance with the above.
General
Any out-of-range clinical safety laboratory test value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
The central laboratory will be notified by the sponsor when the biological samples may be 
destroyed.
10.6.3
Vital Signs
The investigator may appoint a designee to measure vital signs, provided this is permitted 
according to local regulations and provided the investigator has trained the designee how to 
measure vital signs. The investigator must take responsibility for reviewing the findings.
Pulse rate and blood pressure will be measured using a standard digital meter in either supine 
or sitting position immediately prior to start of IMP administration.
Blood pressure and pulse will be measured immediately prior to IMP administration and pa-
tients will be monitored immediately after IMP administration inclusive of saline flush
(±5 minutes) for immediate drug reactions for a minimum of 2 hours with vital signs taken at 
the end of the saline flush and then every 30 minutes (±5 minutes) from the end of the saline 
flush or until stable, whichever is later (applicable only through Visit 12E).
Beginning at Visit 13E, blood pressure and pulse will only be measured immediately prior to 
and immediately after IMP administration, inclusive of the saline flush (±5 minutes).
Any out-of-range vital sign considered clinically significant by the investigator must be rec-
orded as an adverse event on an Adverse Event Form as according to section 11.1.1.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 85 of 131
10.6.4
Height and Weight
The patient’s height will be measured at screening only.
The patient’s weight will be measured while wearing light clothing and no shoes.
10.6.5
Electrocardiograms
A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to 
the investigator or, upon agreement, to an external cardiology centre. The ECGs will be 
transferred digitally to a central ECG laboratory for evaluation. The investigator will be 
provided with the results and a cardiological interpretation of the ECG from the central ECG 
laboratory. Still, the investigator should examine the ECG according to his own judgement for 
any safety concerns.
The results from the central ECG laboratory will include the RR, PR, QRS, QT, and QTc
intervals.
The investigator has the final decision on the interpretation of the ECG results, except for 
determining exclusion criteria at screening (PR, QRS, and QT interval described in Exclusion
Criterion 22 in section 6.3).
Any abnormal ECG result or out-of-range ECG parameter value considered clinically 
significant by the investigator must be recorded as an adverse event on an Adverse Event 
Form.
10.6.6
Physical and Neurological Examinations
The investigator may appoint a designee to be primarily responsible for performing the 
physical examinations, provided this is permitted according to local regulations. The 
investigator must take responsibility for reviewing the findings. Whenever possible, the same 
individual should perform all physical examinations for the patient.
The physical examination (including height at the Screening Visit only) must, at a minimum, 
include an examination of appearance, extremities, skin, head, neck, eyes, ears, nose, throat, 
lungs, chest, heart, abdomen, and musculoskeletal system and must be performed by a 
physician or physician assistant. The examination will include recording of use of feeding 
tube and/or wheelchair (full-time user – no walking ability; occasional user – limited walking 
ability).
Genito-urinary system examinations are often not part of routine neurologic practice. For 
most patients, an external inspection of the genitals should be sufficient. A full gynaecological
examination should only be performed if warranted by symptoms or medical history. The 
renal regions will be examined as part of the abdominal examination.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 86 of 131
The neurological examination must be performed by a physician. The neurological 
examination comprises examination of mental status, cranial nerves, motor system, reflexes, 
sensory system, coordination, station and gait.
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
10.6.7
Columbia-Suicide Severity Rating Scale
The C-SSRS18 is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study. The C-SSRS has 
5 questions addressing suicidal ideation, 5 sub-questions assessing the intensity of ideation, 
and 4 questions addressing suicidal behaviour. For this study, the following versions of the 
scale are used: the “Baseline/ Screening” version (lifetime and 6 months assessment) and the 
“Since last visit” version (for all subsequent visits). It takes approximately 5 to 10 minutes to 
administer and rate the C-SSRS.
The C-SSRS must be administered in the local language.
The C-SSRS should only be administered by a rater who has adequate experience with 
clinical studies in CNS indications. The rater should be a clinician, such as a neurologist, 
geriatrician, psychiatrist, (neuro-) psychologist, or study nurse involved in clinical practice or 
regularly evaluating patients. For each individual patient, the same certified rater should 
preferably rate the patient throughout the study. In case of unforeseen circumstances, certified 
back-up raters should be available throughout the study. Any exceptions must be discussed 
and approved by Lundbeck and/or its designee.
Rater training and certification will be conducted by the MedAvante-Prophase as agreed with 
the sponsor. Raters will complete their designated training curriculum based on their initial 
qualification status and assigned role. Only raters who qualify on study-specific Rater 
Certification Programme will be authorized to administer the C-SSRS in the study. C-SSRS 
rater certification will be provided by Kelly Posner online training. Documentation of training 
and certification will be provided to raters for archiving in the investigator TMF. No patient 
must be rated before the documentation has been archived. New raters joining the study must 
be trained and certified by using the same certification process. Detailed instructions on how 
to administer the C-SSRS will be provided to the site in a C-SSRS Guideline.
Any finding on the C-SSRS that is considered clinically significant by the investigator should 
be reported as an adverse event.
10.6.8
Anti-drug Antibody Assessments
The plasma samples for ADA quantification in plasma will be drawn in accordance with 
Panel 2 and Panel 3.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 87 of 131
The blood sampling and handling procedures are described in the Laboratory Specification 
Manual. In total, 8.0 mL are needed for all ADA assays in plasma.
Plasma samples will be analyzed to determine presence or absence of ADA. Samples 
confirmed positive for ADA will be evaluated for clearing ADAs by evaluation of exposure 
and TE.
The plasma samples will be analyzed for anti-Lu AF82422 antibodies using a bioanalytical 
method validated for screening, confirmation and titration.
The samples will be analyzed using a validated bioanalytical method by a bioanalytical 
laboratory under the responsibility of sponsor. Analysis method and samples analysis will be 
reported in a separate report.
10.6.9
Other Safety Assessments
All MRI scans during the DBP will be analyzed for safety assessments, especially evaluation 
of clinically important findings for example, microhaemorrhages, infarcts and 
meningoencephalitis. Details on MRI findings are specified in the Imaging Charter. Principal 
investigator provides assessment of MRI result.
Clinically significant MRI changes to be reported as adverse event.
10.7
Other Assessments
The following other assessments are performed:

Exit Interviews (in all patients in the US; note that the caregivers participate in this 
assessment as in UMSARS and OGI-S scores)

Study Experience Interviews (in a subset of patients in the US; note that the caregivers 
participate in this assessment)
10.7.1
Exit Interviews
At US sites, semi-structured, qualitative interviews will be performed in the Exit Interview 
subset (to be detailed in a separate interview protocol) on consenting subsets of patients and 
caregivers (hereafter referred to as “Exit Interview subset”). Patients and caregivers from the 
Exit Interview subset will participate in an Exit interview within 3 weeks after the EoTDBP
Visit or within 3 weeks after the DBP Withdrawal Visit. For patients withdrawing from the 
study, the Exit interview will only be performed if they have been in the DBP for at least 
48 weeks.
Interviews will be conducted over the phone by trained third-party interviewers following 
dedicated semi-structured interview guides. Each individual interview will last about 
45 minutes with the patients and about 60 minutes with the caregivers.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 88 of 131
Interviews will be audio-recorded and then transcribed verbatim. Transcripts will be 
de-identified and considered source documents.
The patients and caregivers may also withdraw from the interviews without having to 
withdraw from the main study.
Details on recording and reporting of adverse events/SAEs from the Exit interviews are 
described in the separate interview protocol.
10.7.2
Study Experience Interviews
At US sites, patients and caregivers may be contacted to participate in a semi-structured, 
qualitative interview (to be detailed in a separate interview protocol) with consenting subsets 
of patients and caregivers (hereafter referred to as “Study Experience Interview subset”). The 
interview will focus on the overall study experience, including topics such as logistical 
considerations, satisfaction with participation in the study, and suggestions for improvement
for future studies. Interviews will be conducted within 6 weeks after completion of the Exit 
interview.
Interviews will be conducted by web conferencing platform (for example, Microsoft Teams) 
or by telephone, by trained third-party interviewers following dedicated semi-structured 
interview guides. Each individual interview will last about 30 minutes with the patients and 
about 30 minutes with the caregivers.
Interviews will be audio-recorded and then transcribed verbatim. Transcripts will be 
de-identified and considered source documents.
The patients and caregivers may also withdraw from the interviews without having to 
withdraw from the main study.
Details on recording and reporting of adverse events/SAEs from the Study Experience 
interviews are described in the separate interview protocol.
10.8
Biobanking
10.8.1
General Considerations
Although the potential future exploratory biomarker analyses will help to increase our 
understanding of the aetiology of disease and the molecular basis of the drug response, the 
efforts described in this protocol are strictly research based. Therefore, as the complex 
interactions between genes and disease are currently not characterized to a level that translates 
to a meaningful clinical advantage, individual results from the exploratory biomarker analyses 
will not be given to the patients. For the same reasons, individual results will not be added to 
the patients’ medical records.
The patients will have no direct benefit from the exploratory biomarker analyses.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 89 of 131
The blood samples for gene expression profiling (RNA), metabolomics/proteomics (plasma), 
pharmacogenetics (DNA) (optional), ADA, and CSF sampling analysis will be single-coded 
using the patient’s screening number. The blood samples for genetic biomarker analysis will 
be single-coded using the patient’s screening number.
10.8.2
Blood Sampling for Gene Expression Profiling (RNA)
Blood samples (approximately 5.0 mL per sample) for gene expression profiling (RNA) will 
be collected in PAXgene RNA tubes in accordance with Panel 2.
The blood sampling and handling procedures are described in the Laboratory Manual. The 
maximum volume of blood to be collected during the study for this purpose will be 
approximately 15 mL.
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Azenta Life 
Sciences, Indianapolis, IN, US) for storage.
The samples and any derived material will be destroyed ≤10 years after the end of the study.
10.8.3
Blood Sampling for Metabolomics and/or Proteomics
Blood sample for plasma separation and metabolomics/proteomics biomarkers analysis will 
be collected in one 10 mL K2 EDTA (ethylenediaminetetraacetic acid) tube in accordance 
with Panel 2. The blood sampling and handling procedures are described in the Laboratory
Manual.
The maximum volume of blood to be collected during the study for this purpose will be 
approximately 30 mL. The plasma samples for metabolomics/proteomics biomarkers will be 
shipped to Lundbeck Biobank (at Azenta Life Sciences, Indianapolis, IN, US) for storage.
The samples and any derived material will be destroyed ≤10 years after the end of the study
10.8.4
Blood Sampling for Pharmacogenetics
Sampling for pharmacogenetics is optional and a separate signed informed consent must be in 
place to cover this analysis.
Blood samples (approximately 6 mL) for subsequent DNA extraction will be collected in 
K3 EDTA tube in accordance with Panel 2. The blood sampling and handling procedures are 
described in the Laboratory Manual.
The blood sample will be shipped to ICON central laboratory where DNA will be extracted 
and retained. DNA aliquots will be shipped to Lundbeck Biobank (at Azenta Life Sciences, 
Indianapolis, IN, US) for storage.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 90 of 131
The genetic variants to be analyzed may include single nucleotide polymorphism (SNPs) and 
copy number variations (CNVs). The analytical methods may be polymerase chain reaction 
(PCR), qPCR (quantitative PCR), sequencing, or whole genome scans on microarrays.
The samples and any derived material will be destroyed ≤15 years after the end of the study.
10.8.5
Blood Sampling for Anti-drug Antibody
Additional to the ADA safety assessments described in section 10.6.8, ADA samples taken 
according to Panel 2 and Panel 3 will be shipped to Lundbeck Biobank (at Azenta Life 
Sciences, Indianapolis, IN, USA) for storage.
10.8.6
CSF Sampling for Proteomics and Genomics
CSF samples (approximately 10 mL) for subsequent experiments will be collected in a 
specified sampling tube.
Different proteins, aggregates or post-translational modifications may be analyzed through a 
variety of methods that could include chemoluminescence or electrochemoluminescence 
based approaches, single molecule measurements, liquid chromatography, or mass 
spectrometry, among others. Also, coding and noncoding RNA species (such as miRNAs, 
circRNAs, etc.) may also be evaluated.
The samples and any derived material will be destroyed ≤10 years after the end of the study.
10.9
Order of Assessments
The screening assessments can be performed in any order for the best evaluation of eligibility, 
at the discretion of the investigator.
Beginning at Visit 3 and onward, the assessments should be administered in the following 
order:

PROs (PGI-S, COMPASS-S/SC, EQ-5D-5L)/Observer-reported outcome (OGI-S)

Clinician-reported outcomes (UMSARS, CGI-S, SE-ADL)

Safety assessments including ECG and safety labs

Other assessments such as pre-dose PK assessments, blood biomarkers and CSF collection

IMP administration. At visits with multiple PK assessments (Baseline, Visit 9 and 
Visit 15), PK blood sampling will take place after IMP administration as well
10.10 Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 377 mL during the 
DBP, additionally, approximately 136 mL may be sampled for patients completing OLE, for 
patients undergoing the Withdrawal Visit 20 mL will be sampled. Up to 22 to 24 mL total of 
CSF will be collected from lumbar puncture procedures.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 91 of 131
Additional blood samples may be required if the original blood samples are not viable or if 
re-testing is required.
The biobank blood samples and any derived material for potential future exploratory gene 
expression profiling or metabolic or proteomic biomarker analyses will be destroyed 
≤10 years after the end of the study (see definition in volume of blood section 9.8).
The biobank blood samples and any derived material for potential future exploratory 
pharmacogenetic analyses will be destroyed ≤15 years after the end of the study (see 
definition in section 9.8).
To extend the retention period, the biobank blood samples and any derived material for 
potential future exploratory pharmacogenetic/gene expression analysis will be made 
anonymous by destroying the code key stored at specify location. When a blood sample or 
any derived material has been made anonymous, it cannot be traced back to the patient.
10.11 Treatment Compliance
IMP will be administered by a qualified healthcare professional. The exact doses and times of 
administration will be recorded in the eCRF.
11 Adverse Events
11.1
Definitions
11.1.1
Adverse Event Definitions19
Adverse event – is any untoward medical occurrence in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, 
vital signs, ECG, C-SSRS), symptom, or disease temporally associated with the use of a 
medicinal product, regardless of whether it is considered related to the medicinal product.
Worsening of concomitant illness and medical history
Medical conditions, which existed prior to the time of informed consent into the clinical study 
are part of the patient’s medical history and are not considered an adverse event. Unchanged, 
chronic, non-worsening or sign/symptoms considered as part of the natural progression of the 
disease or pre-existing conditions from the time of informed consent are not adverse events 
and should not be reported as such. A clinically significant worsening of a pre-existing or 
chronic condition (for example, worsening of asthma) must be reported as an adverse event.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 92 of 131
Worsening of MSA
Sign/symptoms/diagnosis related to known natural progression of MSA or re-emergence or 
worsening of MSA should not be reported as adverse events, except if fulling the seriousness 
criteria listed below.
Sign/symptoms/diagnosis (non-serious and serious adverse events) not considered part of the 
natural progression of MSA according to the investigator judgement should be reported as 
adverse events.
Fall
Falls fulfilling one or more seriousness criteria should be reported as a SAE. Falls that do not 
fulfil one or more seriousness criteria should not be reported as an adverse event. Clinically 
significant consequences (for example, cerebral trauma, fractures) of falls should be reported 
as a separate SAE.
An adverse event includes any changes in any safety assessment (including C-SSRS, 
out-of-range values from laboratory test results, MRI, vital signs and ECGs) which are 
clinically significant, that is, an abnormality that suggests a disease and/or organ toxicity and 
is of a severity that requires active management. Active management includes active 
treatment, further investigations or more frequent follow-up due to the abnormality.
It is Lundbeck policy to collect and record all adverse events, including pre-treatment signs 
and symptoms, that is, those that start after the patient has signed the Informed Consent Form
and prior to the first dose of IMP.
Serious adverse event – is any adverse event that:

Results in death

Is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not adverse 
events. Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 93 of 131
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.
Suspected unexpected serious adverse reaction– is any adverse event that is assessed as 
serious, unexpected (its nature or intensity is not consistent with the current version of the 
Investigator’s Brochure7), and related to a medicinal product by either the investigator or 
Lundbeck.
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
11.1.2
Adverse Event Assessment Definitions
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form:

Mild – the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the patient’s normal activities.

Moderate – the adverse event is sufficiently uncomfortable to produce some impairment of 
the patient’s normal activities.

Severe – the adverse event is incapacitating, preventing the patient from participating in the 
patient’s normal activities.
Assessment of Causal Relationship
The investigator must assess the causal relationship between the adverse event and the IMP 
using the following definitions, and record it on the Adverse Event Form and the Serious 
Adverse Event Form (if applicable):

Probable – the adverse event has a strong temporal relationship to the IMP or recurs on 
re-challenge, and another aetiology is unlikely or significantly less likely.

Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology is equally or less likely.

Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent disorder or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event).
An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible.
For pre-treatment adverse events, a causality assessment is not relevant.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 94 of 131
Assessment of Outcome
The investigator must assess the outcome of the adverse event using the following definitions, 
and record it on the Adverse Event Form and the Serious Adverse Event Form (if applicable):

Recovered – the patient has recovered completely, and no symptoms remain.

Recovering – the patient’s condition is improving, but symptoms still remain.

Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).

Not recovered – the patient’s condition has not improved, and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic).

Death.
11.1.3
Study-specific Adverse Event Definitions – Adverse Events Requiring 
Additional Data Collection
Adverse events (any sign or symptom) which are experienced by the patient during and/or 
after the infusion of the IMP and which are likely to be immunologically mediated should be 
considered a hypersensitivity reaction and additional data collection is required as adverse 
events requiring additional data collection. Anaphylaxis represents a subgroup of 
hypersensitivity reactions. If a systemic hypersensitivity reaction occurs, a tryptase blood 
sample will be drawn from the patient after the event, see below.
For key clinical features of hypersensitivity reactions including anaphylaxis and 
immune-complex related reactions, please refer to Appendix III.
For adverse events requiring additional data collection, a specific hypersensitivity form20 must 
be completed in the eCRF in addition to the Adverse Event Form (see Appendix V for more 
details about the hypersensitivity form). For systemic hypersensitivity reactions adverse 
events requiring additional data collections (as defined in Appendix III), additional blood 
samples must be collected at the site and results recorded in the eCRF (Hypersensitivity 
Form):

Serum total tryptase collected as per central laboratory procedures: optimally to be 
collected between 30 minutes to 2 hours after symptom onset. At least 24 hours after total 
resolution of sign and symptoms and in due time (expected 10 days of return of test 
results) prior to next IMP dosing the investigator must call the patient in for an 
unscheduled visit to collect a serum total tryptase sample to evaluate baseline level making 
sure to receive the results in time for the next IMP dosing. The investigator must assess the 
result (see below) prior to next IMP dosing.
A clinically significant increase of serum total tryptase at the time of systemic 
hypersensitivity reaction of >2 ng/mL+1.2 × patient’s baseline serum total tryptase supports 
the diagnosis of anaphylaxis.21 Systemic hypersensitivity reaction algorithm described in 
Appendix V.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 95 of 131
11.1.4
Management of Reactions to Study Drug
There is no specific antidote to an infusion of Lu AF82422.
A medical emergency should be treated appropriately by the investigator using proper 
standard of care, according to their typical clinical practice and local guidelines for that 
emergency condition.
Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgement should be used to provide the appropriate response including the 
consideration of pausing or discontinuation of the IMP. Any events believed to be allergic 
reactions should be discussed with the medical monitor.
11.2
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form, as well as on a Pregnancy Reporting Form
(paper), even if no adverse event associated with the pregnancy has occurred. Pregnancies 
must be reported to Lundbeck using the same expedited reporting timelines as those for 
SAEs.
An uncomplicated pregnancy should not be reported as an SAE; hospitalization for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with an SAE, 
the appropriate serious criterion must be indicated on the Serious Adverse Event Form. 
Examples of pregnancies to be reported as SAEs (medically important) are spontaneous 
abortions, stillbirths, and malformations.
The investigator must follow-up on the outcome of the pregnancy and report it on a 
Pregnancy Outcome Form (paper). The follow-up must include information on the neonate at 
least up until the age of 1 month.
If the partner of a man participating in the study becomes pregnant, the pregnancy should be 
reported on the Pregnancy Reporting Form (paper) and the outcome of the pregnancy should 
be followed and reported (Pregnancy Outcome Form) if the partner agrees. The partner must 
sign a pregnant partner Informed Consent Form to allow the investigator to collect 
information to report to Lundbeck.
11.3
Recording Adverse Events
Adverse events (including pre-treatment adverse events after signing Informed Consent Form) 
must be recorded on an Adverse Event Form. In addition, if the adverse event fulfils the 
definition of an adverse event requiring additional data collection, a specific Hypersensitivity 
Form must be filled out (for further details on the content of the form, see Appendix IV). The 
investigator must provide information on the adverse event, preferably with a diagnosis, or at 
least with signs and symptoms; start and stop dates (and start and stop time if the adverse 
event lasts less than 24 hours or occurs on the day of IMP administration); intensity; causal 
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 96 of 131
relationship to the IMP; action taken; and outcome. If the adverse event is not related to the 
IMP, an alternative aetiology must be recorded, if available. If the adverse event is an 
overdose, underdose, the nature of the overdose/underdose must be stated (for example, 
medication error, accidental overdose). Other medication errors for example, wrong technique 
of infusion, wrong infusion rate etc. should likewise be recorded. If the intensity changes 
during the course of the adverse event, this must be recorded on the Adverse Event Intensity 
Log.
If the adverse event is serious, this must be indicated on the Adverse Event Form. 
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to Lundbeck immediately (within 24 hours) after becoming aware of it (see section 11.4).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
11.4
Reporting Serious Adverse Events
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after 
becoming aware of them by completing a Serious Adverse Event Form in the eCRF.
The initial Serious Adverse Event Form must contain as much information as possible and, if 
more information about the patient’s condition becomes available, the Serious Adverse Event 
Form must be updated with the additional information.
If the investigator cannot report the SAE in eCRF (Rave®), then he or she must complete and 
sign the Serious Adverse Event Fallback Form and send it to:
Fax:
+45 36 30 99 67
email: ICSRquery@lundbeck.com
If sent by email, the investigator must ensure that the Serious Adverse Event Fallback Form is 
sent password protected and that the password is sent in a separate email.
If the SAE, reported on the Serious Adverse Event Fallback Form, concerns an adverse event
requiring additional data collection, the investigator must complete and sign the 
Hypersensitivity Form and send it together with the Serious Adverse Event Fallback Form.
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
of SAEs to the EC or IRB and to act accordingly.
11.5
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 97 of 131
The investigator must follow-up on non-SAEs until resolution or completion of a Safety 
Follow-up Visit, whichever comes first. At the Safety Follow-up Visit, information on new 
adverse events (non-serious and serious adverse events), if any, and stop dates for previously 
reported adverse events must be recorded.
The investigator must follow-up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator after completion of the 
Safety Follow-up Visit must be handled in the same manner as SAEs that occur during the 
study. These SAEs will be recorded in the Lundbeck safety database.
Patients with a clinically significant out-of-range clinical safety laboratory test value at an
EoT or any Withdrawal Visit must be followed in accordance with usual clinical practice. If 
the clinically significant out-of-range clinical safety laboratory test value has not normalized
or stabilized or a diagnosis or a reasonable explanation has not been established by the Safety 
Follow-up Visit, the investigator must decide whether further follow-up visits are required 
(this may include an additional medical examination and/or additional blood sampling). If 
further follow-up visits are made, these must be documented in the patient’s medical records 
and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 6.4) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) should be considered. A 
gastroenterology or hepatology consultation should also be considered.
For patients who attend the DBP Safety Follow-up Visit before entering the OLE:
The investigator must continue to follow-up on non-SAEs until resolution or completion of 
the SFU-E Visit, whichever comes first. At the SFU-E Visit, information on new adverse
events (non-serious and serious adverse events), if any, and stop dates for previously reported 
adverse events must be recorded.
11.6
Study Monitoring Committee(s)
11.6.1
Independent Data Monitoring Committee
The iDMC is an independent, external committee composed of members whose expertise 
covers relevant specialities. In the DBP, the iDMC will monitor SAEs on an on-going basis in 
addition to cumulative safety data including adverse events at pre-defined time points (every
3 months ±1 month) as well as adhoc. This is in order to protect the safety of the patients and 
to evaluate the safety risk. The iDMC will have access to unblinded data, and will provide 
recommendations on study continuation, modification or termination. The iDMC will be 
informed to what extent the data and analyses provided to them have been quality controlled. 
Members of the DMC will not be involved in other study˗related tasks.
The iDMC procedures are described in the DMC Charter.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 98 of 131
12 Data Handling and Record Keeping
12.1
Data Collection
12.1.1
Electronic Case Report Forms
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 12.1.2.
This data collection tool is a validated electronic data capture (EDC) system that contains a 
system generated audit trail. Data required according to this protocol are recorded by web 
based EDC software system (Rave®). The investigator shall ensure that all data from 
participant visits are promptly entered into the eCRFs (ideally during the visit or as soon as 
possible <3 days thereafter), in accordance with the specific instructions given. The 
investigator must sign each eCRF to verify the integrity of the data recorded. All internal 
designated CRO and external investigational site personnel seeking access to the eCRF are 
supported by Lundbeck Rave System Administration and Medidata Helpdesk. Access to the 
system will only be granted after appropriate and documented training.
As a central laboratory has been selected to conduct any or all tests, it is essential that all 
samples be analyzed at that laboratory.
The investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. All 
information in the eCRF must be traceable to the source documents in the participant’s file.
The investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, independent ethics committee (IEC)/IRB review and 
regulatory inspection.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
12.1.1.1
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed (see 
section 11.4).
12.1.2
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The following electronic data will be transferred by the vendor and kept in a secure 
designated storage area outside the eCRF:

IMP quantification data (including CSF)
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 99 of 131

Biomarker analysis data (including CSF)

ECG data

Clinical Safety Laboratory data

PAMSys

Biobanking data: RNA, Metabolomics/Proteomics, DNA (optional)

FeetMe®

MRI data

ADAs

Exit Interviews/Study Experience Interviews will be audio-recorded and then transcribed 
verbatim. As audio-recordings will not be retained, transcripts will be de-identified and 
considered source documents.
The following electronic data will be captured within the Medidata and MedAvante-Prophase 
(covering electronic COA [eCOA] for UMSARS) systems as a separate application.

eDiary

eCOA
The following electronic data will be captured in Medidata and processed by Mayo Clinic

COMPASS-S and COMPASS-SC
12.2
Retention of Study Documents at the Site
12.2.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed. After the study has been 
completed, all user access to the eCRF will be revoked. Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage 
of these data at the site is the responsibility of the investigator. When confirmation of receipt 
of the data has been received from all sites, all user access to the eCRF will be revoked. If, for 
some reason, the data are not readable for the full retention period (25 years or in accordance 
with national requirements, whichever is longer), the investigator may request that the data be 
re-sent.
12.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer. Lundbeck will remind the investigator in writing 
of this obligation when the Clinical Study Report Synopsis is distributed to the site.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 100 of 131
If off-site storage is used, a study-specific binder will remain at the site after the other 
study-specific documents have been shipped for off-site storage. This binder is considered 
part of the investigator TMF and must be kept in a secure place by the site for the required 
period of time. The binder must contain, at a minimum, the following documents: a copy of 
the Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations.
13 Monitoring Procedures
Prior to allowing patients to participate in the study, the investigator must sign a source data 
agreement that identifies the source documents (original documents, data, and records) at the 
site. The document will also list which data may be recorded directly on the eCRFs.
If the investigator does not have a patient’s medical records, the investigator must attempt to 
obtain copies or a written summary of relevant medical records from the doctor who had 
treated the patient earlier and include the pertinent documentation in the patient’s medical 
records at the site. The investigator must obtain medical records documenting the patient’s 
lifetime episodes and general medical history for the 3 months prior to the study.
During the study, there will be both blinded and unblinded monitoring visits conducted by 
CRAs to ensure that the protocol is being adhered to and that all issues are being recorded, 
and to perform source data verification. The blinded monitoring visit will focus on the 
procedures involving direct patient care. The unblinded monitoring visit will focus on IMP 
accountability and maintaining the blind. The visit intervals will depend on the outcome of 
the remote monitoring of the eCRFs, the site’s recruitment rate, and the compliance of the site 
to the protocol and Good Clinical Practice. In addition, the CRA will be available for 
discussions by telephone.
Source data verification requires that the CRA be given direct access to all the source 
documents. Direct access includes permission to examine and verify any records that are 
important for the evaluation of the study.
It must be possible to verify all other data in the eCRFs against source documents in the 
patient’s medical records, or in the location stated in the source data agreement.
COVID-19 mitigation strategy for CRAs will be captured in a living, constantly updated 
document “COVID-19 Mitigation Plan” describing the respective contingency measures.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 101 of 131
14 Audits and Inspections
Authorized personnel from Medical, Regulatory and Clinical Quality Assurance, 
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the study 
at any time to assess compliance with the protocol and the principles of GMP and all other 
relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records. The investigator must notify Lundbeck and 
designated CRO, without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records. No personal identification apart from the screening or randomization 
numbers will appear on these copies.
Patient data will not be disclosed to unauthorized third parties, and patient confidentiality will 
be respected at all times.
15 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, 
and document the implications of the deviation.
16 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time. The reasons for such action may include, but are not limited to:

Safety concerns

Proven lack of efficacy of the IMP in other studies
If the study is terminated or suspended, the investigator must promptly inform the patients 
and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or sponsor 
must promptly inform the EC or IRB and provide a detailed written explanation. The 
pertinent regulatory authorities must be informed in accordance with national regulations.
If the risk/benefit evaluation changes after the study is terminated, the new evaluation must be 
provided to the EC or IRB if it will have an impact on the planned follow-up of the patients 
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 103 of 131
17.2
Responsibilities
The responsibility for performing the below described statistical analysis will be at Lundbeck. 
All analyses will be based on data received from ICON.
17.3
Analysis Sets
The patients and data will be classified into the analysis sets according to these definitions at a 
Classification Meeting held after the study database has been released, but before the blind 
has been broken (except for the PK subset which will be classified after unblinding).

all-patients-randomized set (APRS) – all randomized patients

all-patients-treated set (APTS) – all patients in the APRS who received at least one dose of 
double-blind IMP

all-patients-treated-follow-up set (APTS-FU) – all patients in the APTS who complete the 
DBP and who has data collected up to and at the Safety Follow-up DBP Visit

full-analysis set (FAS) – all patients in the APTS who had a valid baseline assessment and 
at least one valid post-baseline assessment of the UMSARS Part I and Part II, prior to, or 
at withdrawal from treatment in the DBP

PK subset (PKS) – all patients in the APTS with quantifiable plasma or CSF concentration 
of Lu AF82422

sensor-based subset (SBS) – all patients in the APTS who consented to wear at least one of 
the included sensor-based devices and who had a valid baseline assessment and at least 
one valid post-baseline assessment

exit interview subset (EIS) – all patients in the FAS having a complete Exit interview with 
the patient and/or the caregiver

study experience interview subset (SEIS) – all patients in the FAS having a complete Study 
Experience interview with the patient and/or the caregiver

open-label treatment extension set (OLES) – all patients in the FAS who consented to par-
ticipate in the OLE and who had at least one dose of open-label IMP for the OLE
The efficacy analyses will be based on the FAS and the OLES, and the safety analyses will be 
based on the APTS, APTS-FU, and the OLES unless otherwise specified. Listings will be 
based on the APRS.
17.4
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables 
and counts and, if relevant, percentages will be presented for categorical variables.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 104 of 131
17.5
Patient Disposition
Patient disposition will be summarized by period and treatment group and include the number 
of patients in the APTS who completed or withdrew from treatment, as well as the number of 
patients in each analysis set (APRS, APTS, FAS, PKS, SBS, EIS, SEIS, and OLES).
The number of patients who completed or withdrew from the study will also be summarized.
The number of patients who withdrew from treatment will be summarized by period and 
treatment group and primary reason for withdrawal as well as by treatment group and all 
reasons for withdrawal. A Kaplan-Meier plot will be presented for time-to-withdrawal for all 
reasons per treatment group, if appropriate.
17.6
Demographics and Baseline Characteristics
Demographics (sex, age, race, and region), baseline characteristics (weight, body mass index 
[BMI], and possible or probable MSA-P or MSA-C), baseline efficacy variables, and other 
disease characteristics will be summarized by treatment group for the DBP.
17.7
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code and generic drug name by period and treatment group.
17.8
Exposure and Compliance
Exposure and compliance will be calculated per patient and summarized by period and 
treatment group.
17.9
Efficacy Analyses
17.9.1
General Efficacy Analysis Methodology
Unless otherwise specified, all the efficacy analyses for the DBP will be based on the FAS. 
All endpoints will be presented with descriptive statistics and the one-sided 95% confidence 
intervals for both absolute values and change from baseline. Histograms will be explored and 
presented for the UMSARS scores observed cases; otherwise only in case of compromising 
findings for the secondary endpoints.
Since the primary, key secondary and selected secondary analyses for the UMSARS scores 
will be performed in a Bayesian framework, the success threshold for the Bayesian posterior 
probability of superiority relative to placebo will be calibrated through simulations to 
correspond to a significance level of 5% evaluated one-sided. For the frequentist analyses, the 
significance level will be 5%, which will be applied one-sided.
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
$WHVWLQJVWUDWHJ\ZLOOEHDSSOLHGLQFOXGLQJWKHSULPDU\DQDO\VLVRQ806$5676DQGWKHNH\
VHFRQGDU\DQDO\VLVRQP806$56WRSURWHFWWKHW\SH,HUURUIRUWKHVHDQDO\VHV)XUWKHU
GHWDLOVLQWKHVHFWLRQ7HVWLQJ6WUDWHJ\
(IILFDF\DQDO\VHVIRUWKH2/(ZLOOEHH[SORUDWRU\EDVHGRQWKH2/(6$OOSDWLHQWVLQWKH2/(
ZLOOUHFHLYHDFWLYHWUHDWPHQW+RZHYHUSDWLHQWVUHFHLYLQJSODFHERLQWKH'%3DQGKHQFH
VZLWFKLQJWUHDWPHQWZLOOEHGHILQHGDQGKDQGOHGDVDVHSDUDWHJURXS
17.9.2
Primary Analysis of the Primary Endpoint(s)
7KHSULPDU\HIILFDF\DQDO\VLVRI806$5676IROORZLQJXSWR ZHHNV RIWUHDWPHQWLQWKH
'%3ZLOOEHEDVHGRQD%D\HVLDQUHSHDWHGPHDVXUHVPRGHORIWKHFKDQJHIURPEDVHOLQH
WKURXJKXSWR ZHHNV7KXVDOVRGHILQHGDVWKHHVWLPDWRUXVHGIRUWKHSULPDU\HVWLPDQG
7KHUHSHDWHGPHDVXUHVPRGHOZLOOEHEDVHGRQREVHUYHGFDVHVRQO\WKDWLVQRLPSXWDWLRQ
DQGLQFRUSRUDWHVWKHIROORZLQJIHDWXUHV

)L[HGHIIHFWVIRUFKDQJHLQ806$5676SURJUHVVLRQSHUYLVLWDQG
 ZHHNV

3DUWLFLSDQWOHYHOUDQGRPHIIHFWVIRUWKHUDWHRI806$56SURJUHVVLRQDFURVVYLVLWV

)L[HGPXOWLSOLFDWLYHWUHDWPHQWHIIHFWșIRULQFUHDVHRUGHFUHDVHLQWKHRYHUDOOUDWHRI
806$56SURJUHVVLRQRI /X $) UHODWLYHWRSODFHERFRPPRQDFURVVDOOYLVLWV,Q
SDUWLFXODULIșWKHDFWLYHWUHDWPHQWVORZVWKHUDWHRISURJUHVVLRQRI806$56UHODWLYHWR
SODFHER,Iș!WKHDFWLYHWUHDWPHQWLQFUHDVHVWKHUDWHRISURJUHVVLRQRI806$56UHODWLYH
WRSODFHER ,Iș  WKHUDWHRISURJUHVVLRQRI806$56LVWKHVDPHIRUERWKDFWLYH
WUHDWPHQWDQGSODFHER

)L[HGPXOWLSOLFDWLYHFRYDULDWHHIIHFWVLQWKHLQFUHDVHRUGHFUHDVHLQWKHRYHUDOOUDWHRI
SURJUHVVLRQRI806$56IRU

DQGUHJLRQ86DQG-DSDQFRPPRQDFURVVDOOYLVLWV
 3ULRUGLVWULEXWLRQIRUPRGHOSDUDPHWHUVVHOHFWHGLQDFRQVHUYDWLYHDQGQRQLQIRUPDWLYH
PDQQHUXVLQJUHODWLYHO\ODUJHRXWFRPHVSDFHV
7KH%D\HVLDQSRVWHULRUGLVWULEXWLRQVRIDOOPRGHOSDUDPHWHUVDUHFDOFXODWHGXVLQJ0DUNRY
FKDLQ0RQWH&DUOR0&0&7KHDOJRULWKPDOORZVWKHJHQHUDWLRQRIDWOHDVW0  
GUDZVIURPWKHMRLQWSRVWHULRUGLVWULEXWLRQIRUDOOPRGHOSDUDPHWHUV,QSDUWLFXODUVXPPDULHV
RIWKH%D\HVLDQSRVWHULRUGLVWULEXWLRQIRUWKHWUHDWPHQWHIIHFWFRPSDUHGWRSODFHER, 휃ZLOOEH
SURYLGHGLQFOXGLQJWKHPHDQPHGLDQDQGFUHGLEOHLQWHUYDOVWKHSUREDELOLW\WKDW
/X $) LVVXSHULRUWRSODFHER Pr 휃< 1ZKLFKFRQVWLWXWHVWKHSULPDU\DQDO\VLVRIWKH
VWXG\$GGLWLRQDOO\ WKHSUREDELOLW\WKHWUHDWPHQWVORZVWKHUDWHRISURJUHVVLRQE\DWOHDVW
Pr 휃< .9; DQGWKHSUREDELOLW\WKHWUHDWPHQWVORZVWKHUDWHRISURJUHVVLRQE\DWOHDVW
Pr 휃< .8ZLOOEHSURYLGHG
)LQDOO\VXPPDULHVRIWKH%D\HVLDQSRVWHULRUGLVWULEXWLRQIRUWKHUHPDLQLQJPRGHOSDUDPHWHUV
ZLOOEHSURYLGHGLQFOXGLQJWKHPHDQPHGLDQDQGFUHGLEOHLQWHUYDOV
CCI
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 106 of 131
17.9.3
Sensitivity Analyses of the Primary Endpoint(s)
Sensitivity analyses to the primary analysis will be performed evaluating, in particular, the 
model assumptions (effect proportionality, etc.), performance (sensitivity to priors, potential 
bias, etc.) and the impact of missing data; with special focus of events of death and drop-outs 
with no follow-up data available. For these events, different imputation strategies will be 
applied and evaluated in a parametric setting.
In addition, a non-parametric worst-rank analysis will be performed to account for 
informatively missing data by ranking patients based jointly on their last available UMSARS 
score and mortality.
Further details on sensitivity analyses are in the study SAP.
17.9.4
Testing Strategy
To protect the type I error for the primary analysis, that is, analysis of UMSARS TS and the 
key secondary analysis, that is, analysis of mUMSARS, both using the Bayesian progression 
model, a testing strategy will be applied. Firstly, both endpoints will be evaluated individually 
by applying the pre-defined threshold to the posterior probability for Lu AF82422 being 
superior to placebo, where the thresholds have been calibrated to be equivalent to the targeted 
5% significance level evaluated one-sided. Following, the Fixed-Sequence Method will be 
applied evaluating the two prioritized analyses in a hierarchical manner.
Step 1: UMSARS TS evaluated using the derived posterior probability (test equivalent to a 
one-sided 5% level). If significant,
Step 2: mUMSARS evaluated using the derived posterior probability (test equivalent to a 
one-sided 5% level).
The applied success thresholds for the posterior probabilities will be identified through 
simulations and will be specified in the study SAP.
17.9.5
Analysis of the Key Secondary Endpoint
For the key secondary endpoint, that is, the changes in mUMSARS from baseline up to EoT, 
a Bayesian repeated measures model will be applied similar to the primary analysis
Sensitivity analyses to the key secondary analysis will be set up similar to the sensitivity 
analyses described for the primary endpoints under section 17.9.3.
17.9.6
Analysis of the Secondary Endpoint(s)
For secondary endpoints in the DBP the following methodology will be applied:

For the secondary endpoints UMSARS Part I and UMSARS Part II up to EoT, a Bayesian 
repeated measures model will be applied similar to the primary analysis.
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI

)RUUHPDLQLQJFRQWLQXRXVVHFRQGDU\HQGSRLQWVIRUH[DPSOHFOLQLFDOVFDOHVDVVHVVPHQWV
DQG05,YROXPHWULFSDUDPHWHUVD0L[HG0RGHOIRU5HSHDWHG0HDVXUHPHQWV0050
ZLOOEHDSSOLHGWRWKHFKDQJHVIURPEDVHOLQHXSWR:HHN ,IUHTXLUHGDORJ
WUDQVIRUPDWLRQZLOOEHDSSOLHGIRUQRUPDOL]DWLRQ7KHPRGHOZLOOFRQWDLQWKHIROORZLQJ
HIIHFWVEDVHOLQHVFRUHWUHDWPHQWYLVLWEDVHOLQHEORRG1I/5HJLRQWUHDWPHQWYLVLWDQG
EDVHOLQHVFRUHYLVLWDVIL[HGHIIHFWVDQGVXEMHFWDVUDQGRPHIIHFW7UHDWPHQWHVWLPDWHVZLOO
EHGHULYHGIRUHDFKVXEVHTXHQWYLVLW7KHSULPDU\FRPSDULVRQZLOOEHDW:HHN ZKHUHDV
:HHN ZLOOEHH[SORUDWRU\,QLWLDOO\DQXQVWUXFWXUHGFRYDULDQFHPDWUL[ZLOOEHILWWHG,Q
FDVHRILVVXHVFRQYHUJLQJD&RPSRXQG6\PPHWU\VWUXFWXUHZLOOEHXVHG

$OOFDWHJRULFDOVHFRQGDU\HQGSRLQWVZLOOEHDQDO\]HGDSSO\LQJDORJLVWLFUHJUHVVLRQ
7UHDWPHQWHIIHFWHYDOXDWHGDW:HHN ZLOOEHSULPDU\

1XPEHURIIDOOVSHULQGLYLGXDOSHUIDOOGLDU\SHULRGDFFRUGLQJWRWKHSDWLHQWIDOOGLDU\ZLOO
EHDQDO\]HGDSSO\LQJDQHJDWLYHELQRPLDOUHJUHVVLRQPRGHO

$GGLWLRQDOWLPHWRHYHQWVHFRQGDU\DQGH[SORUDWRU\HQGSRLQWVIROORZLQJ ZHHNV DQG
 ZHHNV RIWUHDWPHQWZLOOEHDQDO\]HGDSSO\LQJD&R[SURSRUWLRQDOKD]DUGVPRGHO
:HHN ZLOOEHSULPDU\

/X $) SODVPDFRQFHQWUDWLRQV&6)FRQFHQWUDWLRQVDQGWKH&6)SODVPD
FRQFHQWUDWLRQUDWLRVGXULQJWUHDWPHQWIRUDOOSDWLHQWVZLOOEHSUHVHQWHGGHVFULSWLYHO\7KH
GDWDZLOOEHLQFOXGHGLQDVHSDUDWHO\UHSRUWHGSRSXODWLRQ3. DQDO\VLV

$EVROXWHYDOXHVDQGFKDQJHVIURPEDVHOLQHXSWR:HHN DQG:HHN LQEORRG
ELRPDUNHUVDQG:HHN LQ&6)ELRPDUNHUVZLOOEHDQDO\]HGGHVFULSWLYHO\)RUVHOHFWHG
SDUDPHWHUVD0050ZLOOEHDSSOLHGIRUWKHFKDQJHVIURPEDVHOLQHWR(R7,IUHTXLUHGD
ORJWUDQVIRUPDWLRQZLOOEHDSSOLHGIRUQRUPDOL]DWLRQ

7(RI/X $) WRĮV\QXFOHLQLQ&6)ZLOOEHSUHVHQWHGGHVFULSWLYHO\DV³IUHH´
V\QXFOHLQ³WRWDO´ ĮV\QXFOHLQDQGUDWLRRI³IUHH´ WR³WRWDO´ ĮV\QXFOHLQ

*DLWDQGEDODQFHSDUDPHWHUVGHULYHGIURPWKHVHQVRUEDVHG)HHW0H GHYLFHZLOOSULPDULO\
EHDQDO\]HGGHVFULSWLYHO\IRUWKH6%6,IDSSURSULDWHD0050PRGHOOLNHWKHRQH
GHVFULEHGDERYHIRUFRQWLQXRXVVHFRQGDU\DQGH[SORUDWRU\HQGSRLQWVZLOOEHDSSOLHG
&RUUHODWLRQWRWKHNH\SURJUHVVLRQPDUNHUVWKDWLVWKH806$56VFRUHVDQG05,
SDUDPHWHUVZLOOEHH[SORUHGJUDSKLFDOO\

7KHSRWHQWLDOLQIOXHQFHRIFRYDULDWHVLQDGGLWLRQWR
DQGUHJLRQ
ZLOOEHLQYHVWLJDWHGXVLQJDIUHTXHQWLVWUHSHDWHGPHDVXUHVDQDO\VLVZLWKIL[HGHIIHFWV
$PRQJWKHFRYDULDWHVWREHLQYHVWLJDWHGDUHDJHJHQGHUFRXQWU\UDFHWLPHVLQFHGLDJQR
VLV GRVHRI3DUNLQVRQ¶VGLVHDVHPHGLFDWLRQH[SUHVVHGDVOHYRGRSDHTXLYDOHQWGDLO\GRVH
>/(''@EDVHOLQH05,VLJQDODQGEDVHOLQHSODVPD&6)ĮV\QXFOHLQDQG06$VXEW\SH

8VHRIFRQFRPLWDQWPHGLFDWLRQDQGFKDQJHVLQPHGLFDWLRQGXULQJWKHFRXUVHRIWKHVWXG\
ZLOOEHSUHVHQWHGDQGFRPSDUHGGHVFULSWLYHO\DFURVVWUHDWPHQWDUPV
$QXPEHURIDGGLWLRQDODQDO\VHVLVSODQQHGWRHYDOXDWHWKHUHODWLRQVKLSEHWZHHQWKHSULPDU\
DQGVHOHFWHGVHFRQGDU\H[SORUDWRU\HQGSRLQWV

5HODWLRQVKLSVEHWZHHQVHOHFWHGFRQWLQXRXVHQGSRLQWVWKDWLV806$56WRWDODQG
VXEGRPDLQV&203$6666&&*,63*,62*,66($'/JDLWSDUDPHWHUVDQG
(4'/ZLOOEHH[SORUHGDWOHDVWWKURXJKFRUUHODWLRQDQDO\VLVRQDEVROXWHYDOXHVDQG
FKDQJHIURPEDVHOLQH,QDGGLWLRQFRUUHODWLRQEHWZHHQ806$5605,EORRG&6)1I/
ĮV\QXFOHLQDQGRWKHUSRWHQWLDOELRPDUNHUVZLOOOLNHZLVHEHH[SORUHG
CCI
Y 
&/,B

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI

7KHPLQLPDOFOLQLFDOO\LPSRUWDQWGLIIHUHQFHZLWKLQSDWLHQW0&,'RQHDFKVFDOHZLOOEH
HVWLPDWHGIRUH[DPSOH ZLWKDQDQFKRUEDVHGPHWKRGHVWLPDWLQJ0&,'EDVHGRQWKH&*,6
VFDOHDFFRPSDQLHGE\GHQVLW\ DQGFXPXODWLYHGLVWULEXWLRQIXQFWLRQFXUYHVRIFKDQJHLQ
HDFKVFDOHIURPEDVHOLQHWR:HHN ZLWKRQHFXUYHSHU&*,6VFRUHDW:HHN )XUWKHU
GHWDLOVRQWKHZRUNLGHQWLI\LQJWKH0&,'ZLOOEHGHVFULEHGLQDVSHFLILFVHSDUDWH
Psychometric SAP
17.9.7
Analysis of the Exploratory Endpoint(s)
)RUH[SORUDWRU\HQGSRLQWVLQWKH'%3WKHIROORZLQJPHWKRGRORJ\ZLOOEHDSSOLHG

)RU FRQWLQXRXV H[SORUDWRU\HQGSRLQWV D0050ZLOOEHDSSOLHGIRUREVHUYHGGDWD
FRPELQHGZLWKLPSXWDWLRQZLWKZRUVWUDQNIROORZLQJHYHQWVRIGHDWKLIDSSOLFDEOHDQG
REVHUYHGGDWDIURPWKH:LWKGUDZDO9LVLWIRUSDWLHQWVGURSSLQJRXWIRURWKHUUHDVRQVWKDQ
GHDWKLIDYDLODEOH7KHPRGHOZLOOFRQWDLQWKHIROORZLQJHIIHFWVEDVHOLQHVFRUHWUHDWPHQW
YLVLWEDVHOLQHEORRG1I/UHJLRQWUHDWPHQWYLVLWDQGEDVHOLQHVFRUHYLVLWDVIL[HGHIIHFWV
DQGVXEMHFWDVUDQGRPHIIHFW7KHSULPDU\FRPSDULVRQZLOOEHDW:HHN DQG:HHN 
UHVSHFWLYHO\,QLWLDOO\DQXQVWUXFWXUHGFRYDULDQFHPDWUL[ZLOOEHILWWHG,QFDVHRILVVXHV
FRQYHUJLQJD&RPSRXQG6\PPHWU\VWUXFWXUHZLOOEHXVHG

&DWHJRULFDOH[SORUDWRU\HQGSRLQWVXSWR(R7'%3 ZLOOEHDQDO\]HGDSSO\LQJDORJLVWLF
UHJUHVVLRQ

7LPHWRHYHQWH[SORUDWRU\HQGSRLQWVXSWR(R7'%3 ZLOOEHDQDO\]HGDSSO\LQJD&R[
SURSRUWLRQDOKD]DUGVPRGHO

1XPEHURI IDOOVSHULQGLYLGXDODFFRUGLQJWRWKHVHQVRUEDVHG3$06\VGHYLFHZLOOEH
DQDO\]HGDSSO\LQJDQHJDWLYHELQRPLDOUHJUHVVLRQPRGHOLIDSSOLFDEOHLQFOXGLQJGDWDIURP
WKHSUHGHILQHGSHULRGVRQO\

7KHDQDO\VLVRIVHPLVWUXFWXUHGTXDOLWDWLYH([LW LQWHUYLHZVZLOOEHSUHVSHFLILHGLQD
VSHFLILF4XDOLWDWLYH$QDO\VLV3ODQ4$3:KHQHYHUDFRPELQHGTXDQWLWDWLYHDQG
TXDOLWDWLYHDSSURDFKLVFRQVLGHUHGWRDQDO\]H WKHVHLQWHUYLHZVD0L[HG0HWKRGV
4XDOLWDWLYH$QDO\VLV3ODQ004$3ZLOOEHGHYHORSHG
$QDO\VLVRI2/(HIIHFWGDWD

$QDO\VLVRIH[SORUDWRU\HIILFDF\GDWDFROOHFWHGLQWKH2/(ZLOOEHEDVHGRQWKH2/(6
ZKHUHWKHRULJLQDOSODFHERSDWLHQWVZLOOEHKDQGOHGDVDVHSDUDWHJURXS

$OOFRQWLQXRXVHQGSRLQWVLQWKH2/(ZLOOSULPDULO\EHDQDO\]HGGHVFULSWLYHO\SUHVHQWLQJ
ERWKDFWXDOYDOXHVDQGFKDQJHVIURPEDVHOLQHZKHUHFKDQJHVZLOOEHFDOFXODWHGXVLQJERWK
WKHEDVHOLQHIURPWKH'%3DQGWKHEDVHOLQHIURPWKH2/(UHVSHFWLYHO\,QDGGLWLRQDQ
H[SORUDWRU\0050DVGHVFULEHGDERYHZLOOEHDSSOLHGWRWKHFKDQJHVIURPWKH'%3
EDVHOLQHYLVLW1RIRUPDOWHVWLQJZLOOEHDSSOLHG
17.9.8
Analysis of Subgroups
6XEJURXS$QDO\VHVRIWKH3ULPDU\(QGSRLQWZLOOEHSHUIRUPHGXVLQJWKH%D\HVLDQUHSHDWHG
PHDVXUHVSULPDU\DQDO\VLVPRGHOE\DGGLQJVHOHFWHGVXEJURXSVDVPXOWLSOLFDWLYHIL[HG
FRYDULDWHHIIHFWV)RUWKLVSXUSRVHWKHPRGHOZLOOEHH[FOXGLQJ HIIHFWVRI

DQGUHJLRQUHVSHFWLYHO\$PRQJWKHVXEJURXSVWREHLQYHVWLJDWHGDUH
CCI
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 109 of 131

age (categorized as <50 years; 50 to 60 years; >60 years)

MSA subgroup and diagnosis certainty (possible/probable MSA-P/-C)

gender (female/male)

country (with small countries pooled)

race

time-since-diagnosis (as yearly intervals)

use of concomitant and PD medication (expressed; both categorized appropriately prior to 
database release) as LEDD 

baseline MRI atrophy and diffusivity (grouped using 25th and 50th percentiles)

baseline plasma/CSF α-synuclein and CSF NfL (grouped using 25th and 50th percentiles)

baseline disease severity according to CGI-S and SE-ADL (grouped using 25th and 50th 
percentiles) and UMSARS part IV

occurrence of ADAs, that is, ADA positive vs. ADA negative patients
17.10 Safety Analyses
17.10.1 Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:

pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date of first dose of IMP

treatment-emergent adverse event – an adverse event that starts or increases in intensity 
during or after administration of first dose of IMP
Adverse events, sorted by system organ class and preferred term, will be summarized by 
period and treatment group.
Data on adverse events related to systemic hypersensitivity reaction collected via the 
dedicated Hypersensitivity Form will likewise be summarized by period and treatment group.
Allocation of TEAEs to Study Periods
TEAEs will be assigned to periods according to the following:

Adverse events in the DBP – all TEAEs with date of onset or worsening of 
intensity/seriousness after first dose of IMP in the DBP and until final visit at EoTDBP 
(assigned APHASE = DOUBLE-BLIND)

Adverse events in the Safety Follow-up Period in the DBP – TEAEs with date of onset or 
worsening of intensity/seriousness occurring in the Safety Follow-up Period following the 
DBP (assigned APHASE = SAFETY)

Adverse events in the OLE – TEAEs with date of onset or worsening of intensity/serious-
ness after first dose of IMP in the OLE (assigned APHASE = TEP)
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 111 of 131
account for differences in treatment duration due to the study design, approximately 50% of 
the patients are expected to contribute with 60 weeks data and 25% of the patients with full 
72 weeks data. On top, an overall 20% drop-out rate has been accounted for. For comparison, 
it is expected that the frequentist repeated measures model used for simulation is quite similar 
in relation to performance to the primary Bayesian repeated measures model.
17.13 Statistical Analysis Plan
A Study Statistical Analysis Plan, a Psychometric Statistical Analysis Plan and a Qualitative 
Analysis Plan describing the detailed handling of data issues and the planned analyses in more 
detail will be prepared by Lundbeck or Lundbeck’s designees before database release.
18 Clinical Study Report and Publications
18.1
Data Ownership
The data collected in this study are the property of Lundbeck.
18.2
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared.
18.3
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the 
right to be informed by the investigator about the overall study results.
18.4
Publications
The results of this study will be submitted for publication.
Lundbeck will submit results information to ClinicalTrials.gov.
The primary publication based on this study must be published before any secondary 
publications. Authors of the primary publication must fulfil the criteria defined by the 
International Committee of Medical Journal Editors (ICMJE).22
19 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this 
study has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and GMP.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 112 of 131
20 Finance
20.1
Site Agreements
The financial agreements with each site are addressed in one or more documents. Both parties 
must sign the agreements before each site is initiated.
20.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
20.3
Equipment
Equipment owned or rented by Lundbeck that has been provided to the sites for use during the 
study must be returned at the end of the study.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 113 of 131
Reference
1.
Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015; 372(3): 249-263.
2.
Petrovic IN, Ling H, Asi Y, et al. Multiple system atrophy-parkinsonism with slow progression 
and prolonged survival: a diagnostic catch. Mov Disord. 2012;27(9):1186-1190.
3.
Krismer F, Wenning GK. Multiple system atrophy: insights into a rare and debilitating movement 
disorder. Nat Rev Neurol. 2017;13(4):232-243.
4.
Sakushima K, Nishimoto N, Nojima M, et al. Epidemiology of Multiple System Atrophy in Hok-
kaido, the Northernmost Island of Japan. Cerebellum. 2015;14(6):682-687.
5.
Singer W, Low PA. Optimizing Clinical Trial Outline for multiple system atrophy: lessons from 
the rifampicin study. Clin Auton Res. 2015;25(1):47-52.
6.
Colosimo, C., Tiple, D. & Wenning, G. Management of multiple system atrophy: state of the art. 
J Neural Transm 112, 1695–1704 (2005).
7.
Investigator’s Brochure, Lu AF82422, current version.
8.
World Medical Association (WMA). Declaration of Helsinki: Ethical principles for medical re-
search involving human subjects. [Internet] wma.net/en/30publications/10policies/b3/index.html.
9.
ICH. ICH Harmonised Guideline E6(R2): Integrated addendum to ICH E6(R1): Guideline for 
Good Clinical Practice. November 2016.
10. Wenning GK, Tison F, Seppi K, et al. Multiple System Atrophy Study Group. Development and 
validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord. 
2004;19(12):1391-402.
11. Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s disease. In: 
Gillingham FJ, Donaldson MC, eds. Third synopsium on Parkinson’s disease. Edinburgh: Liv-
ingston, 1969:152-157.
12. Collection of Race and Ethnicity Data in Clinical Trials. Guidance for Industry and Food and 
Drug Administration Staff. FDA 26 Oct 2016.
13. ICH guideline E17 on general principles for planning and design of multi-regional clinical trials. 
Reference number EMA/CHMP/ICH/453276/2016, published 18 Dec 2017.
14. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, 
Colosimo C, Dürr A, Fowler CJ, Kaufmann H. Second consensus statement on the diagnosis of 
multiple system atrophy. Neurology. 2008 Aug 26;71(9):670-6.
15. Lipp A, Sandroni P, Ahlskog E, et al. Prospective Differentiation of Multiple System Atrophy 
from Parkinson Disease, With and Without Autonomic Failure.Arch Neurol 2009;66(6):742-750.
16. Suarez GA, Opfer-Gehrking TL, Offord KP, et al. The Autonomic Symptom Profile: a new in-
strument to assess autonomic symptoms. Neurology. 1999 Feb;52(3):523-8.
17. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Quality of Life Research. 2011;20:1727–1736.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 114 of 131
18. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial va-
lidity and internal consistency findings from three multisite studies with adolescents and adults. 
Am J Psychiatry. 2011;168:1266–1277.
19. ICH. ICH Harmonised Tripartite Guideline E2A: Clinical safety data management: definitions 
and standards for expedited reporting. October 1994.
20. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler H J, Schlößer HA, Schlaak M, & 
von Bergwelt-Baildon MS (2018). Cytokine release syndrome. Journal for immunotherapy of 
cancer, 6(1), 56.
21. Garvey LH, Ebo DG, Mertes PM, Dewachter P, Garcez T, Kopac P, Laguna JJ, Chiriac AM, Ter-
reehorst I, Voltolini S, Scherer K. An EAACI position paper on the investigation of perioper-ative 
immediate hypersensitivity reactions. Allergy. 2019 Oct;74(10):1872-84.
22. International Committee of Medical Journal Editors (ICMJE). Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals. [Internet] ic-mje.org/ic-
mje-recommendations.pdf. December 2017.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 115 of 131
Appendix I
Clinical Study Protocol
Authentication and Authorization
v. 2.0
CLI_02112413

+/XQGEHFN$6
&RQILGHQWLDO
6WXG\$± &OLQLFDO6WXG\3URWRFRO
3DJH RI
Clinical Study Protocol
Authentication and Authorization
6WXG\WLWOH
,QWHUYHQWLRQDOUDQGRPL]HGGRXEOHEOLQGSDUDOOHOJURXSSODFHERFRQWUROOHG
PXOWLFHQWUHVWXG\WRDVVHVVWKHHIILFDF\VDIHW\DQGWROHUDELOLW\RI/X $) LQ
SDWLHQWVZLWK0XOWLSOH6\VWHP$WURSK\
6WXG\1R
$
(GLWLRQ1R

'DWHRIHGLWLRQ
 0D\ 
7KLVGRFXPHQWKDVEHHQVLJQHGHOHFWURQLFDOO\7KHVLJQDWRULHVDUHOLVWHGEHORZ
Authentication
,KHUHE\FRQILUPWKDW,DPRIWKHRSLQLRQWKDWWKHHWKLFDODQGVFLHQWLILFEDVLVRIWKLVVWXG\LVVRXQG
*OREDO7ULDO0DQDJHU
*OREDO7ULDO/HDG
+HDGRI%LRVWDWLVWLFV
+HDGRI0HGLFDO6DIHW\
Authorization
,KHUHE\FRQILUPWKDW,DPRIWKHRSLQLRQWKDWWKHHWKLFDODQGVFLHQWLILFEDVLVRIWKLVVWXG\LVVRXQG
7KHUDSHXWLF$UHD/HDG
%M¡UQ$DULV*U¡QQLQJ9LFH3UHVLGHQW
&OLQLFDO'HYHORSPHQW
PPD
Y 
&/,B

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 117 of 131
Appendix II
Recent and Concomitant Medication Disallowed
or Allowed with Restrictions
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 118 of 131
Recent and Concomitant Medication: 
Disallowed or Allowed with Restrictions
In the table below, recent and concomitant medications that are disallowed or allowed with 
restrictions with respect to their use prior to or during the study are listed.
Drug Class
Details
Disallowed:
Any investigational products 
Disallowed within 30 days before the Screening Visit or 5 half-lives –
whichever is longer, and throughout the whole study
Inhibitor of α-synuclein 
aggregation
Treatment targeting α-synuclein and/or MSA disease progression within 
the last 12 months and throughout the whole study
Monoclonal antibodies
anti-α-synuclein monoclonal antibody within the last 12 months and 
throughout the whole study
Vaccines
past or current treatment with an active vaccine targeting α-synuclein 
and throughout the whole study
Allowed with restriction:
Drugs acting against parkinsonism or autonomic dysfunction
Anticholinergic agents 
All, stable dose for at least 8 weeks prior to randomization
Anticholinesterases
All, stable dose for at least 8 weeks prior to randomization
Cardiac stimulants
Adrenergic and dopaminergic agents, stable dose for at least 8 weeks 
prior to randomization
Corticosteroids for systemic use
Fludrocortisone; stable dose for at least 8 weeks prior to randomization
Dopaminergic agents
All, stable dose for at least 8 weeks prior to randomization
Drugs for urinary frequency and 
incontinence
All, stable dose for at least 8 weeks prior to randomization
Hypothalamic hormones
Octreotide; stable dose for at least 8 weeks prior to randomization
Posterior pituitary lobe hormones
Vasopressin and analogues; stable dose for at least 8 weeks prior to 
randomization
If medically necessary, initiation of or change of dose of concomitant medication allowed with restriction is 
allowed per investigator discretion.
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 119 of 131
Appendix III
Guidance for Key Clinical Features of Hypersensitivity
Related Reactions
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 120 of 131
Guidance for Key Clinical Features of Hypersensitivity
Related Reactions
Definition of Hypersensitivity reactions (study-specific adverse events requiring additional 
data collection)
-
Type I hypersensitivity reaction: Anaphylaxis
Anaphylaxis is a serious, acute allergic reaction and involves specific immunoglobulin E 
(IgE) antibodies. The definition relies on clinical accepted diagnostic criteria.
National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis 
Network (NIAID/FAAN) criteria for Anaphylaxis:
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 122 of 131
Mild cases may display cough and tachypnoea but can progress to acute respiratory 
distress syndrome (ARDS). In addition, laboratory abnormalities that are common in 
patients with CRS include cytopenias, elevated creatinine and liver enzymes, deranged 
coagulation parameters, and a high sensitivity C-reactive protein.
Type III hypersensitivity reaction: Immune-complex related reactions
Immune-complex related reaction is a delayed hypersensitivity (“Serum sickness”) and 
secondary to immune-complex formation and complement activation.
Clinical signs may include delayed onset of fever, rash, arthralgia, myalgia, haematuria, 
proteinuria, serositis, CNS complications and hemolytic anaemia. (Ref. FDA Guidance for 
industry: Immunogenicity Assessment for Therapeutic Protein Products -August 2014)
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 123 of 131
Appendix IV
Hypersensitivity Form
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 124 of 131
Hypersensitivity Form
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 125 of 131
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 126 of 131
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 127 of 131
Systemic Hypersensitivity Reaction Algorithm
v. 2.0
CLI_02112413

H. Lundbeck A/S
Confidential
Study 18331A – Clinical Study Protocol
Page 128 of 131
Appendix V
Gilman Criteria
v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

v. 2.0
CLI_02112413

v. 2.0
CLI_02112413