Conditions: Medication-Induced Dyskinesia
Keywords: Levodopa Dyskinesia Parkinson´s disease L-dopa NLX-112 Befiradol LID
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks.

Detailed description:
This is a two-arm, double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day of NLX 112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day (1 mg BID) or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks.

Patients will report to the study clinic for a screening visit (Visit 1), followed by a baseline visit on Day 1 (Visit 2) where patients will be randomized and begin treatment. Two remote safety visits over telephone (Days 7 and 49 \[Visit 3 and Visit 8\]) will be conducted. Once treatment has commenced, there will be 2 in-person safety visits to the clinic (Days 14 and 21 \[Visit 4 and Visit 5\]), 2 in-person efficacy visits to the clinic (Days 28 and 42 \[Visit 6 and Visit 7\]) and one follow-up in person final safety visit (Day 70 \[Visit 9\]). In total, patients will report to the clinic for 7 in-person visits. Patients entering the study will be randomized in a 2:1 ratio (16:8 patients) to receive either NLX 112 or placebo.

At Visits 2, 6 and 7, efficacy assessments will start 30 minutes after the patient has taken 150% of his or her regular L-DOPA dose, when the patient is ON and experiencing typical dyskinesia.

A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver with concordance in ON time with dyskinesia between study staff and patient. Two consecutive 24-hour diaries will be completed prior to randomization (baseline, Visit 2) and prior to the clinic visits on Days 28 and 42 (Visits 6 and 7).

A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day period prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on Days 28 and 42 (Visits 6 and 7, respectively).

Blood will be collected for possible NLX-112 plasma concentration measurements on Days 14, 21, 28, 42 and 70 (Visits 4, 5, 6, 7 and 9).

Arms:
arm 1: Patients will self-administer NLX-112 2 times each day, once in the morning and once in the evening. Up-titration over 4 weeks, maximal dose of 2 mg/day during 2 weeks, down-titration over 2 weeks. arm 2: Patients will self-administer placebo 2 times each day, once in the morning and once in the evening. Up-titration of number of tablets over 4 weeks, number of tablets equivalent to maximal dose of 2 mg/day NLX-112 during 2 weeks, down-titration over 2 weeks.

Interventions: intervention 1: NLX-112 intervention 2: Placebo
Intervention descriptions: intervention 1: NLX-112 will be supplied as tablets containing 0.25 mg NLX-112. NLX-112 is a structurally novel centrally acting, high-efficacy selective 5-HT1A receptor agonist with nanomolar affinity for 5-HT1A receptors. Proposed as a treatment for L-DOPA-induced-dyskinesia in Parkinson's disease. intervention 2: Placebo will be matching tablets (identical weight, shape and color) without NLX-112.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan NLX-112-DYS-101 FINAL v1.0 20FEB2023 
CONFIDENTIAL 
1(40) 
Statistical Analysis Plan 
EudraCT no. 
2020-006053-22 
Investigational medicinal product NLX-112 
Study code 
NLX-112-DYS-101 
Protocol version and date 
Final version 3.1; 
07MAR2022 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO ASSESS THE SAFETY, 
TOLERABILITY AND PRELIMINARY EFFICACY OF 
NLX-112 VERSUS PLACEBO IN LEVODOPA-INDUCED 
DYSKINESIA IN PARKINSON’S DISEASE 
Sponsor signatory 
2 rue Georges Charpak L’Arobase Le Causse 
Espace d’Entreprises 
FR-81290 Labruguière 
France 
CTC biostatistician 
Clinical Trial Consultants AB (CTC) 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
This  Statistical Analysis Plan is the property of Neurolixis and is a confidential 
document. It is not to be copied or distributed to other parties without written approval 
from Neurolixis. 
Statistical Analysis Plan
Version and date
Final v1.0 20FEB2023




 
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2 
TABLE OF CONTENTS 
1 
SIGNATURES .................................................................................................................. 2 
2 
TABLE OF CONTENTS ................................................................................................. 3 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................. 5 
4 
INTRODUCTION ............................................................................................................ 7 
4.1 
Study design .............................................................................................................. 7 
4.2 
Study objectives and endpoints ............................................................................... 7 
4.3 
Randomization and number of subjects ................................................................. 8 
4.4 
Subject replacement ................................................................................................. 9 
4.5 
Blinding ..................................................................................................................... 9 
5 
STATISTICAL AND ANALYTICAL PLANS ........................................................... 10 
5.1 
Statistical hypotheses ............................................................................................. 10 
5.2 
Sample size calculation .......................................................................................... 10 
5.3 
Definition of analysis sets ....................................................................................... 10 
5.4 
Compliance ............................................................................................................. 10 
5.5 
Definition of baseline .............................................................................................. 11 
5.6 
Rounding principles ............................................................................................... 11 
5.7 
Significance level .................................................................................................... 11 
5.8 
Multiple comparisons/multiplicity ........................................................................ 11 
5.9 
Handling of dropouts, missing data and outliers ................................................ 11 
6 
CHANGES FROM THE CLINICAL STUDY PROTOCOL .................................... 12 
7 
CLINICAL DATABASE PROCESSING .................................................................... 13 
7.1 
General information ............................................................................................... 13 
7.1.1 
CDISC Compliance ............................................................................................ 13 
7.2 
Database modeling of study design ....................................................................... 13 
8 
STATISTICAL DELIVERABLES ............................................................................... 15 
9 
STATISTICAL METHODOLOGY ............................................................................. 16 
9.1 
Analysis of the primary endpoints ........................................................................ 16 
9.1.1 
Adverse events ................................................................................................... 16 
9.1.2 
Physical examination .......................................................................................... 16 
9.1.3 
Vital signs ........................................................................................................... 16 
9.1.4 
12-lead ECG ....................................................................................................... 16 
9.1.5 
Columbia Suicide Severity Rating Scale (C-SSRS) .......................................... 16 
9.1.6 
Safety laboratory analyses .................................................................................. 16 
9.2 
Analysis of secondary endpoints ........................................................................... 16 
9.2.1 
Statistical inferential analysis of efficacy endpoints .......................................... 16 
9.2.2 
Unified Dyskinesia Rating Scale (UdysRS) total score ..................................... 17 


 
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9.2.3 
ON Time Without Troublesome Dyskinesia ...................................................... 18 
9.2.4 
Unified Parkinson’s Disease Rating Scale (UPDRS) ........................................ 19 
9.2.5 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms ......... 19 
9.2.6 
Dyskinesia measured by a wearable dyskinesia assessment device .................. 19 
9.3 
Analysis of tertiary/exploratory endpoints .......................................................... 19 
9.3.1 
King’s Parkinson’s Disease Pain Scale (KPPS) total score ............................... 19 
9.3.2 
Parkinson’s Disease Questionnaire (PDQ39) total score ................................... 19 
9.3.3 
Hospital Anxiety Depression Scale (HADS) ..................................................... 20 
9.3.4 
International Consultation on Incontinence Questionnaire Overactive Bladder 
Module (ICIQ-OAB) total score ...................................................................................... 20 
9.3.5 
Epworth Sleepiness Scale (ESS) ........................................................................ 20 
9.4 
Description of study population ............................................................................ 20 
10 DATA DISPLAY PLAN ................................................................................................ 21 
10.1 
Table of contents DDP ........................................................................................... 21 
 
 List of tables 
Table 1 
Analysis sets 
10 
Table 2 
Changes in the planned statistical analyses 
12 
Table 3 
UDyRS analyses to be performed 
18 
 
List of figures 
Figure 1 
Schematic representation of the SDTM study design 
14 
 


 
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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical  
CDISC 
Clinical Data Interchange Standards Consortium  
CI 
Confidence interval 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Controlled terminology 
CTC 
Clinical Trial Consultants AB 
CV 
Coefficient of variation 
DDP 
Data display plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESS 
The Epworth Sleepiness Scale 
FAS 
Full analysis set 
FDA 
United States Food and Drug Administration 
HADS 
The Hospital Anxiety Depression Scale 
ICIQ-OAB 
International Consultation on Incontinence Questionnaire 
Overactive Bladder Module 
IG 
Implementation guideline 
IMP 
Investigational medicinal product 
KPPS 
King’s Parkinson’s disease Pain Scale 
L-DOPA 
Levodopa, L-3,4-dihydroxyphenylalanine 
LID 
Levodopa-induced dyskinesia 
LMM 
Linear mixed model 
LS 
Least square 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
NA 
Not applicable/not available 


 
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Abbreviation 
Explanation 
NC 
Not calculated 
NCA 
Non-compartmental analysis 
NCS 
Not clinically significant 
PD 
Parkinson’s disease 
PDQ39 
The Parkinson’s Disease Questionnaire 
PK 
Pharmacokinetic(s) 
PKAS 
PK analysis set 
PT 
Preferred term 
Q 
Quantile 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SOC 
System organ class 
UDysRS 
Unified Dyskinesia Rating Scale 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
WHO 
World Health Organization 


 
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4 
INTRODUCTION 
4.1 
Study design 
This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, 
tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo 
in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson’s disease 
(PD). NLX-112 will be up-titrated (patients will self-administer tablets) to either 2 mg/day or 
to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-
tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks. 
 
For more details on the study design, please refer to the CSP. 
4.2 
Study objectives and endpoints  
Objectives 
Endpoints 
Assessments 
Analyses Data 
display 
plan 
(DDP) 
Primary objective 
Primary endpoint 
Assessments 
Analyses DDP 
To evaluate the safety 
and tolerability of NLX-
112, titrated up to a 
maximum of 2 mg/day, 
compared to placebo 
during 8 weeks of daily 
treatment in PD patients 
with LID. 
Frequency, intensity and seriousness of 
AEs 
AE reporting  
Section 
9.1.1 
Section 
10.2.2.1 
Clinically significant changes from 
baseline in: ECG, Vital signs, Safety 
laboratory parameters, and Physical 
examinations 
ECG 
Section 
9.1.4 
Section 
0 
Vital signs 
Section 
9.1.3 
Section 
10.2.2.3 
Safety laboratory 
parameters 
Section 
9.1.6 
Section 
0 
Physical 
examinations  
Section 
9.1.2 
Section 
0 
Suicidal ideation/behavior as assessed 
by the Columbia Suicide Severity 
Rating Scale (C-SSRS). 
C-SSRS 
Section 
9.1.5 
Section 
10.2.2.5 
Secondary objective 
Secondary endpoints 
Assessments 
Analyses DDP 
To assess the preliminary 
efficacy of NLX-112 
treatment in reducing 
troublesome LID. 
Change from baseline at the final 
efficacy clinic visit (Day 42) in the 
Unified Dyskinesia Rating Scale 
(UDysRS) total score [Timeframe: 
Baseline to Day 42]. Patients will be 
challenged with 150% of their standard 
L-DOPA dose (maximum L-DOPA 
dose 250 mg) 30 minutes prior to the 
first UDysRS assessment. 
UDysRS 
Section 
9.2.1 
Section 
10.2.3.1 
Change from baseline in UDysRS total 
score at Day 28, after a 150% L-DOPA 
dose challenge. 
UDysRS 
Section 
9.2.1 
Section 
10.2.3.1 
Change from baseline in total objective 
score (Parts III, IV) of the UDysRS at 
Day 28 and Day 42, after a 150% L-
DOPA dose challenge. 
UDysRS 
Section 
9.2.1 
Section 
10.2.3.1 
Change from baseline in ON Time 
Without Troublesome Dyskinesia (ON 
Without Dyskinesia plus ON With 
ON Time Without 
Troublesome 
Dyskinesia 
Section 
9.2.3 
Section 
10.2.3.2 


 
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Objectives 
Endpoints 
Assessments 
Analyses Data 
display 
plan 
(DDP) 
Non-troublesome Dyskinesia) based on 
a PD Home Dyskinesia Diary. 
Change from baseline in Unified 
Parkinson's Disease Rating Scale 
(UPDRS) scores (Part III, motor 
examination). 
UPDRS 
Section 
9.2.4 
Section 
10.2.3.3 
Change from baseline in UPDRS 
combined scores (Parts I, II, III and 
IV). 
UPDRS 
Section 
9.2.4 
Section 
10.2.3.3 
Clinical Global Impression of Change 
(CGI-C) in overall PD symptoms 
CGI-C 
Section 
9.2.5 
Section 
10.2.3.4 
Change from baseline in dyskinesia 
scores measured by the Kinesia 360 
(Great Lakes Neurotechnologies, Inc) 
wearable dyskinesia assessment 
system. 
Kinesia 360 
Section 
9.2.6 
Section 
10.2.3.5 
Exploratory objective 
Exploratory endpoints 
Assessments 
Analyses DDP 
To assess the preliminary 
efficacy of NLX-112 
treatment in improving 
selected non-motor 
symptoms of PD, 
including pain, bladder 
function, sleep function, 
mood and quality of 
living with PD. 
Change from baseline in the King’s 
Parkinson’s Disease Pain Scale (KPPS) 
total score and in each of the seven 
pain domain sub-scores. 
KPPS 
Section 
9.3.1 
Section 
10.2.4.1 
Change from baseline in the 
Parkinson’s Disease Questionnaire 
(PDQ39) total score and domain 
scores. 
PDQ39 
Section 
9.3.2 
Section 
10.2.4.2 
Change from baseline in the Hospital 
Anxiety Depression Scale (HADS) 
HADS 
Section 
9.3.3 
Section 
10.2.4.3 
Change from baseline in the 
International Consultation on 
Incontinence Questionnaire (ICIQ) 
Overactive Bladder Module (ICIQ-
OAB) total score. 
ICIQ-OAB 
Section 
9.3.4 
Section 
10.2.4.4 
Change from baseline in the Epworth 
Sleepiness Scale (ESS). 
ESS 
Section 
9.3.5 
Section 
10.2.4.5 
To collect blood samples 
for potential NLX-112 
plasma concentration 
analysis. 
Plasma concentrations of NLX-112. 
Plasma 
concentrations 
 
 
4.3 
Randomization and number of subjects 
On Day 1, patients were randomized to receive either NLX-112 or placebo with the ratio 2:1 
for active treatment to placebo. This will give approximately 16 patients who received NLX-
112 and 8 patients who received placebo in the study. In addition, approximately the same ratio 
was intended to be attained within each site. The study used competitive enrolment between 5 
sites. 


 
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4.4 
Subject replacement 
Patients who were prematurely withdrawn from the study for any reason except the occurrence 
of AEs assessed as possibly or probably related to study treatment could be replaced during the 
course of the study. 
4.5 
Blinding 
This is a double-blind study and the allocation of treatments will not be disclosed until clean 
file has been declared and the database has been locked. 
 


 
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5 
STATISTICAL AND ANALYTICAL PLANS 
5.1 
Statistical hypotheses 
Hypotheses tests will be performed at the 5% alpha level with the aim of proving superiority of 
NLX-112 compared to placebo on the change from baseline on a number of efficacy 
parameters. Any inference of superiority of NLX-112 compared to placebo will be based on 
these tests. Further testing within each treatment (NLX-112 or placebo respectively) at the 5% 
alpha level will be done with the aim of proving a beneficial shift from baseline, as a result of 
the IMP intervention. 
Considering the small dimension of the study and the many tests performed, statistically 
significant findings should be viewed more as indicative results rather than confirmatory. 
5.2 
Sample size calculation 
No formal sample size calculation has been performed. The sample size of 24 patients is 
considered sufficient to evaluate the primary objective and to allow for a preliminary efficacy 
evaluation. 
5.3 
Definition of analysis sets 
The analysis sets defined for the study are outlined inTable 1. 
Table 1 
Analysis sets 
Analysis 
set 
Definition 
Use of analysis set  
Full 
analysis 
set (FAS) 
The full analysis set (FAS) will 
comprise all randomized patients who 
were dosed. 
Safety and efficacy evaluations. See section 10 below for 
more details. 
Per 
protocol 
set (PPS) 
The per protocol set (PPS) will consist 
of all patients included in the FAS 
population who do not have any major 
protocol violations assessed to 
compromise the analysis of study data. 
All protocol violations will be judged 
as major or minor prior to database 
lock. The patient must have an overall 
calculated compliance of 75% to be 
included in the PPS. 
Efficacy evaluations. See section 10 below for more 
details. 
5.4 
Compliance  
Percent compliance will be calculated as: 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= 100 ∗𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐−𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
 
 
Expected number of capsules is derived through the maximum dose tolerated and the steady 
state dose recorded in the eCRF, the dosing scheduled stipulated in the CSP, actual number of 
days in each dosing stage (the up-titration period and the stable dosing period) per patient and 


 
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comments of dosing stated in the eCRF and the monitoring reports. Data indicating individual 
treatment compliance will be listed and calculated compliance will be summarized 
descriptively. 
5.5 
Definition of baseline 
Baseline will be defined as the last non-missing data point prior to the first administration of 
IMP. 
5.6 
Rounding principles 
Generally, no rounding of data will be done prior to calculating statistics. However, if reported 
data contains more than 8 significant digits it will be rounded to 8 significant digits in the 
database.  
In statistical output and descriptive summaries, the following principles will be followed: 
• Data will be presented as reported in input data in listings. 
• 2 significant digits will be used for percentages; p-values and similar statistical output 
will be presented using 4 decimal points. 
• Descriptive summaries of all other numerical data (e.g. mean, SD, median etc.) will be 
presented with one extra decimal compared to reported input data. 
5.7 
Significance level 
All hypothesis testing will be two-sided, using a 5% significance level (α=0.05). 
5.8 
Multiple comparisons/multiplicity 
Statistical tests of efficacy outcomes will be for explorative purposes and no adjustment for 
multiple tests will be performed. 
5.9 
Handling of dropouts, missing data and outliers 
Outliers will be included in summary tables and listings and will not be handled separately in 
any analyses. Generally, no imputation of data will be performed. However, in case of a 
substantial amount of missing data, judged to affect analyses conclusions related to secondary 
and exploratory endpoints, imputation methods might be considered or alternative analysis 
approaches, for example analysing mean scores instead of total scores. 
In case of missing start and stop times of AEs that cannot be investigated further, missing data 
will be imputed according to a worst-case scenario. That is, start time will be imputed as the 
closest time point post first intake of IMP and end time as 23:59, resulting in the longest possible 
treatment emergent duration of the AE. 


 
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CHANGES FROM THE CLINICAL STUDY PROTOCOL 
Changes to the planned analyses and the timing of these are summarised in Table 2.  
Table 2 
Changes in the planned statistical analyses 
Change 
category 
Timing 
of 
change 
Description of change 
Reason for change 
Responsible 
for change 
Change in 
the SAP 
compared 
to the 
CSP 
Prior to 
DBL 
The safety analysis set has 
been omitted. 
Safety evaluations based on FAS is 
considered sufficient. 
Joakim 
Englund 
Change in 
the SAP 
compared 
to the 
CSP 
Prior to 
DBL 
The Chi2 test for the ON Time 
Without Troublesome 
Dyskinesia analysis has been 
replaced with a linear mixed 
model approach. 
The CSP prescribes that a chi-square test 
be performed for ON Time Without 
Troublesome Dyskinesia data for the whole 
study period. As there are multiple 
measurements per patient and visit, it is not 
clear how this can be implemented. Hence 
a shift to a mixed model approach has been 
adopted. 
Joakim 
Englund 
Change in 
the SAP 
compared 
to the 
CSP 
Prior to 
DBL 
Wilcoxon signed rank tests 
have been replaced with linear 
mixed modeling with a non-
parametric back-up plan 
should model assumptions fail. 
In order to use all available data in the 
same model, potentially resulting in higher 
power in the analyses, a mixed model 
approach has been adopted instead. 
Joakim 
Englund 
Change in 
the SAP 
compared 
to the 
CSP 
Prior to 
DBL 
The Kinesia 360 wearable 
dyskinesia assessment system 
and PD home dyskinesia diary 
data for up to 4*24 hours prior 
to Visit 6 and 7 is included in 
the analyses. 
The CSP prescribes data from only up to 
2*24 hours to be used in Kinesia 360 
wearable device and home diary analyses. 
However, using the cut-off point of 4*24 
hours prior to Visit 6 and 7 respectively 
was deemed medically acceptable, whereas 
at the same time minimizing the amount of 
missing data in the corresponding analyses. 
Joakim 
Englund 
 


 
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7 
CLINICAL DATABASE PROCESSING 
7.1 
General information 
The clinical database is processed and generated according to The Clinical Data Interchange 
Standards Consortium (CDISC). CDISC is a Standard Developing Organization which 
develops and publishes standards to normalise the structure of clinical study data and thereby 
simplify submissions to and reviews by authorities such as the Food and Drug Administration 
(FDA).  
The CDISC standards for clinical studies are the Study Data Tabulation Model (SDTM) and 
the Analysis Data Model (ADaM). The study data will be structured into a database model 
reflecting the SDTM and be compliant to SDTM Implementation Guide (SDTM-IG) version 
3.2. The data used for statistical analysis will be structured to reflect the Analysis Data Model 
(ADaM) and be compliant to ADaM Implementation Guide (ADaM-IG) version 1.1. 
Data values are collected according to, or mapped into, Controlled Terminology (CT) codelists 
defined by CDISC, whenever possible. The codelists are updated biannually at CTC and the 
latest version available at study start will be used. As per default, CT codelists will be used in 
all tables, listings, and figures. Custom codelists for test or parameter names will be used if 
applicable upon Sponsor’s request, to align with protocol texts, or to adhere to other standard 
naming conventions (e.g., PK parameter name “Tmax” will be used instead of the CDISC term 
“Time of CMAX”). These custom codelists will be mapped in the “Parameter Name” field in 
the ADaM structure, while the CT will be kept in the SDTM predecessor fields to provide 
traceability back to CDISC codelists. 
7.1.1 
CDISC Compliance  
Full CDISC compliance will not be claimed for this study. The clinical database will be 
processed and generated according to CDISC standard to the greatest possible extent, but full 
compliance will not be claimed. No CDISC documentation (e.g., Define XML, Annotated 
eCRF, SDTM Reviewer’s Guide and ADaM Reviewer’s Guide) will be generated. 
7.2 
Database modeling of study design 
The study design is mapped to a SDTM study design model containing the following 
structural components: 
EPOCH: An interval of time in the planned conduct of a study. An epoch is associated with a 
purpose (e.g., screening, randomization, treatment, follow-up), and applies across all arms of 
the study. Study epochs follow a controlled terminology to represent the different study parts 
(e.g. SCREENING, TREATMENT, FOLLOW-UP) 
ELEMENT: Building blocks used to build up the entire study length for all subjects. 
Information on ELEMENTs is extracted from the study design and schedule of events in the 
protocol. ELEMENTs are defined to span the entire study without gaps. One EPOCH may 
contain one or several ELEMENTs. All ELEMENTs must have transition rules in accordance 
with the protocol to determine start and end. 
ARM: Subjects are allocated to study arms depending on the study design, either by 
randomization or other allocation processes defined in the study protocol. ARMs are defined as 
the total number of planned ways a subject can go through the study (unique combination of 
study ELEMENTs). All ARMs must contain a unique sequence of ELEMENTs. 


 
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VISIT: Study visits are defined as planned timepoints during the study where study data is 
collected. A visit can be performed in clinic, by off-site contact with study personnel (phone 
call, video conference or similar), or by subject initiated recordings of data. The visit schedule 
is extracted from protocol and eCRF design. 
A schematic representation of the SDTM study design is presented in Figure 1. 
 
Figure 1 
Schematic representation of the SDTM study design 
 
 


 
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8 
STATISTICAL DELIVERABLES 
The following items will be delivered: 
• Statistical analyses, summary tables, listings and figures as described in Section 10. 
• Clinical study database delivered as a SAS-export file. 
 
 


 
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9 
STATISTICAL METHODOLOGY 
Generally, all collected data will be listed. Listings will be sorted by treatment followed by 
patient. 
Due to small sample size, there will be no summaries using site as a grouping variable. 
However, site will be specified in listings. 
Details on statistical analyses and descriptive summaries are specified below. A complete 
definition of output produced is given in Section 10 below. 
All statistical analysis and descriptive summaries will be performed using SAS version 9.4 or 
later (SAS institute, Cary, NC). 
9.1 
Analysis of the primary endpoints 
9.1.1 
Adverse events 
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented by treatment. Incidence of AEs will be summarized by SOC and PT by treatment. 
Separate tables will be provided, if relevant, for serious AEs (SAEs) or events leading to 
withdrawal from study. Separate tables will be provided with summaries per titration period as 
well (up-titration, stable dosing and down-titration). 
9.1.2 
Physical examination 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by patient and summarized by treatment. 
9.1.3 
Vital signs 
Vital signs (systolic/diastolic blood pressure, orthostatic blood pressure, pulse, respiratory rate 
and body temperature) will be summarized by treatment. Data will be presented with absolute 
and percent change from baseline. 
9.1.4 
12-lead ECG 
All ECGs will be categorized as ”normal”, ”abnormal, not clinically significant”, or ”abnormal, 
clinically significant” (as judged by the Investigator) and summarized by treatment using 
frequency tables. 
9.1.5 
Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS data will be listed by treatment, patient and visit and summarized by treatment. 
9.1.6 
Safety laboratory analyses 
Safety laboratory data will be summarized by treatment with absolute and percent change from 
baseline at each visit. 
9.2 
Analysis of secondary endpoints 
9.2.1 
Statistical inferential analysis of efficacy endpoints 
Absolute change from baseline in efficacy endpoints (secondary and exploratory endpoints) 
will generally be analysed using a linear mixed model with treatment, visit and the interaction 


 
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treatment*visit as fixed categorical effects and subject within treatment as a random effect. The 
baseline value of the dependent variable will be included in the model as a continuous covariate, 
to account for possible differences in change from baseline outcomes due the starting baseline 
level. Visit will be modelled as a repeated effect. Kenward-Roger’s approximation for degrees 
of freedom will be used. 
Providing a significant type III F-test for the interaction effect treatment*visit, differences 
between least square estimates of NLX-112 and placebo for the same visit (i.e. from the 
interaction term treatment*visit, where visit is the same for both NLX-112 and placebo) will be 
estimated and the corresponding p-value will be presented in tables. In addition, differences 
between least square estimates of each post-baseline visit and baseline for NLX -112 and 
placebo respectively (i.e. from the interaction term treatment*visit, where treatment is the same 
for the post-baseline and the baseline visit) will be estimated and the corresponding p-value 
will be presented in tables. 
The model proposed above will be used for FAS and is valid, as long as the underlying data is 
missing at random (MAR). As a sensitivity analysis, the model will also be run for PPS, serving 
as a validity check for the main FAS analysis. The sensitivity analysis will be a complete case 
analysis, i.e., only patients with no missing data for the dependent variable will be used. 
Model diagnostics, for example Shapiro-Wilk’s test for a normally distributed residual term 
and Leven’s test for the homoscedasticity assumption of the residual term as well as Q-Q plots 
and plotting residuals vs. predicted values, will be performed. If model assumptions are deemed 
to be violated, an attempt will be made to transform the dependent variable in order to fulfil 
model diagnostics. 
A box-cox model will be used to find the most appropriate transformation of data. Lambda 
values between -3 and 3 will be tested using increments of 0.25. The dependent variable will 
be transformed accordingly, and the linear mixed model rerun on transformed data. 
Subsequently, the same model diagnostics as described above will be performed. If model 
assumptions are deemed to be violated, the linear mixed model approach will not be further 
pursued for the corresponding dependent variable. 
If transforming data according to the above method fails, the analysis will be done using non-
parametric methods. A Wilcoxon rank sum test will be used to assess statistically significant 
differences between active treatment and placebo for relative change from baseline in efficacy 
endpoints for all post-baseline visits respectively. Furthermore, a Wilcoxon signed rank test 
will be performed for each post-baseline visit and baseline for NLX -112 and placebo 
respectively to assess statistically significant differences between each post-baseline visit and 
baseline for each treatment separately. 
9.2.2 
Unified Dyskinesia Rating Scale (UdysRS) total score 
The UDysRS is a rating instrument designed to assess the core features of dyskinesia in 
Parkinson's Disease. The UDysRS consists of 4 parts: 
 
• Part I, historical disability with regard to the patient's perceptions of the impact on activities 
of ADL of on-dyskinesia.  
• Part II, historical disability with regard to the patient's perceptions of the impact on ADL of 
off-dystonia.  
• Part III, objective impairment, which assesses severity of dyskinesia, affected body parts, 
and type of impairment (choreic vs. dystonic). 


 
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• Part IV, objective disability, based on an evaluation of Part III activities.  
 
Each item in the UDysRS is scored from 0 to 4, with a possible maximum total score of 104. 
 
The UDySRS assessment will be performed at baseline (Day 1, Visit 2), Day 28 and Day 42 
(Visits 6 and 7), see Table 8.1-1, starting approximately 30 minutes after the L-DOPA challenge 
on these days. The UDysRS (Parts III and IV) will be repeated 3 times after each L-DOPA 
challenge, 30 minutes apart, and will hence be performed approximately 30, 60 and 90 minutes 
after each challenge. 
 
The data for all 3 assessments performed at each visit will be entered in the eCRF and the 
Investigator will highlight which of the assessments, corresponding to the assessment where 
the patient had most severe dyskinesia, that will be used in the descriptive summaries of data 
and statistical analyses. However, an additional analysis of only Part III and IV data will be 
performed using the average of the 3 assessment sessions, instead of the assessment marked as 
most severe. 
UdysRS total score at each visit will be summarized using descriptive statistics. The patients’ 
highest recorded score per UDysRS questionnaire item will be used to calculate total UDysRS 
score. However, an additional analysis of only Part III data will be performed using the sum of 
each questionnaire item instead of the highest score. UdysRS total score will be analysed using 
inferential statistics as described under 9.2.1 above. 
The analysis UDysRS total score will be done using data from all Parts as well as using data 
from Part III and IV only (UDysRS total objective score). 
In total, the different analyses outlined above result in the following tables being produced (see 
section 10.2.3.1 below for more details): 
Table 3 
UDyRS analyses to be performed 
Table ID 
UDysRS Parts 
Repeated assessments (30, 60 
and 90 minutes respectively) 
Questionnaire item data handling 
method 
UD 1 
I, II, III and IV 
Session marked as most severe by 
the investigator 
Highest score 
UD 2 
III and IV 
Session marked as most severe by 
the investigator 
Highest score 
UD 3 
III and IV 
Average of all sessions 
Highest score 
UD 4 
III  
Session marked as most severe by 
the investigator 
Sum of each questionnaire scores 
UD 5 
III  
Average of all sessions 
Sum of each questionnaire scores 
 
9.2.3 
ON Time Without Troublesome Dyskinesia 
Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia 
plus ON With Non-troublesome Dyskinesia) based on a PD Home Dyskinesia Diary will be 
summarized using descriptive statistics for all assessment time points. In this analysis, the 
number of records of ON Without Dyskinesia plus ON With Non-troublesome Dyskinesia 
divided by the number of non-missing awake records (sleeping records are excluded) for all 
measurements prior to Visit 2 and for all measurements from 4*24 hours prior to and up until 
Visit 6 and 7 respectively will be used as input data for each patient respectively. If there is not 


 
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at least 8 hours recorded data available for each patient and visit window, the corresponding 
timepoint is set to missing for the patient. ON Time Without Troublesome Dyskinesia will be 
analysed using inferential statistics as described under 9.2.1 above. 
9.2.4 
Unified Parkinson’s Disease Rating Scale (UPDRS) 
Change from baseline in UPDRS combined scores (Parts I, II, III and IV) to Visit 6 (Day 28) 
and Visit 7 (Day 42) respectively will be summarized using descriptive statistics. UPDRS 
combined scores will be analysed using inferential statistics as described under 9.2.1 above. 
The same analysis will be done for UPDRS Part III only. 
9.2.5 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms 
Change from baseline in CGI-C in overall PD symptoms to Visit 6 (Day 28) and Visit 7 (Day 
42) respectively will be summarized using descriptive statistics. In this analysis, rating 0, 
indicating “no assessment” will be excluded. CGI-C will be analysed using inferential statistics 
as described under 9.2.1 above. 
9.2.6 
Dyskinesia measured by a wearable dyskinesia assessment device 
Change from baseline in dyskinesia measured by the Kinesia 360 (Great Lakes 
Neurotechnologies, Inc) wearable dyskinesia assessment system to Visit 6 (Day 28) and Visit 
7 (Day 42) respectively will be summarized using descriptive statistics. In this analysis, the 
mean of all measurements prior to Visit 2 and the mean of all measurements from 4*24 hours 
prior to and up until Visit 6 and 7 respectively for each patient will be used as input data. 
However, recorded episodes of less than 30 minutes have not been used in the analysis. 
Furthermore, if there is not at least 8 hours of valid data according to the rules stipulated above 
for a specific patient and visit, the corresponding timepoint is set to missing for Kinesia 360 
data and hence, not used in the analysis. The Kinesia 360 variable “Dyskinesia detect” will be 
analyzed this way and reported in the CSR. Dyskinesia detect will be analysed using inferential 
statistics as described under 9.2.1 above. 
9.3 
Analysis of tertiary/exploratory endpoints 
9.3.1 
King’s Parkinson’s Disease Pain Scale (KPPS) total score 
Change from baseline in the KPPS individual pain domain scores and total score to Visit 6 (Day 
28) and Visit 7 (Day 42) respectively will be summarized using descriptive statistics. KPPS 
individual pain domain scores and total score will be analysed using inferential statistics as 
described under 9.2.1 above. 
9.3.2 
Parkinson’s Disease Questionnaire (PDQ39) total score 
The PDQ39 questionnaire assesses how often people affected by PD experience difficulties 
across 8 dimensions of daily living. The standard PDQ39 assesses quality of life over the 
previous month. In this study the initial time period assessed at the Baseline Visit will be the 
previous month, with subsequent assessments for the intervening period since the last clinic 
visit (about 3 weeks). 
 
The 8 quality of life dimensions covered in the questionnaire are: 
 
• 
Mobility (10 items #1-10)  
• 
ADL (6 items #11-16)  


 
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• 
Emotional Well Being (6 items #17-22)  
• 
Stigma (4 items #23-26)  
• 
Social Support (3 items #27-29)  
• 
Cognition (4 items #30-33)  
• 
Communications (3 items #34-36)  
• 
Bodily Discomfort (3 items #37-39)  
 
Individual items are rated by the patient on a categorical scale which will be re-coded to a scale 
of 0 to 4. 
Change from baseline in the PDQ39 quality of life dimensions scores and total score to Visit 6 
(Day 28) and Visit 7 (Day 42) respectively will be summarized using descriptive statistics. In 
this analysis each quality-of-life dimensions will be weighted to a scale of 0 to 100 using the 
formula 
Calculated dimension score = total registered score point for the dimension * 100 / maximum 
possible score points for the dimension 
, to allow each dimension to have an equal impact on the total score. PDQ39 quality of life 
dimensions scores and total score will be analysed using inferential statistics as described under 
9.2.1 above. 
9.3.3 
Hospital Anxiety Depression Scale (HADS) 
Change from baseline in the HADS to Visit 6 (Day 28) and Visit 7 (Day 42) respectively will 
be summarized using descriptive statistics. Summaries will be made for the total anxiety score 
and total depression score respectively. HADS will be analysed using inferential statistics as 
described under 9.2.1 above. 
9.3.4 
International Consultation on Incontinence Questionnaire Overactive Bladder 
Module (ICIQ-OAB) total score 
Change from baseline in the ICIQ-OAB total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. In this analysis, individual ICIQ-
OAB answers will be re-coded to a scale of 0-4. ICIQ-OAB total score will be analysed using 
inferential statistics as described under 9.2.1 above. 
9.3.5 
Epworth Sleepiness Scale (ESS) 
Change from baseline in the ESS total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. ESS total score will be analysed 
using inferential statistics as described under 9.2.1 above. 
9.4 
Description of study population 
Other study population/demographics data will be presented in listings and summarized 
descriptively as described in section 10 below.


 
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10 
DATA DISPLAY PLAN 
Tables and figures will only be generated if sufficient data, with sufficient variability exist to 
justify specific output being produced. 
10.1 
Table of contents DDP  
10.2 
Study tables ............................................................................................................. 24 
10.2.1 Demographic data .............................................................................................. 24 
10.2.2 Primary endpoint(s) ............................................................................................ 29 
10.2.2.1 
Adverse events ............................................................................................ 29 
10.2.2.2 
Physical examination .................................................................................. 31 
10.2.2.3 
Vital signs ................................................................................................... 31 
10.2.2.4 
12-lead ECG ................................................................................................ 32 
10.2.2.5 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................... 32 
10.2.2.6 
Safety laboratory analyses .......................................................................... 33 
10.2.3 Secondary endpoint(s) ........................................................................................ 34 
10.2.3.1 
Unified Dyskinesia Rating Scale (UDysRS) total score ............................. 34 
10.2.3.2 
ON Time Without Troublesome Dyskinesia .............................................. 35 
10.2.3.3 
Unified Parkinson’s Disease Rating Scale (UPDRS) ................................. 35 
10.2.3.4 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms . 36 
10.2.3.5 
Dyskinesia scores measured by a wearable dyskinesia assessment device 36 
10.2.4 Exploratory endpoint(s) ...................................................................................... 37 
10.2.4.1 
King’s Parkinson’s Disease Pain Scale (KPPS) total score ........................ 37 
10.2.4.2 
Parkinson’s Disease Questionnaire (PDQ39) total score ............................ 37 
10.2.4.3 
Hospital Anxiety Depression Scale (HADS) .............................................. 37 
10.2.4.4 
International Consultation on Incontinence Questionnaire Overactive 
Bladder Module (ICIQ-OAB) total score ..................................................................... 38 
10.2.4.5 
Epworth Sleepiness Scale (ESS) ................................................................. 38 
10.3 
Study listings ........................................................................................................... 38 
 
List of tables 
Table DM 1 
Baseline characteristics, demographics and estimated compliance (Full 
analysis set) 
24 
 
Table DS 1 
Subject disposition (All subjects) 
25 
 
Table MH 1 
Medical/psychiatric history events by system organ class and preferred term 
(Full analysis set) 
27 


 
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Table CM 1 
Prior medications by ATC levels 1, 3 and 5 (Full analysis set) 
27 
Table CM 2 
Concomitant medications by ATC levels 1, 3 and 5 (Full analysis set) 
28 
 
Table AE 1 
Overview of adverse events (Full analysis set) 
29 
Table AE 2 
Adverse events by system organ class and preferred term (Full analysis set)
 
30 
Table AE 3 
Overview of adverse events per titration period (Full analysis set) 
30 
Table AE 4 
Adverse events by system organ class and preferred term per titration period 
(Full analysis set) 
30 
 
Table PE 1 
 Physical examinations (Full analysis set) 
31 
 
Table VS 1 
Vital signs measurements (Full analysis set) 
31 
 
Table EG 1 
ECG measurements (Full analysis set) 
32 
Table EG 2  
ECG interpretations (Full analysis set) 
32 
 
Table CS 1 
Columbia Suicide Severity Rating Scale (C-SSRS) changes over time (Full 
analysis set) 
32 
 
Table LB 1 
Safety laboratory measurements - clinical chemistry (Full analysis set) 
33 
Table LB 2 
Safety laboratory measurements - haematology (Full analysis set) 
33 
Table LB 3 
Safety laboratory measurements - coagulation (Full analysis set) 
33 
Table LB 4 
Safety laboratory interpretations - urinalysis (Full analysis set) 
33 
 
Table UD 1  
UDysRS total score for all Parts (Full analysis set) 
34 
Table UD 2  
UdysRS total score for Part III and IV – Most severe assessment session and 
highest questionnaire item score (Full analysis set) 
34 
Table UD 3  
UdysRS total score for Part III and IV – Average of assessment sessions and 
highest questionnaire item score (Full analysis set) 
35 
Table UD 4  
UdysRS total score for Part III– Most severe assessment session and sum of 
questionnaire item scores (Full analysis set) 
35 
Table UD 5  
UdysRS total score for Part III– Average of assessment sessions and sum of 
questionnaire item scores (Full analysis set) 
35 
 
Table ON 1  
ON Time Without Troublesome Dyskinesia (Full analysis set) 
35 


 
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Table UP 1 
UPDRS total scores for all Parts (Full analysis set) 
35 
Table UP 2 
UPDRS total scores for Part III (Full analysis set) 
36 
 
Table CG 1 
CGI-S and CGI-C in overall PD symptoms (Full analysis set) 
36 
 
Table DA 1 Kinesia 360 wearable dyskinesia assessment system (Full analysis set) 
36 
 
Table KP 1 
KPPS individual pain domains scores and total score (Full analysis set) 
37 
 
Table PD 1 
PDQ39 calculated dimensions scores and total score (Full analysis set) 
37 
 
Table HA 1 
HADS anxiety and depression scores (Full analysis set) 
37 
 
Table IC 1 
ICIQ-OAB total score (Full analysis set) 
38 
 
Table ES 1 
ESS total score (Full analysis set) 
38 
 


 
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10.2 
Study tables 
10.2.1 
Demographic data 
Table DM 1 Baseline characteristics, demographics and estimated compliance (Full analysis set)  
Assessment (unit) 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
Age (years) 
n 
x 
x 
x 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx x) 
Median (Min, Max) 
xx.x (xx, xx) 
xx.x (xx, xx) 
xx.x (xx, xx) 
Height (cm) 
n 
x 
x 
x 
Mean (SD) 
xxx.x (xx.x) 
xxx x (xx.x) 
xxx.x (xx.x) 
Median (Min, Max) 
xxx.x (xxx, xxx) 
xxx x (xxx, xxx) 
xxx.x (xxx, xxx) 
Weight (kg) 
n 
x 
x 
x 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median (Min, Max) 
xx.xx (xx.x, xx.x) 
xx.xx (xx.x, xx.x) 
xx.xx (xx.x, xx.x) 
Body Mass Index (kg/m2) 
n 
x 
x 
X 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median (Min, Max) 
xx.xx (xx.x, xx.x) 
xx.xx (xx.x, xx.x) 
xx.xx (xx.x, xx.x) 
Sex 
Female 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Male 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Ethnicity 
Hispanic or latino 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Not hispanic or latino 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Not reported 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Unknown 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Race 
American Indian or Alaska Native 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Asian 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Black or African American 
xx (xx%) 
xx (xx%) 
xx (xx%) 


 
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Assessment (unit) 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
Native Hawaiian or Other Pacific Islander 
xx (xx%) 
xx (xx%) 
xx (xx%) 
White 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Compliance (%) 
n 
x 
x 
x 
 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx x) 
 
Median (Min, Max) 
xx.x (xx, xx) 
xx.x (xx, xx) 
xx.x (xx, xx) 
Data based on the Full analysis set. N: number of subjects in treatment group. Mean values and percentages are based on n. n: Number of 
observations. SD: Standard deviation. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-
DDTHH:MM:SS 
 
Table DS 1 
Subject disposition (All subjects)  
 
Total 
(N=XXX) 
Screened subjects 
xxx 
Withdrawn prior to dose 
xxx 
Reason for withdrawal prior to dose 
 
--- Reason 1 
xxx 
--- Reason 2 
xxx 
--- … 
xxx 
Subjects included in study 
xxx 
Allocated to arm 
 
--- NLX-112 
xxx 
--- Placebo 
xxx 
Withdrawn subjects 
 
--- [REASON 1]  
xxx 
--- [REASON 2] 
xxx 
--- … 
xxx 
Completed subjects 
xxx 
Included in Full analysis set 
xxx 


 
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Total 
(N=XXX) 
Included in Per protocol set 
xxx 
Subjects at each visit 
 
--- Visit 1  
xxx 
--- Visit 2 
xxx 
--- Visit 3 
xxx 
--- Visit 4 
xxx 
--- Visit 5 
xxx 
--- Visit 6 
xxx 
--- Visit 7 
xxx 
--- Visit 8 
xxx 
--- Visit 9 
xxx 
Data based on All subjects. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS  
 


 
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Table MH 1 Medical/psychiatric history events by system organ class and preferred 
term (Full analysis set)  
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
System organ class 
      Preferred term 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Total 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Data based on the Full analysis set. n, number of subjects. m, number of events. Percentages 
are based on the number of subjects in the treatment period. The following events are coded 
with multiple terms and are represented as separate events in tables and listings: '[MH TERM 
1], [MH TERM 2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run 
by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
Table CM 1 Prior medications by ATC levels 1, 3 and 5 (Full analysis set) 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
ATC Name Level 1 
     ATC Name Level 3 
          ATC Name Level 5 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Total 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
 
Data based on the Full analysis set. n, number of subjects. m, number of events. Percentages 
are based on the number of subjects in the treatment period. The following records are coded 
with multiple terms and are represented as separate events in tables and listings: '[CM TERM 
1], [CM TERM 2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run 
by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 


 
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Table CM 2 Concomitant medications by ATC levels 1, 3 and 5 (Full analysis set) 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
ATC Name Level 1 
     ATC Name Level 3 
          ATC Name Level 5 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Total 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 1 L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 2 L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[L1 …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 1 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 2 L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [L1 … L3 …L5 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Data based on the Full analysis set. n, number of subjects. m, number of events. Percentages 
are based on the number of subjects in the treatment period. The following records are coded 
with multiple terms and are represented as separate events in tables and listings: '[CM TERM 
1], [CM TERM 2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run 
by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
 
 
 


 
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10.2.2 
Primary endpoint(s) 
10.2.2.1 
Adverse events 
Table AE 1 
Overview of adverse events (Full analysis set)  
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Any AE 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any SAE 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any AE leading to withdrawal from study 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any AE leading to death 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Action taken with study drug 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Dose Not Changed 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Dose Rate Reduced 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Dose Reduced 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Drug Interrupted 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Drug Withdrawn 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
     Not Applicable 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Causality  
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Unlikely 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Possible 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Probable 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Severity  
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Mild 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Moderate 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Severe 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Life-Threatening 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      Death 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
 
Data based on the Full analysis set. N: number of subjects in treatment group. Percentages are 
based on N. n, number of subjects. m, number of events. The following AEs are coded with 
multiple MedDRA terms and are represented as separate AEs in tables and listings: '[AE TERM 
1]', '[AE TERM 2]', '[AE TERM 3]. See listings for detailed information. SAS program: [PROGRAM 
NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
 


 
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Table AE 2 
Adverse events by system organ class and preferred term (Full analysis 
set) 
 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
System organ class 
      Preferred term 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Total 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 1 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC 2 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
      [SOC … PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Data based on the Full analysis set. n, number of subjects. m, number of events. Percentages 
are based on the number of subjects in the treatment period. The following events are coded 
with multiple terms and are represented as separate events in tables and listings: '[AE TERM 
1], [AE TERM 2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run 
by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
If considered appropriate, produce the table above for SAEs only. 
 
Table AE 3 
Overview of adverse events per titration period (Full analysis set) 
Use the same template as for Table AE 1, but include columns (NLX-112 and Placebo 
respectively) for the up-titration period (up to Visit 6), the stable dosing period (Visit 6 to Visit 
7), the down-titration period (from Visit 7) and the Total column -> 7 results columns in all. 
 
Table AE 4 
Adverse events by system organ class and preferred term per titration 
period (Full analysis set) 
Use the same template as for Table AE 2, but include columns (NLX-112 and Placebo 
respectively) for the up-titration period (up to Visit 6), the stable dosing period (Visit 6 to Visit 
7), the down-titration period (from Visit 7) and the Total column -> 7 results columns in all. 
 
 
 


 
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10.2.2.2 
Physical examination 
Table PE 1 
 Physical examinations (Full analysis set) 
Assessment 
Assessment timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 1] 
[Assessment timepoint 1] 
[RESULT 1] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 2] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 3] 
x (xx%) 
x (xx%) 
x (xx%) 
[Assessment timepoint 2] 
[RESULT 1] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 2] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 3] 
x (xx%) 
x (xx%) 
x (xx%) 
Data based on the Full analysis set. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-
MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
10.2.2.3 
Vital signs 
Table VS 1 
Vital signs measurements (Full analysis set) 
Assessment (unit) 
Result category 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 1] 
(unit) 
Measured value 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Absolute change 
from baseline 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Relative change 
from baseline 
(%) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Data based on the Full analysis set. n: Number of observations. SD: Standard deviation. NC: 
Not calculated - number of evaluable observations less than 3. NA: Not available - no 
evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 


 
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10.2.2.4 
12-lead ECG 
Table EG 1 
ECG measurements (Full analysis set) 
Assessment (unit) 
Result category 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 1] 
(unit) 
Measured value 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Absolute change 
from baseline 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Relative change 
from baseline 
(%) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Data based on the Full analysis set. n: Number of observations. SD: Standard deviation. NC: 
Not calculated - number of evaluable observations less than 3. NA: Not available - no 
evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
Table EG 2  ECG interpretations (Full analysis set) 
Assessment 
Assessment timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 1] 
[Assessment timepoint 1] 
[RESULT 1] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 2] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 3] 
x (xx%) 
x (xx%) 
x (xx%) 
[Assessment timepoint 2] 
[RESULT 1] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 2] 
x (xx%) 
x (xx%) 
x (xx%) 
 
[RESULT 3] 
x (xx%) 
x (xx%) 
x (xx%) 
Data based on the Full analysis set. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-
MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
10.2.2.5 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Table CS 1 
Columbia Suicide Severity Rating Scale (C-SSRS) changes over time (Full 
analysis set) 
Use the same template as outlined in Section  0 above. 
 
 


 
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10.2.2.6 
Safety laboratory analyses 
Table LB 1 
Safety laboratory measurements - clinical chemistry (Full analysis set) 
Assessment (unit) 
Result category 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 1] 
(unit) 
Measured value 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Absolute change 
from baseline 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Relative change 
from baseline 
(%) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Data based on the Full analysis set. n: Number of observations. SD: Standard deviation. NC: 
Not calculated - number of evaluable observations less than 3. NA: Not available - no 
evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
Table LB 2 
Safety laboratory measurements - haematology (Full analysis set) 
Use the same format as for Table LB 1. 
 
Table LB 3 
Safety laboratory measurements - coagulation (Full analysis set) 
Use the same format as for Table LB 1. 
 
Table LB 4 
Safety laboratory interpretations - urinalysis (Full analysis set) 
Use the same format as for Table LB 1. 
 
 


 
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10.2.3 
Secondary endpoint(s) 
10.2.3.1 
Unified Dyskinesia Rating Scale (UDysRS) total score 
Table UD 1  UDysRS total score for all Parts (Full analysis set) 
Result category 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
Measured value 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
… 
… 
… 
… 
Absolute change from 
baseline 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
LMMa p-value 
x.xxxxb 
x.xxxxc 
x.xxxxd 
 
[Assessment 
timepoint 3] 
n 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
… 
… 
… 
… 
Relative change from 
baseline (%) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
 
[Assessment 
timepoint 3] 
n 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
… 
… 
… 
… 
a) Linear mixed model (LMM) with treatment, visit and the interaction treatment*visit as fixed 
categorical effects and subject within treatment as a random effect. The baseline value of the 
dependent variable has been included in the model as a continuous covariate. Kenward-Roger’s 
approximation for degrees of freedom will be used. 
b) p-value for the difference between NLX-112 at the assessment timepoint and at baseline. 
c) p-value for the difference between placebo at the assessment timepoint and at baseline. 
d) p-value for the difference between NLX-112 and placebo absolute change from baseline at the 
assessment timepoint. 
Data based on the Full analysis set. The session marked as most severe for Part III and IV 
have been used. For Part III, the highest score for each individual questionnaire item has 
been used. All UDysRS item scores for Part I, II, III and IV have been summarized pre patient 
and assessment timepoint and used as input data to the table. N: Number of observations. SD: 
Standard deviation. NC: Not calculated – number of evaluable observations less than 3. NA: Not 
available – no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] 
YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
Produce the table above for PPS as well, providing there is any de facto difference between the 
analysis sets. If the LMM is performed using transformed data, insert a footnote about this as 
well. If the LMM approach is dropped in favour of non-parametric tests, update the table and 
footnotes accordingly. 
 
Table UD 2  UdysRS total score for Part III and IV – Most severe assessment session 
and highest questionnaire item score (Full analysis set) 
Use the same format as for Table UD 1. Produce the table above for PPS as well, providing 
there is any de facto difference between the analysis sets. If the LMM is performed using 
transformed data, insert a footnote about this as well. If the LMM approach is dropped in favour 
of non-parametric tests, update the table and footnotes accordingly. 


 
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Table UD 3  UdysRS total score for Part III and IV – Average of assessment sessions 
and highest questionnaire item score (Full analysis set) 
Use the same format as for Table UD 1, but update the explanatory footnote to reflect the 
content of the table. Produce the table above for PPS as well, providing there is any de facto 
difference between the analysis sets. If the LMM is performed using transformed data, insert a 
footnote about this as well. If the LMM approach is dropped in favour of non-parametric tests, 
update the table and footnotes accordingly. 
Table UD 4  UdysRS total score for Part III– Most severe assessment session and sum 
of questionnaire item scores (Full analysis set) 
Use the same format as for Table UD 1, but update the explanatory footnote to reflect the 
content of the table. Produce the table above for PPS as well, providing there is any de facto 
difference between the analysis sets. If the LMM is performed using transformed data, insert a 
footnote about this as well. If the LMM approach is dropped in favour of non-parametric tests, 
update the table and footnotes accordingly. 
Table UD 5  UdysRS total score for Part III– Average of assessment sessions and sum 
of questionnaire item scores (Full analysis set) 
Use the same format as for Table UD 1, but update the explanatory footnote to reflect the 
content of the table. Produce the table above for PPS as well, providing there is any de facto 
difference between the analysis sets. If the LMM is performed using transformed data, insert a 
footnote about this as well. If the LMM approach is dropped in favour of non-parametric tests, 
update the table and footnotes accordingly. 
10.2.3.2 
ON Time Without Troublesome Dyskinesia 
Table ON 1  ON Time Without Troublesome Dyskinesia (Full analysis set) 
Use the same format as for Table UD 1. Add a footnote stating that the sum of records of ON 
Without Dyskinesia plus ON With Non-troublesome Dyskinesia for the 2*24 hours 
measurements prior to each visit has been used as input data for each patient respectively. 
Produce the table above for PPS as well, providing there is any de facto difference between the 
analysis sets. If the LMM is performed using transformed data, insert a footnote about this as 
well. If the LMM approach is dropped in favour of non-parametric tests, update the table and 
footnotes accordingly. 
10.2.3.3 
Unified Parkinson’s Disease Rating Scale (UPDRS) 
Table UP 1 
UPDRS total scores for all Parts (Full analysis set) 
Use the same format as for Table UD 1. Include all visits with UPDRS data in the table.  Produce 
the table above for PPS as well, providing there is any de facto difference between the analysis 
sets. If the LMM is performed using transformed data, insert a footnote about this as well. If 
the LMM approach is dropped in favour of non-parametric tests, update the table and footnotes 
accordingly. 
 
 


 
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Table UP 2 
UPDRS total scores for Part III (Full analysis set) 
Use the same format as for Table UD 1. Include all visits with UPDRS data in the table. Produce 
the table above for PPS as well, providing there is any de facto difference between the analysis 
sets. If the LMM is performed using transformed data, insert a footnote about this as well. If 
the LMM approach is dropped in favour of non-parametric tests, update the table and footnotes 
accordingly. 
10.2.3.4 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms 
Table CG 1 CGI-S and CGI-C in overall PD symptoms (Full analysis set) 
Assessment 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
CGI-S 
 
 
 
CGI-C 
 
 
 
CGI-C 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
 
LMMa p-value 
x.xxxxb 
x.xxxxc 
x.xxxxd 
[Assessment 
timepoint 3] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
 
 
LMMa p-value 
x.xxxxb 
x.xxxxc 
x.xxxxd 
 
Data based on the Full analysis set. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-
MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
Specify CGI-S or CGI-C in the assessment column. Do not include rating 0, indicating “no 
assessment” in the summary/analysis. There is no result category column, since change from 
baseline is included in the definition of CGI-C. Produce the table above for PPS as well, 
providing there is any de facto difference between the analysis sets. If the LMM is performed 
using transformed data, insert a footnote about this as well. If the LMM approach is dropped in 
favour of non-parametric tests, update the table and footnotes accordingly. 
10.2.3.5 
Dyskinesia scores measured by a wearable dyskinesia assessment device 
Table DA 1 Kinesia 360 wearable dyskinesia assessment system (Full analysis set) 
Use the same format as for Table UD 1. Add a footnote describing that the mean values per 
patient and visit have been used as input data to the table. Produce the table above for PPS as 
well, providing there is any de facto difference between the analysis sets. If the LMM is 
performed using transformed data, insert a footnote about this as well. If the LMM approach is 
dropped in favour of non-parametric tests, update the table and footnotes accordingly. 


 
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10.2.4 
Exploratory endpoint(s) 
10.2.4.1 
King’s Parkinson’s Disease Pain Scale (KPPS) total score 
Table KP 1 
KPPS individual pain domains scores and total score (Full analysis set) 
Assessment 
(unit) 
Result category 
Assessment 
timepoint 
 
NLX-112 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
[PARAMETER 
1] (unit) 
Measured value 
[Assessment 
timepoint 1] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
… 
… 
… 
… 
Absolute change from 
baseline 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
LMMa p-value 
x.xxxxb 
x.xxxxc 
x.xxxxd 
Relative change from 
baseline (%) 
[Assessment 
timepoint 2] 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) x.xx (x.x, x.x) 
Data based on the Full analysis set. n: Number of observations. SD: Standard deviation. NC: 
Not calculated - number of evaluable observations less than 3. NA: Not available - no 
evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
Produce the table above for PPS as well, providing there is any de facto difference between the 
analysis sets. If the LMM is performed using transformed data, insert a footnote about this as 
well. If the LMM approach is dropped in favour of non-parametric tests, update the table and 
footnotes accordingly. 
10.2.4.2 
Parkinson’s Disease Questionnaire (PDQ39) total score 
Table PD 1 
PDQ39 calculated dimensions scores and total score (Full analysis set) 
Use the same format as for Table KP 1. Produce the table above for PPS as well, providing 
there is any de facto difference between the analysis sets. If the LMM is performed using 
transformed data, insert a footnote about this as well. If the LMM approach is dropped in favour 
of non-parametric tests, update the table and footnotes accordingly. 
10.2.4.3 
Hospital Anxiety Depression Scale (HADS) 
Table HA 1 HADS anxiety and depression scores (Full analysis set) 
Use the same format as for Table KP 1. Produce the table above for PPS as well, providing 
there is any de facto difference between the analysis sets. If the LMM is performed using 
transformed data, insert a footnote about this as well. If the LMM approach is dropped in favour 
of non-parametric tests, update the table and footnotes accordingly. 


 
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10.2.4.4 
International Consultation on Incontinence Questionnaire Overactive Bladder 
Module (ICIQ-OAB) total score 
Table IC 1 
ICIQ-OAB total score (Full analysis set) 
Use the same format as for Table UD 1. Produce the table above for PPS as well, providing 
there is any de facto difference between the analysis sets. If the LMM is performed using 
transformed data, insert a footnote about this as well. If the LMM approach is dropped in favour 
of non-parametric tests, update the table and footnotes accordingly. 
10.2.4.5 
Epworth Sleepiness Scale (ESS) 
Table ES 1 
ESS total score (Full analysis set) 
Use the same format as for Table UD 1. Produce the table above for PPS as well, providing 
there is any de facto difference between the analysis sets. If the LMM is performed using 
transformed data, insert a footnote about this as well. If the LMM approach is dropped in favour 
of non-parametric tests, update the table and footnotes accordingly. 
 
 
10.3 
Study listings 
16.2.1 Discontinued patients 
• Listing 16.2.1- 1 
Discontinued patients (All patients) 
Include reason for discontinuation and site in the listing. 
• Listing 16.2.1- 2 
Non-eligible patients (All patients) 
• Listing 16.2.1- 3 
Disposition (All patients) 
• Listing 16.2.1- 4 
Patient visits (All patients) 
• Listing 16.2.1- 5 
Patient elements (All patients) 
16.2.2 Protocol deviations 
• Listing 16.2.2- 1 
Protocol deviations (All patients) 
Include site in the listing. 
16.2.3 Population definitions 
• Listing 16.2.3- 1 
Patients excluded from Per protocol set (All patients) 
• Listing 16.2.3- 2 
Population definitions (All patients) 
 
 


 
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16.2.4 Demographic data 
• Listing 16.2.4- 1 
Demography (Full analysis set) 
• Listing 16.2.4- 2 
Medical and psychiatric History (Full analysis set) 
• Listing 16.2.4- 3  
Prior and concomitant medications (Full analysis set) 
• Listing 16.2.4- 4 
Hoehn and Yahr scale (Full analysis set) 
• Listing 16.2.4- 5 
MMSE (Full analysis set) 
16.2.5 Compliance and/or Drug Concentration Data 
• Listing 16.2.5- 1  
Compliance – Evaluation (Full analysis set)  
• Listing 16.2.5- 2  
Compliance – NLX-112 plasma concentrations (Full analysis 
set) 
Listing 16.2.5- 3  IMP administration (Full analysis set) 
16.2.6 Individual Efficacy Response Data 
• Listing 16.2.6- 1 
UDysRS (Full analysis set) 
• Listing 16.2.6- 2 
UPDRS, parts I-IV (Full analysis set) 
• Listing 16.2.6- 3 
CGI-S, CGI-C (Full analysis set) 
• Listing 16.2.6- 4 
KPPS (Full analysis set) 
• Listing 16.2.6- 5 
PDQ39 (Full analysis set) 
• Listing 16.2.6- 6 
HADS (Full analysis set) 
• Listing 16.2.6- 7 
ICIQ-OAB (Full analysis set) 
• Listing 16.2.6- 8 
ESS (Full analysis set) 
• Listing 16.2.6- 9 
Kinesia 360 wearable device data (Full analysis set) 
• Listing 16.2.6- 10 
PD Home Dyskinesia Diary (Full analysis set) 
16.2.7 Adverse event listings (each patient) 
• Listing 16.2.7- 1 
Adverse events (Full analysis set) 
Include site in the listing. 
• Listing 16.2.7- 2  
Serious adverse events (Full analysis set) 
Include site in the listing. 
 
 


 
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16.2.8 Listings of individual laboratory measurements by patient 
• Listing 16.2.8- 1  
Safety laboratory measurements (Full analysis set) 
Abnormal values and assessment of clinical significance must be included. 
• Listing 16.2.8- 2  
Other laboratory measurements (Full analysis set) 
16.2.9 Listings of vital signs, ECG, physical examination and C-SSRS data by patient  
• Listing 16.2.9- 1  
Vital signs (Full analysis set) 
• Listing 16.2.9- 2  
ECG (Full analysis set) 
• Listing 16.2.9- 3  
Physical examinations (Full analysis set) 
• Listing 16.2.9- 4  
C-SSRS (Full analysis set) 

Prot_000.pdf: 


 
 
 
 
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1 
STUDY SYNOPSIS 
Study title 
A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and 
Preliminary Efficacy of NLX-112 versus Placebo in Levodopa-induced Dyskinesia in Parkinson’s 
Disease 
Study code 
NLX-112-DYS-101 
Planned study period 
Q3 2021 to Q4 2022 
Phase of development 
IIa 
Principal Investigator 
 
ASC Torsplan, Stockholm, Sweden 
Study design 
This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, 
tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo in 
patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson’s disease (PD). 
NLX-112 will be up-titrated to either 2 mg/day or to the highest well-tolerated dose less than 
2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then 
down-titrated over 2 weeks. 
Objectives  
Primary objective 
To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared 
to placebo during 8 weeks of daily treatment in PD patients with LID. 
Secondary objective  
To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID. 
Exploratory objectives 
To assess the preliminary efficacy of NLX-112 treatment in improving selected non-motor symptoms 
of PD, including pain, bladder function, sleep function, mood and quality of living with PD.  
To collect blood samples for potential NLX-112 plasma concentration analysis.  
Endpoints 
Primary endpoints 
• 
Frequency, intensity and seriousness of adverse events (AEs) 
• 
Clinically significant changes from baseline in electrocardiogram (ECG), vital signs, safety 
laboratory parameters and physical examinations. 
• 
Suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale 
(C-SSRS).   


 
 
 
 
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Secondary endpoints 
• 
Change from baseline at the final efficacy clinic visit (Day 42) in the Unified Dyskinesia 
Rating Scale (UDysRS) total score [Timeframe: Baseline to Day 42]. Patients will be 
challenged with 150% of their standard L-DOPA dose (maximum L-DOPA dose 250 mg) 
30 minutes prior to the first UDysRS assessment. 
• 
Change from baseline in UDysRS total score at Day 28, after a 150% L-DOPA dose 
challenge. 
• 
Change from baseline in total objective score (Parts III, IV) of the UDysRS at Day 28 and 
Day 42, after a 150% L-DOPA dose challenge. 
• 
Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia 
plus ON With Non-troublesome Dyskinesia) based on a PD Home Dyskinesia Diary. 
• 
Change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) scores (Part III, 
motor examination). 
• 
Change from baseline in UPDRS combined scores (Parts I, II, III and IV). 
• 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms 
• 
Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes 
Neurotechnologies, Inc) wearable dyskinesia assessment system. 
Exploratory endpoints 
• 
Change from baseline in the King’s Parkinson’s Disease Pain Scale (KPPS) total score and in 
each of the 7 pain domain sub-scores. 
• 
Change from baseline in the Parkinson’s Disease Questionnaire (PDQ39) total score and 
domain scores. 
• 
Change from baseline in the Hospital Anxiety Depression Scale (HADS) 
• 
Change from baseline in the International Consultation on Incontinence Questionnaire (ICIQ) 
Overactive Bladder Module (ICIQ-OAB) total score. 
• 
Change from baseline in the Epworth Sleepiness Scale (ESS). 
• 
Plasma concentrations of NLX-112. 
The NLX-112 plasma concentration analysis may only be performed if the Sponsor deems it 
necessary to answer any questions regarding compliance. The outcome of the results may not be 
reported in the clinical study report (CSR). 
Number of patients planned 
A total of 24 patients will be randomized in the study. Patients will be recruited at 5 clinical sites, with 
an average of 4 to 6 patients per site.  
To account for potential drop-outs, additional patients may be included in the study. For replacements 
of patients who discontinue from the study. 
Diagnosis and main eligibility criteria 
Inclusion criteria:  
1. Patient is 30 – 85 years old (inclusive) with a diagnosis of idiopathic PD according to the UK 
Parkinson’s Disease Society Brain Bank Clinical Diagnosis criteria.  
2. PD patient is stably and optimally treated with L-DOPA; other anti-PD treatments are allowed if 
used for at least 4 weeks of previous continuous treatment.  
3. Patient agrees to be challenged with 150% of their normal L-DOPA dose (maximum L-DOPA dose 
250 mg) 30 minutes prior to efficacy assessments at baseline (Visit 2) and at the 2 efficacy clinic visits 
(Visits 6 and 7). 


 
 
 
 
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4. PD patient exhibits troublesome peak-dose LID, confirmed by a score of at least 1 on part IV, 
item 33 (disability) of the Unified Parkinson’s Disease Rating Scale (UPDRS) at screening (Visit 1) 
and at Day 1 (baseline, Visit 2).   
5. At least 90 minutes in total for each 24-hour period during 2 days are indicated as “ON with 
troublesome dyskinesia” (according to the PD Home Dyskinesia Diary) prior to Day 1 (baseline, 
Visit 2).  
6. Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home Dyskinesia 
Diary entries during the screening visit.  
7. Patient can read well enough to understand the informed consent document and other subject 
materials.  
8. Female patients of child-bearing potential must have a negative urine pregnancy test at screening 
(Visit 1) and on Day 1 (Visit 2), must agree to avoid pregnancy during the study, and must practice 
abstinence (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to 
use a highly effective method of contraception with a failure rate of < 1% to prevent pregnancy 
(combined [oestrogen and progestogen containing] hormonal contraception associated with inhibition 
of ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception associated 
with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD] or intrauterine 
hormone-releasing system [IUS]) starting from 4 weeks prior to administration of the study drug and 
continuing during the course of the study until 4 weeks after last after IMP administration. Female 
subjects must agree to refrain from donating eggs from the date of dosing until 3 months after dosing 
with the IMP. Their male partner must agree to use a condom during the same time frame if he has not 
undergone vasectomy.  
Females of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal 
ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone 
hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in 
questionable cases a blood sample with detection of follicle stimulating hormone [FSH] 25-140 IE/L 
is confirmatory).  
Male patients must be either vasectomised, consent to use condom or practice sexual abstinence to 
prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of 
dosing until 3 months after dosing with the IMP. Their female partner of child-bearing potential must 
use highly effective contraceptive methods with a failure rate of < 1% to prevent pregnancy (see 
above) during the same period. 
Exclusion criteria:  
1. Patient has severe PD with a Hoehn and Yahr stage = 5.  
2. Patient has unstable medical status, prior brain surgery against tumors or hemorrhage (excluding 
deep brain stimulation [DBS], i.e., DBS patients will be allowed to be enrolled) or is scheduled to 
receive surgery during the trial period.  
3. Patient has orthostatic hypotension: a decrease in systolic blood pressure (at least 20 mm Hg) or 
diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the patient standing up, compared to 
pressures obtained while in a sitting position for at least 5 minutes. At screening and baseline visits 
(Visit 1 and Visit 2), vital signs to assess orthostatic hypotension will be conducted in triplicate, 
15-20 minutes apart, with the average of the 3 assessments used for exclusion.  
4. Patient has dementia (MMSE <20).  
5. Patient has clinically significant renal or liver disorder.  
6. Patient currently exhibits generalized obsessive-compulsive disorder, panic disorder, bipolar 
disorder, post-traumatic stress syndrome (PTSD), clinically significant parasomnias or any other 
psychotic disorder as established by structured clinical interview for DSM disorders (SCID). Visual 
hallucinations are allowed.  


 
 
 
 
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7. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted 
attempt, aborted attempt, or preparatory acts or behavior).  
8. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and intent). 
9. Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or 
buspirone within 4 weeks of baseline (Day 1, Visit 2).  
10. Patient has taken, within 4 weeks of baseline (Day 1, Visit 2), any medication that inhibits or up-
regulates CYP450 3A4.  
11. Patient is concurrently participating in another investigational drug trial or has participated in 
another investigational drug trial within the past 3 months.  
12. Patient is at high risk of non-compliance in the Investigator’s opinion.  
Methodology 
Patients will report to the study clinic for a screening visit (Visit 1), followed by a baseline visit on 
Day 1 (Visit 2) where patients will be randomized and begin treatment. Two remote safety visits over 
telephone (Days 7 and 49 [Visit 3 and Visit 8]) will be conducted. Once treatment has commenced, 
there will be 2 in-person safety visits to the clinic (Days 14 and 21 [Visit 4 and Visit 5]), 2 in-person 
efficacy visits to the clinic (Days 28 and 42 [Visit 6 and Visit 7]) and one follow-up in-person final 
safety visit (Day 70 [Visit 9]). In total, patients will report to the clinic for 7 in-person visits. Patients 
entering the study will be randomized in a 2:1 ratio (16:8 patients) to receive either NLX-112 or 
placebo. 
At Visits 2, 6 and 7, efficacy assessments will start 30 minutes after the patient has taken 150% of his 
or her regular L-DOPA dose, when the patient is ON and experiencing typical dyskinesia.  
A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver with 
concordance in ON time with dyskinesia between study staff and patient. Two consecutive 24-hour 
diaries will be completed prior to randomization (baseline, Visit 2) and prior to the clinic visits on 
Days 28 and 42 (Visits 6 and 7). 
A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day period 
prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on Days 28 and 
42 (Visits 6 and 7, respectively). 
Blood will be collected for possible NLX-112 plasma concentration measurements on Days 14, 21, 
28, 42 and 70 (Visits 4, 5, 6, 7 and 9). 
Patients will self-administer NLX-112 or placebo 2 times each day, once in the morning and once in 
the evening. Tablets should be taken with approximately 240 mL water during a meal. Active tablets 
will contain 0.25 mg NLX-112. Dose escalation will be as follows: 
Up-titration period (4 weeks):  
• 
Days 1-4 (0.25 mg/day): 1 tablet in the morning, none in the evening 
• 
Days 5-8 (0.5 mg/day): 1 tablet in the morning and 1 tablet in the evening 
• 
Days 9-12 (0.75 mg/day): 2 tablets in the morning, 1 tablet in the evening 
• 
Days 13-16 (1.0 mg/day): 2 tablets in the morning, 2 tablets in the evening  
• 
Days 17-20 (1.25 mg/day): 3 tablets in the morning, 2 tablets in the evening  
• 
Days 21-24 (1.5 mg/day): 3 tablets in the morning, 3 tablets in the evening  
• 
Days 25-28 (1.75 mg/day): 4 tablets in the morning, 3 tablets in the evening 


 
 
 
 
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Constant dose period (2 weeks): 
• 
Days 29-42 (2 mg/day): 4 tablets in the morning, 4 tablets in the evening  
Down-titration period (2 weeks, down-titration by 0.25 mg/day every 2 days):  
• 
Days 43-44 (start of down-titration period [1.75 mg/day]) 
• 
Days 45-46 (1.5 mg/day)  
• 
Days 47-48 (1.25 mg/day)  
• 
Days 49-50 (1 mg/day)  
• 
Days 51-52 (0.75 mg/day)  
• 
Days 53-54 (0.5 mg/day)  
• 
Days 55-56 (0.25 mg/day) 
Patients in the placebo arm will follow the same dose escalation, constant dose and down-titration 
schedule, but will be taking the matching placebo tablets. Patients who have intolerable adverse events 
(AEs) during the 28-day up-titration period will be allowed to return to the previous tolerated dose at 
the discretion of the Investigator, or they may withdraw from the study if they so choose. 
Investigational Medicinal Product (IMP), dosage and mode of administration 
NLX-112, also known as F13640 and Befiradol, in tablets of 0.25 mg administered orally. NLX-112 
will be up-titrated to 2 mg/day (or to the highest well-tolerated dose less than 2 mg/day) over 4 weeks, 
maintained at that dose for 2 weeks, then followed by a 2 week down-titration period. 
Placebo will be matching tablets (identical weight, shape and color) administered orally using the 
same dose escalation, constant dose and down-titration schedule.  
Duration of treatment 
Patients will be treated for a total of 8 weeks (56 days), receiving the IMP twice daily, once in the 
morning and once in the evening.  
Duration of each patient’s involvement in the study 
The total duration of participation for each patient will be approximately 10 weeks, not including 
screening. 
Safety assessments  
Safety/tolerability assessments will include: medical history (screening), physical examination 
(screening and follow-up), 12-lead ECG (all clinic visits), vital signs (all clinic visits), AEs (from 
baseline visit through follow up visit), assessment of suicidal ideation/behavior (C-SSRS; all clinic 
visits), and clinical labs (hematology, blood chemistry, and urinalysis; all clinic visits). 
Efficacy assessments  
• 
UDysRS 
• 
PD Home Dyskinesia Diary (ON time without troublesome dyskinesia) 
• 
UPDRS, parts I-IV 
• 
CGI-S, CGI-C 
• 
Wearable dyskinesia assessment device data collection 
• 
KPPS 
• 
PDQ39 
• 
HADS 
• 
ICIQ-OAB  


 
 
 
 
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• 
ESS 
Efficacy assessments will be collected on Days 1, 28 and 42 (Visits 2, 6 and 7, respectively). 
Diary data will be based on 2 consecutive 24-hour diaries taken prior to the baseline visit (Visit 2) and 
prior to Days 28 and 42 (Visits 6 and 7, respectively). Similarly, wearable data collection will take 
place during a 2-day period prior to the baseline visit (Visit 2) and a 2-day period prior to the clinic 
visits on Days 28 and 42 (Visits 6 and 7, respectively).  
Rater and self-assessments 
An independent neurologist or the treating physician will rate patients at each clinical site. At each 
applicable visit (Visits 2, 6 and 7) the same rater (if possible) will conduct efficacy assessments 
beginning 30 minutes after the patient has taken 150% of his or her regular L-DOPA dose, when the 
patient is ON and experiencing typical dyskinesia. The UDysRS assessments will be videotaped at 
Visits 2, 6 and 7. 
Patients (and/or caregivers) need to demonstrate the ability to complete the electronic PD Home 
Dyskinesia Diary, with concordance in ON time with dyskinesia between study staff and patient. 
A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day period 
prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on Days 28 and 
42 (Visits 6 and 7, respectively). 
Plasma concentration assessment 
Blood samples, for possible later assessment of NLX-112 plasma concentration, will be collected at 
clinic visits on days 14, 21, 28, 42 and 70 (Visits 4, 5, 6, 7 and 9, in total 5 samples per patient).  
Statistical methods 
Analysis Populations 
• 
Safety analysis set: All enrolled patients who receive at least one dose of study medication. 
• 
Full analysis set (FAS): All randomized patients who were dosed and who provided at least 
one post-baseline assessment of the UDysRS. 
• 
Per protocol set (PPS): All patients included in the FAS population who do not have any 
major protocol violations assessed to compromise the analysis of study data. 
General 
Data will be summarized and presented by treatment, and by assessment time as applicable. Individual 
patient data will be listed by patient number, treatment, and by assessment time. 
Safety analysis 
The safety analyses will be based on the safety dataset.  
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be presented 
by treatment group. Incidence of AEs and SAEs will be summarized by system organ class (SOC) and 
preferred term (PT) by treatment. Separate tables will be provided, if relevant, for serious AEs (SAEs) 
or events leading to withdrawal from study. 
Summary statistics by treatment group and time point will be produced for vital signs, ECG 
parameters and physical examinations. Laboratory data will also be summarized for baseline and all 
post-treatment clinic visits. 
Efficacy analysis 


 
 
 
 
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All efficacy analyses will be performed separately on both the FAS and PP sets if deemed appropriate. 
To explore statistically significant differences between active treatment and placebo, Wilcoxon 
signed-rank tests for efficacy endpoints will performed by each assessment timepoint. 
Sample size 
No formal sample size calculation has been performed. The sample size of 24 patients is considered 
sufficient to evaluate the primary objective and to allow for a preliminary efficacy evaluation.  
Study reporting 
After completion of the study, an International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) E3 compliant CSR will be prepared. 


 
 
 
 
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2 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS .................................................................................................. 2 
2 
TABLE OF CONTENTS ......................................................................................... 9 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 13 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................................... 16 
4.1 
Medical emergencies contacts ............................................................................... 16 
5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......... 16 
6 
INTRODUCTION .................................................................................................. 18 
6.1 
Background ............................................................................................................. 18 
 
Overview of NLX-112......................................................................................... 18 
 
Non-clinical studies: toxicology and pharmacokinetics .................................. 18 
 
Clinical experience.............................................................................................. 21 
6.2 
Study rationale........................................................................................................ 23 
6.3 
Risk/benefit assessment.......................................................................................... 24 
 
Potential risks...................................................................................................... 24 
 
Potential benefits ................................................................................................ 25 
 
Risk-benefit conclusion ...................................................................................... 25 
 
Risk assessment with regards to the Covid-19 pandemic: .............................. 26 
7 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 26 
7.1 
Primary objective ................................................................................................... 26 
 
Primary endpoints .............................................................................................. 26 
7.2 
Secondary objective................................................................................................ 26 
 
Secondary endpoints .......................................................................................... 26 
7.3 
Exploratory objectives ........................................................................................... 27 
 
Exploratory endpoints........................................................................................ 27 
8 
STUDY DESIGN .................................................................................................... 28 
8.1 
Overall study design and schedule of events ........................................................ 28 
8.2 
Order of assessments .............................................................................................. 34 
8.3 
Rationale for study design ..................................................................................... 34 
8.4 
Selection of dose ...................................................................................................... 35 
9 
STUDY POPULATION ......................................................................................... 36 
9.1 
Recruitment ............................................................................................................ 36 
9.2 
Screening and enrolment log ................................................................................. 36 
9.3 
Number of patients ................................................................................................. 36 
9.4 
Inclusion criteria .................................................................................................... 36 
9.5 
Exclusion criteria.................................................................................................... 37 
9.6 
Restrictions during the study ................................................................................ 38 
 
General restrictions ............................................................................................ 38 
 
Prior and concomitant therapy ......................................................................... 39 
9.7 
Screen failures ........................................................................................................ 39 
9.8 
Patient withdrawal ................................................................................................. 40 


 
 
 
 
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General withdrawal criteria .............................................................................. 40 
 
QTc withdrawal criteria .................................................................................... 40 
 
Liver chemistry withdrawal criteria ................................................................. 41 
 
Procedures for discontinuation of a patient from the study ........................... 41 
 
Patient replacement ............................................................................................ 41 
9.9 
Randomization ........................................................................................................ 41 
9.10 
Blinding ................................................................................................................... 42 
9.11 
Emergency unblinding during the study .............................................................. 42 
10 
TREATMENTS ...................................................................................................... 42 
10.1 
Identity of investigational medicinal products .................................................... 42 
10.2 
Manufacturing, packaging and labelling ............................................................. 42 
10.3 
Importation, release and distribution................................................................... 42 
10.4 
Conditions for storage ............................................................................................ 42 
10.5 
Dispensing and accountability............................................................................... 43 
10.6 
Treatment administration ..................................................................................... 43 
10.7 
Continuation of treatment with investigational medicinal product .................. 43 
10.8 
Treatment compliance ........................................................................................... 43 
10.9 
Return and destruction of investigational medicinal products .......................... 43 
11 
STUDY ASSESSMENTS ....................................................................................... 44 
11.1 
Recording of data ................................................................................................... 44 
 
Informed consent ................................................................................................ 44 
 
Eligibility criteria................................................................................................ 44 
 
Demographic information.................................................................................. 44 
 
Weight and height............................................................................................... 44 
 
Medical and psychiatric history ........................................................................ 44 
 
Prior and concomitant medication.................................................................... 44 
 
Pregnancy test ..................................................................................................... 45 
 
Hoehn and Yahr scale ........................................................................................ 45 
 
Mini Mental Status Exam .................................................................................. 45 
 
Baseline symptoms.............................................................................................. 45 
11.2 
Assessments related to primary endpoints........................................................... 45 
 
Adverse events .................................................................................................... 45 
 
Physical examination .......................................................................................... 51 
 
Vital signs ............................................................................................................ 51 
 
Electrocardiogram .............................................................................................. 52 
 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 52 
 
Laboratory safety assessments .......................................................................... 52 
11.3 
Assessments related to secondary endpoints ....................................................... 53 
 
L-DOPA challenge .............................................................................................. 54 
 
Unified Dyskinesia Rating Scale (UDysRS) ..................................................... 54 
 
PD Home Dyskinesia Diary ............................................................................... 55 
 
Unified Parkinson’s Disease Rating Scale (UPDRS) ....................................... 55 
 
Clinical Global Impression of Severity and Change (CGI-S, CGI-C) ........... 56 
 
Wearable dyskinesia assessment device ........................................................... 56 
11.4 
Assessments related to exploratory endpoints ..................................................... 56 
 
King’s Parkinson’s Disease Pain Scale (KKPS) .............................................. 56 
 
Parkinson’s Disease Questionnaire (PDQ39) ................................................... 57 


 
 
 
 
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Hospital Anxiety Depression Scale (HADS) ..................................................... 57 
 
International Consultation on Incontinence Questionnaire Overactive 
Bladder Module (ICIQ-OAB) ............................................................................................... 57 
 
Epworth Sleepiness Scale (ESS) ........................................................................ 58 
 
Plasma concentration of NLX-112 .................................................................... 58 
11.5 
Appropriateness of measurements ....................................................................... 58 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES .............................................. 58 
12.1 
Sample collection .................................................................................................... 58 
12.2 
Volume of blood ...................................................................................................... 58 
12.3 
Handling, storage and destruction of laboratory samples.................................. 59 
12.4 
Chain of custody of biological samples ................................................................. 59 
12.5 
Withdrawal of informed consent for donated biological samples ..................... 59 
13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .............................................................................................................................. 59 
13.1 
Quality management: critical process, system and data identification ............. 59 
13.2 
Quality assurance and quality control ................................................................. 60 
14 
ETHICAL AND REGULATORY REQUIREMENTS ...................................... 60 
14.1 
Ethical conduct of the study .................................................................................. 60 
14.2 
Ethics and regulatory review ................................................................................ 60 
14.3 
Patient information and consent ........................................................................... 61 
14.4 
Patient information card ....................................................................................... 61 
14.5 
Patient data protection........................................................................................... 61 
14.6 
Changes to the approved clinical study protocol................................................. 62 
14.7 
Audits and inspections ........................................................................................... 62 
14.8 
Insurance ................................................................................................................. 62 
15 
STUDY MANAGEMENT ..................................................................................... 63 
15.1 
Training of study site personnel ............................................................................ 63 
15.2 
Clinical monitoring ................................................................................................ 63 
15.3 
Source data documents .......................................................................................... 64 
15.4 
Study agreements ................................................................................................... 64 
15.5 
Study timetable and end of study.......................................................................... 64 
15.6 
Criteria for site termination .................................................................................. 65 
15.7 
Termination of the study ....................................................................................... 65 
15.8 
Reporting and publication ..................................................................................... 65 
 
Clinical study report........................................................................................... 65 
 
Annual safety report........................................................................................... 66 
 
Confidentiality and ownership of study data ................................................... 66 
 
Publication........................................................................................................... 66 
15.9 
Archiving ................................................................................................................. 66 
16 
DATA MANAGEMENT ....................................................................................... 67 
16.1 
The web-based eCRF ............................................................................................. 67 
16.2 
The entering of data into the eCRF ...................................................................... 67 
16.3 
The query process................................................................................................... 68 
16.4 
Audit trail ................................................................................................................ 68 
16.5 
External data .......................................................................................................... 68 
16.6 
Medical coding ........................................................................................................ 68 


 
 
 
 
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16.7 
Database lock .......................................................................................................... 68 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE . 69 
17.1 
General .................................................................................................................... 69 
17.2 
Determination of sample size ................................................................................ 69 
17.3 
Analysis populations .............................................................................................. 69 
 
Safety analysis set ............................................................................................... 69 
 
Full analysis set ................................................................................................... 69 
 
Per protocol set ................................................................................................... 70 
17.4 
Description of study population ............................................................................ 70 
 
Demographics and baseline characteristics ..................................................... 70 
 
Medical/psychiatric history and prior/concomitant medication .................... 70 
 
Treatment compliance........................................................................................ 70 
17.5 
Analysis of primary endpoints .............................................................................. 70 
 
Adverse events .................................................................................................... 70 
 
Physical examination .......................................................................................... 70 
 
Vital signs ............................................................................................................ 70 
 
12-lead ECG ........................................................................................................ 71 
 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 71 
 
Safety laboratory analyses ................................................................................. 71 
17.6 
Analysis of secondary endpoints ........................................................................... 71 
 
Unified Dyskinesia Rating Scale (UDysRS) total score .................................... 71 
 
ON Time Without Troublesome Dyskinesia .................................................... 71 
 
Unified Parkinson’s Disease Rating Scale (UPDRS) ....................................... 71 
 
Clinical Global Impression of Change (CGI-C) in overall PD symptoms .... 72 
 
Dyskinesia scores measured by a wearable dyskinesia assessment device .... 72 
17.7 
Analysis of exploratory endpoints ........................................................................ 72 
 
King’s Parkinson’s Disease Pain Scale (KPPS) total score ............................ 72 
 
Parkinson’s Disease Questionnaire (PDQ39) total score ................................ 72 
 
Hospital Anxiety Depression Scale (HADS) ..................................................... 72 
 
International Consultation on Incontinence Questionnaire Overactive 
Bladder Module (ICIQ-OAB) total score ............................................................................. 72 
 
Epworth Sleepiness Scale (ESS) ........................................................................ 72 
18 
REFERENCES ....................................................................................................... 73 
19 
SIGNATURES ........................................................................................................ 75 
19.1 
Principal Investigator statement ........................................................................... 75 
19.2 
Signature page (approval of the clinical study protocol) .................................... 76 
List of Tables 
Table 4.1-1 
Medical emergencies contact ........................................................................... 16 
Table 6.1-1 
Most Common Drug-related TEAEs (incidence > 2% of patients) Listed By 
Number of Patients in Each Dose Group in Study CP201 ....................................................... 22 
Table 8.1-1 
Schedule of events ............................................................................................ 31 
Table 8.2-1 
Order of efficacy assessments .......................................................................... 34 
Table 11.2-1 
Safety laboratory parameters ........................................................................ 53 
List of Figures 
Figure 1 
Overview of study design ..................................................................................... 29 


 
 
 
 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or term        Explanation 
5-HT 
5-hydroxytryptamine, serotonin 
ADL 
Activities of daily living 
AE 
Adverse event 
ADR 
Adverse drug reaction 
AIM 
Abnormal Involuntary Movements  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC 
Area under the plasma concentration versus time curve 
BMI 
Body mass index 
CA 
Competent authority 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
CPK 
Creatine phosphokinase 
Cmax 
Maximum plasma concentration 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTC AB 
Clinical Trial Consultants AB 
CTCAE 
Common terminology criteria for adverse events 
DA 
Dopamine 
DBS 
Deep brain stimulation 
DMP 
Data management plan 
DNP 
Diabetic neuropathy  
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
ESS 
The Epworth Sleepiness Scale 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 


 
 
 
 
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GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GMP 
Good manufacturing practice 
GGT 
Gamma glutamyl transpeptidase  
HADS 
The Hospital Anxiety Depression Scale 
Hb 
Hemoglobin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use  
ICIQ-OAB 
International Consultation on Incontinence Questionnaire 
Overactive Bladder Module  
IEC 
Independent ethics committee 
IME 
Important medical event 
IMP 
Investigational medicinal product 
ISF 
Investigator site file 
KPPS 
King’s Parkinson’s disease Pain Scale 
L-DOPA 
Levodopa, L-3,4-dihydroxyphenylalanine 
LID 
Levodopa-induced dyskinesia 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
mmHg 
Millimeter mercury (unit for blood pressure measurements) 
MMSE 
Mini Mental Status Exam 
N 
number 
NCS 
Not clinically significant 
NOAEL 
No observed adverse effect level 
NOEL 
No observed effect level  
PD 
Parkinson’s disease 
PD-LID 
L-DOPA- induced-dyskinesia in Parkinson’s disease  
PDQ39 
The Parkinson’s Disease Questionnaire 
PII 
Personally Identifiable Information 
PK 
Pharmacokinetic 
PK (INR) 
Prothrombin complex international normalized ratio 
PPS 
Per protocol set 
PT 
Preferred term 
PTSD 
Post-traumatic stress syndrome  
QA 
Quality assurance  
QC 
Quality control 


 
 
 
 
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RBC 
Red blood cell 
RBM 
Risk-based monitoring 
RSI 
Reference safety information 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCID 
Structured clinical interview for DSM disorders  
SD 
Standard deviation 
SDV 
Source data verification 
SOC 
System organ class 
SOP 
Standard operating procedures 
SSRI 
Selective serotonin reuptake inhibitor 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Half-life  
Tmax 
Time to Cmax 
TEAE 
Treatment emergent adverse event  
TMF 
Trial master file 
UDysRS 
Unified Dyskinesia Rating Scale 
ULN 
Upper limit of normal 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
WBC 
White blood cell 
WHO 
World Health Organization 






 
 
 
 
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6 
INTRODUCTION 
6.1 
Background  
 Overview of NLX-112 
NLX-112, also known as F13640 and Befiradol, or 4-piperidinemethanamine, 1-(3-chloro-4-
fluorobenzoyl)-4-fluoro-N-[(5-methyl-2-pyridinyl)-methyl], (2E)-2-butenedioate, is a 
structurally novel, centrally acting, high-efficacy selective 5-HT1A receptor agonist with 
nanomolar affinity for 5-HT1A receptors. It was previously developed for the treatment of 
neuropathic pain by Pierre Fabre, but was ineffective in the clinic and is being re-purposed by 
Neurolixis as a treatment for L-DOPA- induced-dyskinesia in Parkinson’s disease (PD-LID). 
The serotonin (5-hydroxytryptamine, 5-HT) system has emerged as a key player in the 
induction of LID. 5-HT neurons possess the enzymes necessary to convert exogenous 
L-DOPA to dopamine (DA) and mediate its vesicular storage and ´false neurotransmitter´ 
release. However, 5-HT neurons lack appropriate control mechanisms to regulate synaptic DA 
levels (e.g., via presynaptic D2 receptors or DA transporters), resulting in excessive DA 
release and pulsatile stimulation of post-synaptic DA receptors that generate dyskinesia. 
Compelling neurophysiological, pharmacological, and clinical evidence supports this model, 
as well as the hypothesis that a potent, highly selective 5-HT1A agonist such as NLX-112 
should be effective in treating LID. 
NLX-112 rapidly penetrates the brain from the oral compartment and does not modify 
L-DOPA pharmacokinetics (PK) upon co-administration. Systemically administered 
NLX-112 fully occupies rat brain 5-HT1A receptors in brain regions implicated in motor 
control. NLX-112 occupies 5-HT1A receptors at doses that reduce or eliminate dyskinesia in 
rat models of LID. NLX-112 efficaciously and completely inhibits the electrical activity of 
dorsal raphe 5-HT neurons via activation of presynaptic 5-HT1A autoreceptors. Serotonergic 
activity due to striatal 5-HT release is profoundly reduced by NLX-112 in 6-OH-DA-lesioned 
rats treated with L-DOPA, confirming the capacity of NLX-112 to inhibit 5-HT neurons 
responsible for the “false neurotransmitter” surge in DA levels. Abnormal Involuntary 
Movements (AIM) scores in hemiparkinsonian rats chronically treated with L-DOPA were 
dose-dependently reduced or eliminated by NLX-112. These anti-AIM effects of NLX-112 
were entirely reversed by a selective 5-HT1A antagonist. In addition, the anti-AIM activity of 
NLX-112 was maintained upon chronic treatment (14 days), consistent with studies of older 
serotonergic drugs showing that the antidyskinetic effects of 5-HT1A agonists do not show 
desensitization. In non-human primate experiments, NLX-112 significantly attenuated LID in 
parkinsonian (i.e. MPTP-treated) marmosets, a robust model of anti-dyskinetic activity with 
high predictive value for clinical efficacy. Importantly, NLX 112 did not negatively affect the 
therapeutic-like actions of L-DOPA and even exhibited anti-parkinsonian activity of its own. 
Neurolixis also tested NLX-112 in a second non-human primate species (MPTP-treated 
macaques). Once again, NLX-112 significantly attenuated LID and did not negatively affect 
the therapeutic-like actions of L-DOPA. 
 Non-clinical studies: toxicology and pharmacokinetics  
As with other 5-HT1A agonists (e.g., buspirone), acute exposure of rats to NLX-112 causes 
various, transient in vivo expressions of 5-HT1A receptor activation, including signs of the 
behavioral 5-HT syndrome, hypothermia, and hyperglycemia. With continuous treatment, 


 
 
 
 
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tachyphylaxis develops such that those effects are no longer apparent after a few hours or 
days. 
A battery of safety pharmacology studies has been performed to evaluate the effects of NLX-
112 on the central nervous, cardiovascular, and respiratory systems. Concerning the central 
nervous system and after oral administration in mice, observed effects were hypothermia 
(from 0.625 mg/kg onward), modification of gait (from 2.5 mg/kg onward), decrease in 
exploration, traction capacity and reaction to touch, and increase of ataxia (from 10 mg/kg 
onward). Pro-convulsant effects occurred at 2.5 mg/kg and higher doses. 
Concerning the cardiovascular system, oral doses of 0.63 mg/kg and higher decreased blood 
pressure and heart rate in a telemetry study in rats. In a telemetry study in dogs, NLX-112 
from 0.16 mg/kg onward induced a significant decrease in blood pressure and from 
0.40 mg/kg onward, an increase in heart rate. In a hemodynamic study in dogs, the PQ was 
significantly increased only at the highest dose tested (i.e., 160 µg/kg intravenous). In a 
respiratory study in dogs by the oral route, NLX-112 increased the frequency and decreased 
the amplitude of respiration at 0.064 mg/kg and higher doses. 
The PK of NLX-112 have been evaluated in 2 animal species, rat and dog. After oral 
administration, NLX-112 is rapidly absorbed (15 min), with a good resorption (75-80%) and 
bioavailability between 50 and 70%. The plasma concentration and area under the plasma 
concentration versus time curve (AUC) were linear over the dose range in both species. 
After repeated daily dosing in 4- and 13-week toxicology studies, accumulation was observed 
in rat, but not dog or monkey. A gender effect was observed in rat after 4- and 13-week 
administration (plasma levels were higher in female as compared to male rats) and in dog 
after 4-week administration only (plasma levels were higher in male as compared to female 
dogs). In rat, the distribution into the tissues was generally high and rapid. Maximal tissue 
concentrations were observed at l h post­administration and tissue levels were below 
quantifiable limits in male and female rats at 28 days and at 42 days post-administration, 
respectively. In pigmented rats, measurable levels remained in the choroid layer of the eye 
and the pigmented fur/skin at 42 days post­administration. 
NLX-112 was extensively metabolized in both species. Cytochrome P450 enzymes, 
especially CYP3A4, were largely involved in the metabolism of NLX-112. At least 5 
metabolites were generated. The main in vitro metabolites observed were identical between 
human and animal microsomes (rat and dog). There are no known human specific 
metabolites. In vitro, NLX-112 at 3 µM or higher inhibits CYP2C19 activity in human 
hepatocytes. In human hepatocytes in vitro, CYP450 activities were not induced at 10 µM 
NLX-112, while CYP1A2 activity was upregulated at 100 µM. Excretion mass balance was 
complete, mostly during the first 24 hour-period. NLX-112 was excreted via urine and feces 
almost entirely as metabolites (no parent drug in urine; 1-2% parent in feces). 
In an oral single dose toxicity study the LD50 was 910 and 866 mg/kg in male and female rats, 
respectively. Four and 13-week repeat-dose toxicology studies were conducted in rat and dog; 
2 separate 13-week studies were conducted in cynomolgus monkey. In rat, at 2, 10, or 
45 mg/kg/day transient serotonergic effects (lower lip retraction, flat body posture, 
hyperactivity) were seen in all treated groups. Salivation was noted in the 45 mg/kg/day 
group. A slight decrease in mean body weight gain was observed in all treated males during 
pre-treatment (dose-escalation) and treatment periods, but only in the pre-treatment period in 
45 mg/kg/day females. Reversible modifications were observed in some blood and renal 


 
 
 
 
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parameters. There were no treatment-related histological lesions (including spermogram and 
staging) in any dose group. Based on these observations, the no observed adverse effect level 
(NOAEL) in rat after daily administration of NLX-112 over a 4-week period was considered 
to be below 2 mg/kg/day, due to adverse serotonergic (pharmacological) effects. 
In dogs, at daily doses of 0.06, 0.20, and 0.60 mg/kg/day (after a pre-treatment period with 
dose escalation) serotonergic effects were noted from 0.20 mg/kg/day onward (salivation, 
muscular rigidity and trembling) in all animals. There were no significant treatment effects on 
body weight or biological parameters, except for a moderate and reversible increase in the 
bilirubin blood level in females at the highest dose (0.60 mg/kg/day). Slight to moderate 
increases in respiratory frequency were recorded in males at 0.20 mg/kg/day and in both sexes 
at 0.60 mg/kg/day; these respiratory effects were reversible and were not seen in the post 
dosing period. No relevant macroscopic and microscopic changes were noted. Thus, in dog 
after daily oral administration of NLX-112, the no observed effect level (NOEL) was 
considered to be 0.06 mg/kg/day and the NOAEL was considered to be 0.20 mg/kg/day. 
The daily oral repeated administration of NLX-112 to rats for 13 consecutive weeks at 1, 7, 
and 45 mg/kg/day was well-tolerated, but induced reversible, dose-dependent clinical 
(pharmacological) signs. A reversible (slight to moderate), dose-dependent reduction of body 
weight gain was found in males. In males only, there was a reversible, dose-related, slight to 
moderate decrease in urinary volume, urea, creatinine, and electrolytes excretion outputs. No 
relevant histological lesion was noted. Due to the occurrence of serotonergic signs from the 
lowest dose tested onward, the NOEL could not be determined. 
A second 13-week general toxicology study (with a 4-week treatment-free period) was 
conducted in the rat at higher doses of 10, 30, and 90 mg/kg/day (LD, MD, and HD, 
respectively). Again, NLX-112 was reasonably well-tolerated, but induced reversible clinical 
signs in all dose groups, as previously seen; no new, unexpected clinical signs were found at 
the previously unexplored HD of 90 mg/kg/day. Body weight and food/water consumption 
were modestly reduced, but recovered during the treatment-free period, similar to results from 
the previous 13-week rat study. Laboratory analyses of hematology, chemistry, and urinalysis 
did not reveal unexpected, toxicologically relevant changes, or irreversible changes, not 
previously seen in the prior study. There were no adverse macroscopic or microscopic 
changes attributable to NLX-112 treatment. The NOAEL was considered to be 30 mg/kg/day 
for 13 weeks. 
The daily oral repeated administration of NLX-112 to dogs at 0.06, 0.20, and 0.60 mg/kg/day 
during 13 consecutive weeks was well-tolerated but induced reversible clinical signs of 
serotonergic activity (with a dose related frequency and intensity) at each dose level until the 
end of the treatment period. A very slight decrease in mean body weight gain, as well as a 
slight to moderate increase in respiratory frequency during the treatment period, were 
recorded at each dose in both sexes without any apparent dose relationship. All these changes 
were reversed after a 4-week treatment-free period. No relevant histological lesion was related 
to treatment by the oral route with NLX-112. Due to the occurrence of serotonergic signs 
from the lowest dose tested onward, the NOEL could not be determined. 
In the cynomolgus monkey, twice-daily (BID) oral gavage administration of NLX-112 at 
doses of 4, 14, and 40 mg/kg/day (i.e., 2, 7 and 20 mg/kg BID) for 13 weeks (following a 14-
day pre-treatment dose escalation period) produced pharmacological clinical signs of loss of 
balance, decreased activity, shaking, abnormal movements, and increased sexual behavior. 
These pharmacological signs were short-lived (generally ≤l hour) and mainly occurred 


 
 
 
 
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immediately after dosing during the 14-day dose escalation period. Low and mid-dose males 
and LD females experienced transient reductions of heart rate on constant dose Day 1 and 
Day 16; only LD males experienced mild transient bradycardia at the week 13 assessment. LD 
and some MD animals experienced transient QTc prolongation, which may have been related 
to the reduction of heart rate. The QT prolongation was generally seen only at l hour post 
dose. There were no treatment-related changes in body weight. Sporadic reductions in food 
consumption were not correlated with body weight changes so were not considered 
toxicologically relevant. There were no toxicologically relevant ophthalmologic, serum 
chemistry, hematological, or urinary changes. There were no macroscopic or microscopic 
histologic changes. The NOAEL after 13 weeks of oral administration of NLX-112 was 
considered to be 40 mg/kg/day. 
NLX-112 did not show evidence of mutagenic potential.  
Despite maternal toxicity, NLX-112 was free of any embryotoxic and/or teratogenic effects in 
rat (oral doses of 1, 7, and 45 mg/kg/day) and rabbit (0.25, 1, and 4 mg/kg/day) and testicular 
staging in rat was negative.  
 Clinical experience 
One hundred ninety-nine healthy volunteers have been involved in 9 Phase 1 clinical trials. 
NLX-112 was administered to 173 volunteers (26 subjects received placebo). Six hundred 
thirty-four patients have been involved in 5 Phase II clinical studies. NLX-112 was 
administered to 433 patients (200 subjects received placebo); one subject was enrolled but not 
dosed. 
Absorption of NLX-112 after oral administration is rapid, with Tmax occurring between 
0.5 -1 h with an oral solution, and between 1-3 h after dosing with an oral tablet. Cmax and 
AUC increased more rapidly than the dose after single dose, while both parameters increased 
with an apparent dose proportionality after repeated drug administration. The mean half-life 
(T1/2) ranged between 34 and 41 h. 
In young female volunteers, concentration peaks and plasma exposures were slightly higher 
(21% and 35%, respectively) when compared to  those in young male volunteers. The other 
PK parameters (Tmax and T1/2) and inter-individual variability was not different between males 
and females. 
When comparing PK parameters from healthy elderly (≥65 years) males to those in young 
males, a higher plasma exposure was observed in elderly men (about 30%); the gender effect 
observed in young subjects was of the same magnitude in elderly subjects (40% increase in 
plasma AUC in elderly women vs elderly men). For both elderly men and women, the plasma 
T1/2 remained similar to that in young subjects. 
CYP3A4 is the major mediator of NLX-112 biotransformation. A study of the effects of 
single and repeated oral doses of NLX-112 on CYP3A4 activity used midazolam as a 
metabolic probe; in accordance with the standard classification, NLX-112 was characterized 
as a weak CYP3A4 inhibitor. Investigation of the potential impact of repeated oral doses of 
the potent CYP3A4 inhibitor, ketoconazole (given 400 mg q.d.) confirmed the involvement of 
CYP3A4 in NLX-112 metabolism and led to a mean increase of 2.5-fold in NLX-112 plasma 
exposure, with individual values ranging from 1.49 to 3.89-fold.  
The most frequent treatment emergent adverse events (TEAEs) observed in Phase 1 studies 
(observed in more than 20% of volunteers in at least 2 different studies) were: dizziness, 


 
 
 
 
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somnolence, malaise, headache, and nausea, consistent with the PK profile of NLX-112. In 
the Phase 2 study in diabetic neuropathy (DNP) patients, dizziness, headache, nausea, and 
insomnia were the most common TEAEs. These TEAEs occurred mostly during the up-
titration period (when employed) or during the first few days of fixed dose administration and 
were most frequent at the highest doses. Somnolence was seldom seen in the Phase II studies, 
perhaps due to the up-titration periods employed in these studies. 
Undesirable hemodynamic effects, (i.e., decrease in blood pressure, postural hypotension) 
were observed in healthy elderly volunteers. Of the twelve elderly subjects, 2 experienced 
orthostatic hypotension (one episode of moderate intensity in one subject, and 2 episodes of 
severe orthostatic hypotension with syncope in another subject). 
The only SAE noted in the Phase 1 program was one that occurred in a subject that received 
midazolam as a probe (2 mg oral dose) co-administered with NLX-112 (2.25 mg single oral 
dose). The SAE, which was interpreted as a 'partial serotonin syndrome' occurred 30 minutes 
post-dosing and resolved spontaneously within 40 minutes. It should be noted that the subject 
had previously suffered from nausea, headache, and vomiting on Day -1 (prior to inclusion in 
the study) and the administration of a benzodiazepine (alprazolam and/or bromazepam) in 
several subjects exposed to NLX-112 in another Phase 1 study did not induce any 
serotonergic manifestations. 
Two Phase 2 studies provide the bulk of the safety information for NLX-112. A 12-week 
randomized, placebo-controlled study in 124 DNP patients was well-tolerated and safe at 1 
mg BID (i.e. 2 mg/day); the incidence of SAEs was low (3%) and no SAE was related to 
NLX-112 intake. Only one NLX-112-treated subject withdrew from the study due to a TEAE, 
a recurrent mild dizziness. Ninety-four percent of TEAEs were mild or moderate. Only 
dizziness and headache had a greater incidence in the NLX-112 group as compared to placebo 
(difference > 5%). The most frequently reported TEAEs mainly occurred at the beginning of 
the treatment and resolved quickly. No clinically significant changes were observed in 
electrocardiogram (ECG) and laboratory safety tests included glycaemia parameters. 
A follow-on Phase 2 study in DNP with 456 patients tested 3 doses of NLX-112 [0.5, 1.0, and 
1.5 mg BID (1.0, 2.0, 3.0 mg/day)] vs placebo (Study CP201). Safety and tolerability in this 
study, which employed an 11-day up-titration period prior to and a 10-day down titration 
period after the 6-week fixed-dose period, were similar to the previous phase 2 study. Four 
SAEs occurred but none were related to NLX-112. Dizziness, headache, nausea and insomnia 
were the most common TEAEs and occurred predominantly during the up-titration period or 
the first fixed-dose week (Table 6.1-1). Please refer to the NLX-112 Investigators’ Brochure 
for additional details on safety, tolerability and adverse events (AEs) in the NLX-112 phase 2 
clinical program. 
Table 6.1-1 
Most Common Drug-related TEAEs (incidence > 2% of patients) Listed By Number 
of Patients in Each Dose Group in Study CP201 
Preferred Term 
PBO  
(N=112) 
NLX-112 Groups 
1 mg (N=113) 
2 mg (N=114) 
3 mg (N=117) 
Dizziness 
1 (0.9%) 
8 (7.1%) 
15 (13.2%) 
15 (12.9%) 
Nausea 
4 (3.6%) 
6 (5.3%) 
12 (10.5%) 
16 (13.7%) 
Headache 
3 (2.7%) 
3 (2.7%) 
6 (5.3%) 
9 (7.7%) 
Insomnia 
- 
3 (2.7%) 
3 (2.6%) 
6 (5.1%) 


 
 
 
 
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Preferred Term 
PBO  
(N=112) 
NLX-112 Groups 
1 mg (N=113) 
2 mg (N=114) 
3 mg (N=117) 
Withdrawal 
syndrome 
1 (0.9%) 
4 (3.5%) 
4 (3.5%) 
5 (4.3%) 
Paresthesia 
1 (0.9%) 
3 (2.7%) 
4 (3.5%) 
2 (1.7%) 
Vomiting 
- 
- 
- 
5 (4.3%) 
Hypotension 
- 
3 (2.7%) 
2 (1.8%) 
2 (1.7%) 
Accidental 
overdose 
1 (0.9%) 
3 (2.7%) 
3 (2.6%) 
2 (1.7%) 
Hypertension 
- 
1 (0.9%) 
1 (0.9%) 
3 (2.6%) 
Mood Swings 
2 (1.8%) 
- 
2 (1.8%) 
3 (2.6%) 
ALAT increased 
1 (0.9%) 
1 (0.9%) 
3 (2.6%) 
- 
 
Thus, based on Phase 1 and 2 study results, NLX-112 could be safely administered up to the 
dose of 3.0 mg/day with a progressive up-titration to maximize the tolerability of the drug and 
a down-titration to prevent withdrawal symptoms. 
6.2 
Study rationale 
L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine) is the gold-standard pharmacotherapy for 
PD. L-DOPA is converted to DA primarily in dopaminergic neurons and, given that motor 
symptoms of PD are caused by a lack of DA, L-DOPA decreases the severity of these 
symptoms. However, after several years of treatment, use of L-DOPA often leads to 
fluctuations in therapeutic efficacy (ON and OFF periods) and to induction of dyskinesia 
which can be serious and disabling. Dyskinesias are AIMs that interfere with normal 
movements and can occur even at rest. Since dyskinesias are induced by L-DOPA, they are 
often referred to as L-DOPA-induced dyskinesia, or LID [1, 2].  
LID is poorly treated, with few options available to the treating neurologist or physician. 
Some LID patients respond to amantadine, although tolerability and efficacy are limited. 
Alternatively, physicians lower the daily doses of L-DOPA or reduce administration intervals 
and L-DOPA doses to avoid peak-dose LID. However, this may increase periods of OFF and 
increase parkinsonism in PD patients [1, 3, 4]. LID has been shown to reduce the patient’s 
quality of life (QOL), as well as to increase the risk of falls and health care costs. LID has 
been shown to worsen the activities of daily living (ADL), and patients report that their 
dyskinesia negatively impacts walking and balance, public and social settings, exciting or 
emotional settings, doing hobbies and other activities, handwriting, and dressing [5, 6]. 
Although Parkinson’s disease is strongly associated with dysfunction of the dopaminergic 
system, serotonin (5-hydroxytryptamine, 5-HT) levels are also reduced in the brain of PD 
patients, as shown in post-mortem analyses. The dyskinesia observed in PD patients receiving 
L-DOPA is due to the fact that serotonergic neurons can take up L-DOPA and convert it to 
DA (similarly to dopaminergic neurons), but in a dysregulated manner as a ‘false 
neurotransmitter’ [7-9]. Hence, experiments in animal models as well as brain imaging studies 
in human PD-LID patients show that when serotonergic neurons are inhibited, the dyskinesia 
induced by L-DOPA is markedly reduced. These results and others indicate that inhibition of 


 
 
 
 
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5-HT neurons using drugs such as NLX-112, which is an agonist at inhibitory 5-HT1A 
somatodendritic autoreceptors, is a promising strategy to treat LID in PD patients [10-13]. 
NLX-112 (also known as befiradol and F13640) is a novel compound that activates serotonin 
5-HT1A receptors. NLX-112 has 2 main advantages over previous serotonergic drugs: (i) 
NLX-112 is exceptionally selective for 5-HT1A receptors, for which it displays an affinity 
which is over 1000-fold greater than for other receptors and binding sites (Figure 8.1); (ii) 
NLX-112 is an extremely efficacious ‘full agonist’, i.e. it maximally activates 5-HT1A 
receptors, unlike previous serotonergic drugs that only partially activate the receptors [14, 15]. 
NLX-112 has been tested by Neurolixis in a recognized rat model of PD, the 6-OHDA 
lesioned hemiparkinsonian rat. In this animal model, the repeated administration of L-DOPA 
induces dyskinesia that is completely reversed by systemic administration of NLX-112 
without impairing the therapeutic effects of L-DOPA [13, 16]. This distinguishes NLX-112 
from older serotonergic compounds that have been previously tested in the same rat model: 
they only partially reverse LID but also negatively interfere with the therapeutic-like actions 
of L-DOPA [10, 17]. In more recent non-human primate experiments, NLX-112 significantly 
attenuated LID in parkinsonian (i.e. MPTP-treated) marmosets, a robust model of anti-
dyskinetic activity with high predictive value for clinical efficacy [18]. Importantly, NLX-112 
did not negatively affect the therapeutic-like actions of L-DOPA and even exhibited anti-
parkinsonian activity of its own. Neurolixis also tested NLX-112 in a second non-human 
primate species (MPTP-treated macaques). Once again, NLX-112 significantly attenuated 
LID and did not negatively affect the therapeutic-like actions of L-DOPA [19].  
Taken together, these data suggest that NLX-112 is a promising candidate for the treatment of 
LID in PD patients. Neurolixis currently wishes to carry out a phase 2a clinical trial with 
NLX-112 to test its safety and tolerability in PD/LID patients, and preliminary clinical 
efficacy in reducing LID symptoms.  
6.3 
Risk/benefit assessment 
 Potential risks 
In prior clinical studies of NLX-112, the most frequently reported undesirable treatment 
effects were dizziness, somnolence, headache, nausea, and malaise; these effects are 
consistent with the pharmacological profile of NLX-112. These effects occurred mostly 
during the first days of treatment and were most frequent at the highest doses of study drug 
(i.e., ≥3.0 mg/day). 
The study of the tolerability and safety of NLX-112 administered as multiple doses after an 
adaptive dose titration in healthy subjects showed that progressive up-titration, and adjusting 
dose escalation based on individual tolerability, allowed some healthy men to tolerate 
10 mg/day, when administered as 5 mg BID. 
Abrupt discontinuation of NLX-112 after multiple daily dosing of 3.0 mg/day or higher was 
associated with the sporadic occurrence of withdrawal symptoms (mainly nightmare, anxiety, 
hallucination, and euphoric mood) which were reduced in severity with progressive down-
titration. 
Undesirable hemodynamic effects (i.e., decrease in blood pressure and postural hypotension) 
were observed in some elderly subjects. 


 
 
 
 
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Thus, based on prior human experience, NLX-112 can be safely administered up to the dose 
of 3.0 mg/day (1.5 mg BID), with a progressive up-titration to maximize the tolerability of the 
drug and a down-titration regimen after the fixed dose period to minimize potential 
withdrawal symptoms. 
In cases of accidental overdose, standard supportive measures should be adopted as required. 
For further information regarding overdosing, refer to Section 11.2.1.17. 
Each patient will be provided with a patient information card with information about the 
patient’s participation in a study, see Section 14.4.  
The Principal Investigator at the research clinic will ascertain that adequate facilities and 
procedures are available to handle emergency situations should they occur during the study.  
Besides the risks related to the IMP as described above, there may also be risks related to the 
medical devices used in the study, e.g., devices used for venipuncture. However, these are 
devices that are used in routine medical care and the risk associated with their use is 
considered low and ethically justifiable. Study specific evaluations and sampling procedures, 
like blood-pressure measurements using a blood pressure cuff and frequent blood-sampling, 
may cause transient discomfort but the risk is deemed to be low and ethically justifiable.  
 Potential benefits 
NLX-112 is an IMP. Therefore, it is not possible to predict whether there will be a direct 
medical benefit to the study participants. 
Patients will not receive monetary benefits to participate in the study. 
 Risk-benefit conclusion 
The combined safety data from non-clinical and clinical studies, in which 606 subjects have 
been exposed to NLX-112, form the basis for the current knowledge about the safety of 
NLX-112 in humans.  
The available non-clinical data of NLX-112 show findings consistent with an exaggerated 
pharmacological effect, which were reversible after cessation of dosing. There were no 
clinically relevant ophthalmologic, hematologic, serum chemistry or urinary changes, except a 
few reversible chemistry and urinalysis changes in the rat. No macroscopic or microscopic 
histologic changes were seen in any species.  
With regard to clinical data, the most frequently reported undesirable treatment effects in 
human subjects were dizziness, somnolence, headache, nausea and malaise, which are 
consistent with the pharmacological profile of NLX-112. In order to limit the prevalence and 
intensity of these potential adverse reactions and to maximize tolerability, a slow up-titration 
of the dose is applied in the current clinical study where the Investigator has the option to stop 
or decrease the dose if required. 
While keeping the above-mentioned risk factors at a minimum level in order to not expose the 
patients participating in the study for risks that would not be ethically justifiable, it is 
concluded that the planned study assessments are considered sufficient to meet the scientific 
and medical goals for the study. It is further concluded that the potential benefits from the 
study will outweigh the potential risks for the treated patients. 


 
 
 
 
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More detailed information about the known and expected benefits and risks and reasonably 
expected adverse drug reactions (ADRs) of NLX-112 is found in current version of the 
Investigator’s Brochure (IB).  
 Risk assessment with regards to the Covid-19 pandemic: 
Current recommendations from the Public Health Agency of Sweden (Folkhälsomyndigheten) 
and other authorities will be considered on a day-to-day basis. Assessment sessions with 
Sponsors, Investigators and CRO/vendor representative members to align on local 
restrictions, impact assessment, contingency plans and study-specific risk mitigation strategies 
will be made to safeguard the study conduct and the safety of the patients included in the 
study. Risks regarding patient safety, study performance and data quality/integrity will be 
assessed on an ongoing basis during the study. Any identified risks and mitigating actions will 
be documented in a risk log as part of the Sponsor’s trial master file (TMF). 
EMAs Guidance on the Management of Clinical Trials during the Covid-19 (Coronavirus) 
pandemic as well as local guidelines from the Swedish Medical Products Agency will be 
taken into consideration.  
7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary objective 
To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, 
compared to placebo during 8 weeks of daily treatment in PD patients with LID. 
 Primary endpoints 
• Frequency, intensity and seriousness of AEs 
• Clinically significant changes from baseline in: 
o ECG 
o Vital signs 
o Safety laboratory parameters 
o Physical examinations  
• Suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale 
(C-SSRS).  
7.2 
Secondary objective  
To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID. 
 Secondary endpoints 
• Change from baseline at the final efficacy clinic visit (Day 42) in the Unified 
Dyskinesia Rating Scale (UDysRS) total score [Timeframe: Baseline to Day 42]. 
Patients will be challenged with 150% of their standard L-DOPA dose (maximum 
L-DOPA dose 250 mg) 30 minutes prior to the first UDysRS assessment. 


 
 
 
 
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• Change from baseline in UDysRS total score at Day 28, after a 150% L-DOPA dose 
challenge. 
• Change from baseline in total objective score (Parts III, IV) of the UDysRS at Day 28 
and Day 42, after a 150% L-DOPA dose challenge.  
• Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without 
Dyskinesia plus ON With Non-troublesome Dyskinesia) based on a PD Home 
Dyskinesia Diary. 
• Change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) scores 
(Part III, motor examination). 
• Change from baseline in UPDRS combined scores (Parts I, II, III and IV). 
• Clinical Global Impression of Change (CGI-C) in overall PD symptoms 
• Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes 
Neurotechnologies, Inc) wearable dyskinesia assessment system. 
7.3 
Exploratory objectives 
• To assess the preliminary efficacy of NLX-112 treatment in improving selected non-
motor symptoms of PD, including pain, bladder function, sleep function, mood and 
quality of living with PD. 
• To collect blood samples for potential NLX-112 plasma concentration analysis. 
 Exploratory endpoints  
• Change from baseline in the King’s Parkinson’s Disease Pain Scale (KPPS) total score 
and in each of the 7 pain domain sub-scores. 
• Change from baseline in the Parkinson’s Disease Questionnaire (PDQ39) total score 
and domain scores. 
• Change from baseline in the Hospital Anxiety Depression Scale (HADS) 
• Change from baseline in the International Consultation on Incontinence Questionnaire 
(ICIQ) Overactive Bladder Module (ICIQ-OAB) total score. 
• Change from baseline in the Epworth Sleepiness Scale (ESS). 
• Plasma concentrations of NLX-112. 
The NLX-112 plasma concentration analysis may only be performed if the Sponsor deems it 
necessary to answer any questions regarding compliance. The outcome of the results may not 
be reported in the clinical study report (CSR).


 
 
 
 
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8 
STUDY DESIGN 
8.1 
Overall study design and schedule of events 
This is a two-arm, double-blind, randomized, placebo-controlled Phase 2a study evaluating 
the safety, tolerability, and preliminary efficacy of up to 2 mg/day of NLX-112 versus 
placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson’s 
disease (PD). NLX-112 will be up-titrated to either 2 mg/day (1 mg BID) or to the highest 
well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for 
an additional 2 weeks, and then down-titrated over 2 weeks. An overview of the study design 
is shown in Figure 1. 
Patients will report to the study clinic for a screening visit (Visit 1), followed by a baseline 
visit on Day 1 (Visit 2) where patients will be randomized and begin treatment. Two remote 
safety visits over telephone (Days 7 and 49 [Visit 3 and Visit 8]) will be conducted. Once 
treatment has commenced, there will be 2 in-person safety visits to the clinic (Days 14 and 21 
[Visit 4 and Visit 5]), 2 in-person efficacy visits to the clinic (Days 28 and 42 [Visit 6 and 
Visit 7]) and one follow-up in-person final safety visit (Day 70 [Visit 9]). In total, patients 
will report to the clinic for 7 in-person visits. Patients entering the study will be randomized in 
a 2:1 ratio (16:8 patients) to receive either NLX-112 or placebo. 
At Visits 2, 6 and 7, efficacy assessments will start 30 minutes after the patient has taken 
150% of his or her regular L-DOPA dose, when the patient is ON and experiencing typical 
dyskinesia.  
The order of assessments at each visit is specified in Section 8.2. 
A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver 
with concordance in ON time with dyskinesia between study staff and patient. Two 
consecutive 24-hour diaries will be completed prior to randomization (baseline, Visit 2) and 
prior to the clinic visits on Days 28 and 42 (Visits 6 and 7). 
A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day 
period prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on 
Days 28 and 42 (Visits 6 and 7, respectively). 
Blood will be collected for possible NLX-112 plasma concentration measurements on 
Days 14, 21, 28, 42 and 70 (Visits 4, 5, 6, 7 and 9). 




 
 
 
 
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Patients will self-administer NLX-112 or placebo 2 times each day, once in the morning and 
once in the evening. Tablets should be taken with approximately 240 mL water during a meal. 
Active tablets will contain 0.25 mg NLX-112. Dose escalation will be as follows: 
Up-titration period (4 weeks):  
• Days 1-4 (0.25 mg/day): 1 tablet in the morning, none in the evening 
• Days 5-8 (0.5 mg/day): 1 tablet in the morning and 1 tablet in the evening 
• Days 9-12 (0.75 mg/day): 2 tablets in the morning, 1 tablet in the evening 
• Days 13-16 (1.0 mg/day): 2 tablets in the morning, 2 tablets in the evening  
• Days 17-20 (1.25 mg/day): 3 tablets in the morning, 2 tablets in the evening  
• Days 21-24 (1.5 mg/day): 3 tablets in the morning, 3 tablets in the evening  
• Days 25-28 (1.75 mg/day): 4 tablets in the morning, 3 tablets in the evening 
Constant dose period (2 weeks): 
• Days 29-42 (2 mg/day): 4 tablets in the morning, 4 tablets in the evening  
Down-titration period (2 weeks, down-titration by 0.25 mg/day every 2 days):  
• Days 43-44 (start of down-titration period [1.75 mg/day]) 
• Days 45-46 (1.5 mg/day)  
• Days 47-48 (1.25 mg/day)  
• Days 49-50 (1 mg/day)  
• Days 51-52 (0.75 mg/day)  
• Days 53-54 (0.5 mg/day)  
• Days 55-56 (0.25 mg/day) 
Patients in the placebo arm will follow the same dose escalation, constant dose and 
down-titration schedule, but will be taking the matching placebo tablets. Patients who have 
intolerable AEs during the 28-day up-titration period will be allowed to return to the previous 
tolerated dose at the discretion of the Investigator, or they may withdraw from the study if 
they so choose. 
Each patient is expected to participate in the study for approximately 10 weeks, not including 
screening. Patients will be treated with IMP for a total of 8 weeks (56 days). 
The timing of events is summarized in Table 8.1-1. Study assessments are described in 
Section 11. 






 
 
 
 
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KPPS=the King’s Parkinson’s disease Pain Scale, UPDRS=the Unified Parkinson’s Disease Rating Scale, MMSE=Mini Mental Status Exam, PDQ39=the Parkinson’s disease 
Quality of Life Scale (39-item), UDysRS=the Unified Dyskinesia Rating Scale 
1. Also early withdrawal follow-up visit 
2. Confirmation of eligibility 
3. Blood pressure (including orthostatic hypotension assessment), pulse, respiratory rate and temperature. At screening and baseline (Visit 1 and Visit 2), vital signs to 
assess orthostatic hypotension will be conducted in triplicate, 15-20 minutes apart, with the average of the 3 assessments used for exclusion. 
4. Body weight at Visit 1 and Visit 9. Height at Visit 1 only.  
5. The Modified Hoehn and Yahr scale will be used to establish the PD stage of the patient. 
6. Women of child-bearing potential only.  
7. Hematology, coagulation, serum biochemistry and urinalysis. 
8. C-SSRS: the baseline scale will be used at the first assessment (screening, Visit 1) and the follow-up scale will be used at all subsequent visits. 
9. UPDRS - Screening: part IV only. Other visits: parts I-IV 
10. PD Home Dyskinesia Diary: 2 consecutive 24-hour diaries taken prior to the visits indicated above. 
11. Wearable data collection will take place during a 2-day period prior to the visits indicated above. 
12. CGI-S at baseline (Day 1, Visit 2), CGI-C at other visits.  
13. Collection of AEs from the first dose of IMP. 


 
 
 
 
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8.2 
Order of assessments 
Safety assessments should be performed before the L-DOPA challenge at Visit 2, 6 and 7.  
The efficacy assessments at Visits 2, 6 and 7 should be performed in the order outlined in 
Table 8.2-1. 
Table 8.2-1 
Order of efficacy assessments 
Assessment 
Assessor 
Investigator 
Patient 
UDysRS (Parts III and IV repeated 3 times at approximately 
30, 60 and 90 minutes after the 150% L-DOPA challenge) 
X 
 
UPDRS part III in ON (within 30-90 minutes after the 150% 
L-dopa challenge) 
X 
 
UPDRS parts I, II and IV 
X 
X1 
CGI-C 
X 
 
KPPS 
X 
 
UDysRS (Parts I and II) 
 
X 
PDQ39 
 
X 
HADS 
 
X 
ESS 
 
X 
ICIQ-OAB 
 
X 
CGI-C=Clinical Global Impression of Change, ESS=the Epworth Sleepiness Scale, HADS=the Hospital Anxiety 
Depression Scale, ICIQ-OAB=the International Consultation on Incontinence Questionnaire Overactive Bladder 
Module, KPPS=the King’s Parkinson’s disease Pain Scale, UPDRS=Unified Parkinson’s Disease Rating Scale, 
PDQ39=the Parkinson’s disease Quality of Life Scale (39-item), UDysRS=the Unified Dyskinesia Rating Scale 
1End of Part I and Part II 
8.3 
Rationale for study design 
This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, 
tolerability, and preliminary efficacy of up to 2 mg/day of NLX-112 versus placebo in PD 
patients with moderate to severe LID. NLX-112 will be up-titrated to either 2 mg/day (1 mg 
BID) or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the 
well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks. The study 
will provide important safety and preliminary efficacy data to support the design of further 
studies in PD-LID patients.  
Since NLX-112 is being developed as an anti-dyskinetic therapy, its anti-dyskinetic capacity 
will be addressed in the present study. Since dyskinesias vary over time, the patients will be 
given 150% of their regular L-DOPA dose as a challenge before the UDysRS assessment(s). 
The maximum L-DOPA dose to be administered in the study is 250 mg. 150% of the regular 
L-DOPA dose as a challenge is routinely given when L-DOPA tests are done to evaluate 
L-DOPA responsivity in standard clinical practice. Should the Investigator consider it 


 
 
 
 
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medically warranted to reduce the L-DOPA challenge in a specific patient for safety or 
tolerability reasons, this should be approved by the Sponsor prior to implementation. It is 
critical that the same dose is given at all visits with L-DOPA challenges for a given patient. 
A placebo control will be used to establish the frequency and magnitude of changes in 
endpoints that may occur in the absence of active treatment.  
Randomization will be used to minimize bias in the assignment of patients to dose groups and 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) are evenly balanced across treatment groups.  
Blinded treatment will be used to reduce potential bias during data collection and evaluation 
of endpoints. 
Blood samples to be possibly used for measurement of plasma NLX-112 concentration will be 
collected at clinic visits on Days 14, 21, 28, 42 and 70. These plasma levels could serve as a 
rough measure of compliance with the study medication regimen and Sponsor may choose to 
determine the NLX-112 plasma concentration if deemed useful to answer any questions 
regarding compliance. 
8.4 
Selection of dose  
The effective doses of NLX-112 in PD-LID patients were estimated based on PK and 
pharmacodynamic data from animal studies (Neurolixis Position paper NSR-16-005-02). The 
methods employed in these studies have previously been used with a number of CNS 
compounds and have generally predicted outcomes in an appropriate clinical range. The 
methods include: allometric scaling between rat and human; comparisons of total and free 
plasma exposure between rat and human; translational biomarker study on corticosterone / 
cortisol release; translational biomarker study on body temperature decreases; and 
physiologically-based pharmacokinetic and pharmacodynamic (PKPD) modelling. 
Dosing calculations based on biomarker data carry considerable face validity because cortisol 
release and hypothermia are well-characterized responses to central 5-HT1A receptor agonists 
and are highly translatable between rodent and human: they predicted doses in the range 
0.3 to 1.25 mg. These dose predictions tally with those derived from plasma exposure 
calculations (0.5 to 1.25 mg) and allometric scaling predictions (0.45 mg). Overall, the results 
of these analyses suggest that doses in the range from 0.3 to 1.25 mg/day may be efficacious 
in treating PD-LID. The PKPD modeling study yielded a somewhat higher estimate of 3 mg.   
It should be noted that repeated dosing of NLX-112 results in an approximate 2-fold 
accumulation of drug at steady state, and exposure levels of NLX-112 in elderly males were 
30% higher than in young male volunteers (as shown in a Phase 1 study in aged volunteers – 
Study F13640 GE102). This is relevant to the present study because the majority of PD 
patients are typically over 65 years old.   
Taken together, these data suggest that efficacious doses of NLX-112 for treatment of LID 
will be in the low milligram or sub-milligram range.


 
 
 
 
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9 
STUDY POPULATION  
Prospective approval of protocol deviations to eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted.   
9.1 
Recruitment 
Potential participants in the study will be identified according to the routines of the 
clinical study sites. Patients will be recruited at 5 clinical sites, with an average of 4 to 
6 patients per site. 
9.2 
Screening and enrolment log 
Investigators must keep a record of all screened patients even if they were not subsequently 
included in the study. This information is necessary to verify that patients were selected 
without bias. The reason for screen failure should be stated for all patients screened but not 
included. The reason for withdrawal should be stated for all patients included but not 
completed.  
A screening number will be allocated to each patient in connection to the informed consent 
process at the Screening visit. The screening number is generated automatically in the 
electronic case report form (eCRF). The screening number will allow identification of patients 
irrespective of their possible eligibility for the study.  
Patients that are included and randomized will be assigned a randomization number.  
If a patient cannot receive the planned dose of IMP within 28 days after screening (i.e., the 
time interval between signing informed consent until dose administration) the patient should 
be rescreened before proceeding in the study. 
9.3 
Number of patients 
A total of 24 patients will be randomized in the study.  
To account for potential drop-outs, additional patients may be included in the study. For 
replacements of patients who discontinue from the study, see Section 9.8. 
9.4 
Inclusion criteria 
To be eligible to participate in the study, a patient must meet ALL of the following inclusion 
criteria: 
1. Patient is 30 – 85 years old (inclusive) with a diagnosis of idiopathic PD according to 
the UK Parkinson’s Disease Society Brain Bank Clinical Diagnosis criteria. 
2. PD patient is stably and optimally treated with L-DOPA; other anti-PD treatments are 
allowed if used for at least 4 weeks of previous continuous treatment.  
3. Patient agrees to be challenged with 150% of their normal L-DOPA dose (maximum 
L-DOPA dose 250 mg) 30 minutes prior to efficacy assessments at baseline (Visit 2) 
and at the 2 efficacy clinic visits (Visits 6 and 7). 


 
 
 
 
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4. PD patient exhibits troublesome peak-dose LID, confirmed by a score of at least 1 on 
part IV, item 33 (disability) of the UPDRS at screening (Visit 1) and at Day 1 
(baseline, Visit 2). 
5. At least 90 minutes in total for each 24-hour period during 2 days are indicated as 
“ON with troublesome dyskinesia” (according to the PD Home Dyskinesia Diary) 
prior to Day 1 (baseline, Visit 2). 
6. Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home 
Dyskinesia Diary entries during the screening visit. 
7. Patient can read well enough to understand the informed consent document and other 
subject materials. 
8. Female patients of child-bearing potential must have a negative urine pregnancy test at 
screening (Visit 1) and on Day 1 (Visit 2), must agree to avoid pregnancy during the 
study, and must practice abstinence (only allowed when this is the preferred and usual 
lifestyle of the subject) or must agree to use a highly effective method of contraception 
with a failure rate of < 1% to prevent pregnancy (combined [oestrogen and 
progestogen containing] hormonal contraception associated with inhibition of 
ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception 
associated with inhibition of ovulation [oral, injectable, implantable], intrauterine 
device [IUD] or intrauterine hormone-releasing system [IUS]) starting from 4 weeks 
prior to administration of the study drug and continuing during the course of the study 
until 4 weeks after last after IMP administration. Female subjects must agree to refrain 
from donating eggs from the date of dosing until 3 months after dosing with the IMP. 
Their male partner must agree to use a condom during the same time frame if he has 
not undergone vasectomy.  
Females of non-childbearing potential are defined as pre-menopausal females who are 
sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or 
females who have undergone hysterectomy or bilateral oophorectomy; or post-
menopausal defined as 12 months of amenorrhea (in questionable cases a blood 
sample with detection of follicle stimulating hormone [FSH] 25-140 IE/L is 
confirmatory).  
Male patients must be either vasectomised, consent to use condom or practice sexual 
abstinence to prevent pregnancy and drug exposure of a partner and refrain from 
donating sperm from the date of dosing until 3 months after dosing with the IMP. 
Their female partner of child-bearing potential must use highly effective contraceptive 
methods with a failure rate of < 1% to prevent pregnancy (see above) during the same 
period. 
9.5 
Exclusion criteria 
If the patient meets any of the following criteria, the patient MUST NOT be enrolled: 
1. Patient has severe PD with a Hoehn and Yahr stage = 5. 
2. Patient has unstable medical status, prior brain surgery against tumors or hemorrhage 
(excluding deep brain stimulation [DBS], i.e., DBS patients will be allowed to be 
enrolled) or is scheduled to receive surgery during the trial period. 


 
 
 
 
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3. Patient has orthostatic hypotension: a decrease in systolic blood pressure (at least 
20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the 
patient standing up, compared to pressures obtained while in a sitting position for at 
least 5 minutes. At screening and baseline visits (Visit 1 and Visit 2), vital signs to 
assess orthostatic hypotension will be conducted in triplicate, 15-20 minutes apart, 
with the average of the 3 assessments used for exclusion. 
4. Patient has dementia (MMSE <20). 
5. Patient has clinically significant renal or liver disorder. 
6. Patient currently exhibits generalized obsessive-compulsive disorder, panic disorder, 
bipolar disorder, post-traumatic stress syndrome (PTSD), clinically significant 
parasomnias or any other psychotic disorder as established by structured clinical 
interview for DSM disorders (SCID). Visual hallucinations are allowed. 
7. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, 
interrupted attempt, aborted attempt, or preparatory acts or behavior).  
8. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active 
suicidal thought with intent but without specific plan, or active suicidal thought with 
plan and intent). 
9. Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, 
tertatolol or buspirone within 4 weeks of baseline (Day 1, Visit 2). 
10. Patient has taken any medication, within 4 weeks of baseline (Day 1, Visit 2) that 
inhibits or up-regulates CYP4503A4, see Section 9.6.2.  
11. Patient is concurrently participating in another investigational drug trial or has 
participated in another investigational drug trial within the past 3 months. 
12. Patient is at high risk of non-compliance in the Investigator’s opinion. 
9.6 
Restrictions during the study 
The patients must be willing to comply to the following restrictions during the entire study 
duration i.e., from screening to the end-of-study visit. 
 General restrictions 
• Contraception Requirements:  
All females of child-bearing potential must use highly effective contraception (defined 
in inclusion criterion No 8) or practice abstinence during the study and for 4 weeks after 
IMP administration and refrain from donating eggs from the date of dosing until 3 
months after dosing with the IMP. Their male partner is expected to use a condom 
during the same time frame if he has not undergone vasectomy.  
The male patients must be either vasectomised, consent to use condom or practice 
sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from 
donating sperm from the date of dosing until 3 months after dosing with the IMP. Their 
fertile female partner is expected to use highly effective contraceptive methods to 
prevent pregnancy (for details, refer to inclusion criterion No 8) during the same period.  


 
 
 
 
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• Meals and Dietary Restrictions: The IMPs should be taken during a meal and swallowed 
with approximately 240 mL of tap water.  
• Products affecting CYP450 3A4 activity: Consumption of grapefruit and/or grapefruit 
containing products or star fruit is not allowed during the study. 
• Blood donation: The patients must not donate blood or plasma during the study until 
3 months after the final medical examination at the end-of-study visit. 
 Prior and concomitant therapy 
Use of an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or 
buspirone within 4 weeks of baseline (Day 1, Visit 2) and during the study is prohibited. 
In addition, the following drugs which may affect CYP450 3A4 activity are prohibited from 
4 weeks prior to baseline (Day 1, Visit 2) and during the study: 
Inducers: barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, 
phenobarbital, phenytoin, rifampin, Saint-John's wort, troglitazone, oxcarbazepine, 
pioglitazone, rifabutin. 
Inhibitors: amiodarone, aprepitant, chloramphenicol,cimetidine, clarithromycin,delaviridine, 
diethyl-dithiocarbamate, diltiazem, erythromycin, fluconazole, fluvoxamine, gestodene, 
imatinib, indinavir, itraconazole, ketoconazole, mifepristone, nefazodone, nelfinavir, 
norfloxacine, norfluoxetine, mibefradil, verapamil, ritonavir, voriconazole. 
Prohibited concomitant medications also include those, which in the Investigator’s opinion 
(with Sponsor agreement), may negatively interact with the study medication NLX-112 and 
lead to untoward side effects or otherwise affect patient safety.  
Medications considered necessary for the patient’s safety and wellbeing may be given at the 
discretion of the Investigator. Following consultation with the Sponsor, the Investigator will 
determine whether or not the patient should continue in the study.  
Use of selective serotonin reuptake inhibitors (SSRIs), benzodiazepines and amantadine is 
allowed as is occasional use of apomorphine as judged by the Investigator. In addition, 
Covid-19 vaccination is allowed.  
9.7 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study by 
signing the ICF, but do not fulfil all eligibility criteria and are not subsequently randomized in 
the study. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure patients. Minimal information includes documentation of signed 
and dated informed consent form (ICF), age, gender and reason(s) for screening failure. 
Rescreening can be performed once if any of the following were reasons for screening failure 
or non-randomization (as judged by the Investigator): 
• Practical reasons.  
• Non-significant medical conditions (e.g. influenza, nasopharyngitis).  
• Plasma or blood donation or use of prior medications outside allowed time windows. 


 
 
 
 
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For patients who are rescreened, a new screening number will be assigned and a new, signed 
ICF will be collected. 
9.8 
Patient withdrawal 
 General withdrawal criteria  
Patients are free to discontinue their participation in the study at any time and for whatever 
reason without affecting their right to an appropriate follow-up investigation or their future 
care. If possible, the reason for withdrawal of consent should be documented. 
Patients may be discontinued from the study at any time at the discretion of the Investigator. 
Reasons for discontinuation include:  
• Patient decision (withdrawal of consent) 
• Severe non-compliance to study protocol procedures, as judged by the Investigator 
and/or Sponsor 
• Permanent discontinuation of IMP. Temporarily treatment interruptions of ≥3 days may 
result in study discontinuation as judged by the Investigator and Sponsor.    
• Patient is lost to follow-up. If a patient misses a scheduled visit and is repeatedly 
unable to be contacted, the patient will be withdrawn from the study. 
• Significant AEs posing a risk for the patient, as judged by the Investigator and/or 
Sponsor 
• Withdrawal of informed consent to the use of biological samples  
• Pregnancy 
• Death - Request an autopsy report 
• Use of prohibited medication as judged by the Investigator and/or Sponsor 
• 
The patient exhibits serious suicidality, in the clinical judgement of the investigator or 
according to criteria below: 
• 
Any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behavior) 
• 
Any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought with 
intent but without specific plan, or active suicidal thought with plan and intent) 
 QTc withdrawal criteria  
A patient meeting the criteria below will be withdrawn from the study. The same QT 
correction formula will be used to determine discontinuation throughout the study. 
• QTcF > 500 msec  
• Change from baseline: QTc > 60 ms 
Withdrawal decisions will be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrated a prolonged QT interval, 2 more ECGs will be obtained over a brief period and 


 
 
 
 
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the averaged QTc values of the 3 ECGs used to determine whether the patient should be 
discontinued from the study. 
 Liver chemistry withdrawal criteria  
Liver chemistry threshold stopping criteria have been designed to assure patient safety and to 
evaluate liver event etiology. Study treatment will be stopped for the individual patient if any 
of the following liver chemistry stopping criteria, defined in the U.S. Food and Drug 
Administration (FDA) Guidance on Drug-Induced Liver Injury [22], is met: 
• Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN) and total bilirubin ≥ 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR > 1.5) 
NOTE: plasma bilirubin fractionation will be performed. Bilirubin is also measured via 
urine dipstick (a measurement of direct bilirubin, which would suggest liver injury). 
• ALT 5xULN. 
• ALT 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or 
jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
• Patients with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit 
hepatitis symptoms or rash, will be allowed to continue study treatment as long as they 
are monitored weekly for 4 weeks.  
 Procedures for discontinuation of a patient from the study 
A patient who prematurely discontinues participation in the study will always be asked about 
the reason(s) for discontinuation and the presence of any AEs. If a patient withdraws consent, 
the Investigator must ask the patient if he/she is willing, as soon as possible, to be assessed 
according to the procedures scheduled for the final follow-up visit (Visit 9). If the patient 
withdrew consent, was non-compliant, or was lost to follow-up, no further follow-up will take 
place after the final clinical evaluation. The Sponsor will determine on a case-by-case basis if 
a patient who withdraws for other reasons requires follow-up after the final clinical 
evaluation. Any ongoing AEs will be followed as described in Section 11.2.1.15. Pregnancies 
will be followed as described in 11.2.1.16. 
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. 
 Patient replacement 
Patients who are prematurely withdrawn from the study for any reason except the occurrence 
of AEs assessed as possibly or probably related to study treatment may be replaced during the 
course of the study.  
9.9 
Randomization 
On Day 1, patients will be randomized to receive either NLX-112 or placebo. The 
randomization will be performed per site using SAS with the ratio 2:1 for active treatment to 
placebo. This will give approximately 16 patients receiving NLX-112 and 8 patients receiving 


 
 
 
 
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placebo in total in the study. In addition, approximately the same ratio will be attained within 
each site. The study will use competitive enrollment between sites.  
9.10 Blinding 
This is a double-blind study and the allocation of treatments will not be disclosed until clean 
file has been declared and the database has been locked.  
The IMP and the placebo are identical in appearance and taste.  
9.11 Emergency unblinding during the study 
The treatment code may only be broken by the Principal Investigator or delegate in case of 
emergency when knowledge of the treatment received is necessary for the proper medical 
management of the patient. This will either be performed via the EDC system or using sealed 
individual, treatment code envelopes that are kept at the clinic in a locked and restricted area. 
The code breaking procedure should be carefully documented. 
For unblinding procedures in case of a potential suspected unexpected serious adverse 
reaction (SUSAR), refer to Section 11.2.1.14. 
10 TREATMENTS  
10.1 Identity of investigational medicinal products  
NLX-112 will be supplied as tablets containing 0.25 mg NLX-112. 
Placebo will be matching tablets (identical weight, shape and color) without NLX-112.  
10.2 Manufacturing, packaging and labelling  
The IMP, including placebo, is manufactured by Sharp Clinical, Bethlehem, United States. 
Labels will comply with applicable Good Manufacturing Practice (GMP), with Annex 13 of 
the European Union GMP regulations and local regulatory requirements [23].  
10.3 Importation, release and distribution  
The IMP will be imported, released and distributed by ClinStorage, Solna, Sweden. 
10.4 Conditions for storage 
All study drug must be stored and disposed of according to the Sponsor's instructions. Study 
drug must be stored at the study site in a limited-access area or in a locked cabinet at ambient 
room temperature. 
Temperature logs will be kept for the area where the IMP is stored. The temperature should be 
noted on a daily basis (working days only unless automatic temperature readings are 
available).  


 
 
 
 
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IMP that is brought home by the patients should be stored at room temperature. 
10.5 Dispensing and accountability 
The IMP received at the site must be inventoried and accounted for throughout the study. The 
Investigator will maintain a Storage and Accountability Log as well as a Drug Dispensing 
Log detailing the dates and quantities of study medication received, prepared for and used by 
each patient and study medication returned or destroyed at the end of the study. Patients must 
be instructed to return all original containers, whether empty or containing drug.  
Unused study drug, and study drug returned by the patient, must be available for verification 
by the study site monitor during on-site monitoring visits. Any discrepancies between 
prepared and returned study must be explained and documented. Products deliberately and/or 
accidentally destroyed by the site or the patient must be accounted for. 
Study drug must be dispensed under the supervision of the Investigator or qualified designee, 
or by a hospital/clinic pharmacist. 
At Visits 2, 6 and 7 (Day 1, Day 28, and Day 42) patients will be provided with a small bottle 
of tablets with explicit dosing instructions, including a dosing instruction sheet as well as a 
worksheet to keep track of daily doses. The bottle will contain sufficient drug supplies to last 
until the next scheduled clinic visit. Patients will return the previously used bottle at the next 
clinic visit including any unused IMP. 
10.6 Treatment administration 
Patients will self-administer NLX-112 or placebo 2 times each day, once in the morning and 
once in the evening, according to a dosing instruction sheet. Tablets should be taken with 
approximately 240 mL water during a meal. 
10.7 Continuation of treatment with investigational medicinal product 
There will be no treatment with NLX-112 after end of study participation. 
10.8 Treatment compliance 
Patients will self-administer the IMP at home. At each visit to the clinic, patients will be 
asked to return any unused IMP and all empty/partially used IMP containers. 
Treatment compliance may also be addressed by NLX-112 plasma concentration 
measurements at visits outlined in Table 8.1-1. 
10.9 Return and destruction of investigational medicinal products 
Following confirmation by the Sponsor, any unused study medication will be returned to 
ClinStorage AB, Solna, Sweden for destruction or subsequent return to the Sponsor. Empty 
containers will be destroyed at the study site. The Monitor will perform final IMP 
accountability reconciliation at the study end to verify that all unused IMP is adequately 
destroyed/returned and documented. 


 
 
 
 
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11 STUDY ASSESSMENTS 
The study assessments are described in the sections below and the timing of these assessments 
are detailed in the schedule of events (Table 8.1-1) 
11.1 Recording of data 
The Principal Investigator will provide the Sponsor with all data produced during the study 
from the scheduled study assessments. He/she ensures the accuracy, completeness, legibility, 
and timeliness of the data reported to Sponsor in the eCRF and in all required reports. 
 Informed consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14.3. 
 Eligibility criteria 
Eligibility criteria should be checked during screening and verified before randomization. The 
criteria are specified in Sections 9.4 and 9.5. 
 Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 
 Weight and height 
Weight and height will be measured with the patient wearing light clothes and no shoes. Body 
mass index (BMI) will be calculated, with one decimal, from the height and weight recorded. 
 Medical and psychiatric history  
A complete medical and psychiatric history will include evaluation for past or present 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, 
lymphatic, hematologic, immunologic, dermatologic, psychiatric, genitourinary, drug, and 
surgical history, or any other diseases or disorders (including past diagnosis of HIV or 
hepatitis B/C). 
As part of the medical history at screening, patients will be evaluated using the C-SSRS 
(Section 11.2.5), which will be scored by the Investigator to confirm the patient’s eligibility 
for the study. 
 Prior and concomitant medication 
Medications taken within 4 weeks of the screening visit (Visit 1) will be obtained by patient 
interview. 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose) and as concomitant if ongoing on the day of the first dose 
administration, stopped after the first dose administration or started after the first dose 
administration. To distinguish between prior and concomitant medications on Day 1 (i.e. the 


 
 
 
 
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first dosing day), the start time of any newly introduced medication or the stop time of any 
previously ongoing medication must be recorded in the eCRF.  
Any use of prior or concomitant medication from screening until the last end-of-study visit 
must be documented appropriately in the patient’s eCRF. Relevant information (i.e. name of 
medication, dose, dose form, unit, route, frequency, start and stop dates, reason for use) must 
be recorded. All changes in medication should be noted in the eCRF. 
 Pregnancy test  
All women of child-bearing potential will do a urine pregnancy test at screening (Visit 1) and 
at baseline (Visit 2).   
 Hoehn and Yahr scale 
The Modified Hoehn and Yahr scale will be used to establish the PD stage of the patient. The 
modified scale includes 7 stages (1, 1.5, 2, 2.5, 3, 4 and 5) where stage 1 corresponds to 
unilateral involvement only and 5 to wheelchair bound or bedridden unless aided.  
  Mini Mental Status Exam 
The Mini Mental Status Exam (MMSE) is a 30-point questionnaire used to measure cognitive 
impairment. The MMSE will be used to screen for dementia. Any score of 24 or more (out of 
30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate 
(10–18 points) or mild (19–23 points) cognitive impairment.  
 Baseline symptoms  
A baseline symptom is defined as an event that occurs between the patient’s signing of the ICF 
until the first administration of IMP (i.e. an event that occurs during the screening period). 
Such events are not AEs and will be recorded as baseline symptoms in the Medical History 
Log in the eCRF. 
11.2 Assessments related to primary endpoints  
 Adverse events  
The Principal Investigator is responsible for ensuring that all medical staff involved in the 
study is familiar with the content of this section and the content of the standard operating 
procedures (SOPs) of each site regarding emergencies.  
11.2.1.1 Definition of adverse event  
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
Worsening of dyskinesias (except those associated with the 150% L-DOPA challenge) or 
PD symptoms compared to baseline will be reported as AEs.  


 
 
 
 
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11.2.1.2 Definition of serious adverse event  
An SAE is any AE which: 
• results in death, 
• is life-threatening (this refers to a reaction in which the patient was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might 
have led to death if the reaction was more severe), 
• requires in-patient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event (IME) (this refers to a reaction 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 other outcomes defined 
above). 
Examples of IMEs are intensive treatment in an emergency room for allergic bronchospasm 
or blood dyscrasias, convulsions that do not result in hospitalization, development of drug 
dependency, and drug abuse. 
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the ICF and that did not change in intensity are not SAEs. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 
11.2.1.3 Definition of adverse drug reaction 
The term ADR is to be used whenever either the Investigator or Sponsor or designee assessed 
the AE as at least possibly related to the IMP. 
11.2.1.4 Definition of serious adverse drug reaction  
The term Serious Adverse Drug Reaction (SADR) is to be used whenever either the 
Investigator or Sponsor or designee assessed the SAE as at least possibly related to the IMP. 
11.2.1.5 Definition of suspected unexpected serious adverse reaction  
A SUSAR is any SADR whose nature or intensity is not consistent with the current Reference 
Safety Information (RSI) in the IB and therefore is assessed as unexpected. 
11.2.1.6 Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the start of IMP administration until the end-
of-study visit. 
Any AE with start date on the day of IMP administration will, if possible, be recorded with 
start time. 
At the end-of-study visit, information on new AEs or SAEs, if any, and stop dates for ongoing 
events must be recorded as applicable. 


 
 
 
 
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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
11.2.1.7 Assessment of intensity 
The grading of the intensity of AEs will follow the common terminology criteria for AEs 
(CTCAE) v5.0 [24]. Grade refers to the severity of the AE. The CTCAE displays Grades 1 
through 5 with unique clinical descriptions of severity for each AE based on this general 
guideline. 
The Investigator must assess the intensity of an AE using the following definitions, and record 
it on the AE Log in the eCRF: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self- care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self- care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
11.2.1.8  
Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the IMP using the 
definitions below and record it the AE Log of the eCRF: 
Probable 
The event has a strong temporal relationship to the IMP or recurs on re-
challenge, and another etiology is unlikely or significantly less likely. 
Possible 
The event has a suggestive temporal relationship to the IMP, and an 
alternative etiology is equally or less likely. 
Unlikely 
The event has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no 
causal relationship between the IMP and the event). 
 
An AE is considered causally related to the use of the IMP when the causality 
assessment is probable or possible. 


 
 
 
 
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11.2.1.9 Assessment of outcome 
The Investigator must assess the outcome of an AE using the definitions below and record 
it on the AE Log of the eCRF: 
Recovered/resolved 
The patient has recovered completely, and no symptoms remain. 
Recovering/resolving  The patient’s condition is improving, but symptoms still remain. 
Recovered/resolved 
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/not 
resolved 
The patient’s condition has not improved and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic). 
Fatal 
 
Unknown 
 
11.2.1.10 Reporting of action taken with study treatment 
The Investigator must report the action taken with study treatment using the definitions 
below and record it on the AE Log of the eCRF: 
Dose increased   
Dose not changed 
Dose rate reduced 
Dose reduced 
Drug interrupted 
Drug withdrawn 
Not applicable 
Unknown 
11.2.1.11 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the patient.  
• AEs observed by the Investigator or medical personnel. 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel. 
11.2.1.12 Recording adverse events 
AEs must be recorded in the AE Log of the eCRF. The Investigator must provide 
information on the AE, preferably with a diagnosis or at least with signs and symptoms; 
start and stop dates, start and stop time; intensity; causal relationship to IMP; action taken, 
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If the AE is serious, this must be indicated in the eCRF.  
AEs, including out-of-range clinically significant clinical safety laboratory values, must be 
recorded individually, except when considered manifestations of the same medical condition 
or disease state; in such cases, they must be recorded under a single diagnosis. 
11.2.1.13  Reporting of serious adverse events  
SAE reporting should be performed by the Investigator within 24 hours of awareness via the 
eCRF. All available information regarding the SAE should be entered in the eCRF SAE form 
(i.e. term, intensity, causality, outcome, SAE criteria, action taken, narrative including rational 
for causality assessment) for the specific patient. By saving the event as “serious” in the eCRF 
and once the Investigator has signed-off of the event, an e-mail alert is automatically sent to 
predefined recipients to highlight that an SAE has been registered. The same information is 
automatically sent to sae@ctc-ab.se. 
The SAE report is reviewed by a designated person at CTC AB’s Pharmacovigilance 
department to ensure that the report is valid and correct. For fatal or life-threatening SAEs 
where important or relevant information is missing, immediate follow-up is undertaken and 
queries to the site are raised. Investigators or other site personnel should inform the 
Pharmacovigilance department of any follow-up information (including rational for changes, 
e.g. changes in causality assessment and intensity, that should be described in the SAE 
narrative) on a previously reported SAE immediately but no later than within 24 hours of 
awareness.  
If the SAE report in the eCRF is updated and signed by the Investigator, a new e-mail alert 
will be sent. 
If any additional documentation is required (e.g. autopsy report), CTC Pharmacovigilance 
will request this information from the study site.  
In case the eCRF cannot be accessed, the SAE should be reported by manual completion of 
the paper SAE Form, provided in the Investigator Site File (ISF). The completed, signed and 
dated paper SAE Form should, within 24 hours, be scanned and e-mailed to:  
Medical Monitor: 
 
 
 
A copy of the paper SAE form must also be e-mailed to CTC AB at: sae@ctc-ab.se. 
The study site should notify the site Monitor via phone or e-mail about the submission of 
the SAE report. As soon as the site personnel have access to the eCRF, the SAE should be 
reported electronically as well. 
11.2.1.14 Reporting of SUSARs to EudraVigilance, local competent authority and 
independent ethics committee 
The term SADR is used whenever either the Investigator or Medical Monitor deems a blinded 
SAE as possibly or probably related to IMP. If an SADR is assessed as unexpected by the 
Medical Monitor, it is a potential SUSAR and under such circumstances an EudraVigilance 
reporter will be unblinded. In case the event is regarded as a SUSAR the EudraVigilance 


 
 
 
 
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reporter will report the SUSAR to the local competent authority (CA), via the EudraVigilance 
database, and to the independent ethics committee (IEC) in accordance with local regulations 
and CTC AB’s SOPs within the following timelines: 
• 7 calendar days if fatal or life-threatening (follow-up information within an additional 8 
days) 
• 15 calendar days if non-fatal and non-life-threatening (follow-up information as soon 
as possible) 
The clock for expedited initial reporting (Day 0) starts as soon as the Sponsor becomes aware 
of an SAE. The date should be documented on an acknowledgement receipt. 
The Medical Monitor is responsible for medical review of the SAE narrative in the Council 
for International Organizations of Medical Sciences (CIOMS) for (or equivalent) prior to 
expedited reporting. 
The Sponsor has delegated to CTC AB the responsibility to report SUSARs to the 
EudraVigilance database.  
The Sponsor or delegate is responsible for, once a year throughout the clinical study (or on 
request), submitting a safety report to the CA and the IEC taking into account all new 
available safety information received during the reporting period. 
11.2.1.15 Treatment and follow-up of adverse events 
Patients with AEs that occur during the study must be treated according to daily clinical 
practice at the discretion of the Investigator. 
AEs must be followed up until resolution or to the end-of-study visit, whichever comes first. 
At the end-of-study visit, information on new AEs, if any, and stop dates for previously 
reported AEs must be recorded (if known). AEs assessed as stable by the Investigator at the 
end-of-study visit will not have to be followed up until resolution. 
It is the responsibility of the Investigator to follow up on all SAEs until the patient has 
recovered, stabilized, or recovered with sequelae, and to report to the Sponsor all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultation. 
Patients who withdraw from the study due to an AE must be followed by the Investigator for 
30 days after the last dose of NLX-112 or until the AE is considered resolved or stabilized.  
11.2.1.16 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of any female patients the study 
treatment must be stopped immediately, and the patient discontinued from participation in the 
study. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP may have 
interfered with the effectiveness of the contraceptive medication. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even after the patient was discontinued 
from the study. The outcome of all pregnancies of a female partner to a male patient must also 


 
 
 
 
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be followed up and documented, yet the male patient does not need to be discontinued from 
the study. 
Patients who withdraw from the study due to pregnancy will be followed until the resolution 
of the pregnancy. Follow-up for pregnancy will include regular documented patient contacts 
to ascertain the pregnancy status until the final outcome of the pregnancy is known.  
All events of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
should also be reported and handled as AEs. All outcomes of pregnancy must be reported to 
the Sponsor and the Principal Investigator on the pregnancy outcomes report form. 
11.2.1.17 Treatment of overdose 
An overdose is a dose in excess of the dose specified for each cohort in this clinical study 
protocol (CSP).   
In cases of accidental overdose, standard supportive measures should be adopted as required. 
An overdose should be documented as follows:  
• An overdose with associated AE is recorded as the AE diagnosis/symptoms in the AE 
Log of the eCRF.  
• 
An overdose without associated symptoms is only reported in the patient’s medical 
records. 
• 
Registered in the protocol deviations log.  
No known antidote is available.  
 Physical examination 
The physical examination should include examination of the following: general appearance, 
head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, abdominal 
system, and nervous system.  
Any abnormalities will be specified and documented as clinically significant (CS) or not 
clinically significant (NCS). Abnormal post-dose findings assessed by the Investigator as 
clinically significant will be reported as AEs. 
 Vital signs 
Blood pressure (systolic and diastolic) and pulse will be measured in sitting position after at 
least 5 minutes of rest and then again 3 minutes after standing upright to determine whether 
the patient has orthostatic hypotension (decrease in systolic blood pressure of at least 20 mm 
Hg or diastolic blood pressure of at least 10 mm Hg within 2 minutes of the patient standing 
up, compared to the blood pressure obtained while in the sitting position). At screening and 
baseline (Visit 1 and Visit 2), the investigator should collect 3 assessments, each taken 15 to 
20 minutes apart, in order to obtain an average value. All measurements and the calculated 
average value should be recorded in the eCRF. At other visits, one assessment is sufficient.  
Respiratory rate will be assessed by routine methods. Body temperature will be measured 
orally using a digital thermometer.  


 
 
 
 
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Any vital signs outside the normal ranges at each site will be judged as NCS or CS. The 
assessment will be recorded in the eCRF. Post-dose vital signs judged as “abnormal, clinically 
significant” by the Investigator will be reported as AEs. 
 Electrocardiogram 
Single 12-lead ECG will be recorded in supine position after at least 5 minutes of rest using 
an ECG machine. The following parameters will be recorded: rhythm, ventricular rate, PR 
interval, QRS duration, QT, QTcB, and QTcF. In case of an abnormal ECG, the ECG will be 
repeated once as judged by the Investigator. In case of a QTcF ≥500 ms, refer to the 
withdrawal criterion in Section 9.8.2. 
Any abnormalities will be specified and documented as clinically significant or not clinically 
significant. Abnormal post-dose findings assessed by the Investigator as clinically significant 
will be reported as AEs. 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an assessment tool designed to quantify the severity of suicidal ideation and 
behavior as rated by the investigator. The baseline scale will be used at screening (Visit) and 
the follow-up scale at all subsequent visits as specified in Table 8.1-1.  
The scale contains 6 "yes" or "no" questions in which respondents are asked to indicate 
whether they have experienced several thoughts or feelings relating to suicide over the past 
month and behavior over their lifetime and past 3 months. Each question addresses a different 
component of the respondent's suicide ideation severity and behavior. 
• 
Question 1: wish to be dead 
• 
Question 2: non-specific suicidal thoughts 
• 
Questions 3-5: more specific suicidal thoughts and intent to act 
• 
Question 6: suicidal behavior over the respondent’s lifetime and past 3 months 
• 
If the respondent answers "yes" to Question 2, he/she is instructed to answer 
Questions 3-5. If the respondent answers "no" to Question 2, he/she may skip to 
Question 6. 
An answer of "yes" to any of the 6 questions may indicate a need for referral to a trained 
mental health professional and an answer of "yes" to questions 4, 5 or 6 indicate high-risk. 
 Laboratory safety assessments 
Blood samples for analysis of clinical chemistry, hematology and coagulation parameters will 
be collected through venipuncture or an indwelling venous catheter and analyzed by routine 
analytical methods by local hospital laboratories. Urine analysis will be performed at the 
research clinic using dip sticks. Pregnancy test (urine) will be performed at the research clinic 
at screening.  
All safety laboratory parameters are defined in Table 11.2-1 and will be assessed at time-
points detailed in (Table 8.1-1). The safety laboratory results will be recorded in the eCRF by 
site personnel.  
Any lab values outside the normal ranges will be judged as NCS or CS. The assessment will 
be recorded in the eCRF. Abnormal values assessed by the Investigator as clinically 


 
 
 
 
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significant will be reported as AEs. If an abnormal value is associated with corresponding 
clinical signs or symptoms, the sign/symptom should be reported as the AE. 
Table 11.2-1 Safety laboratory parameters 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total and conjugated) 
Calcium 
Chloride 
C-reactive protein (CRP) (screening only) 
Creatine phosphokinase (CPK) 
Creatinine (eGFR included) 
Gamma glutamyl transpeptidase (GGT) 
Glucose 
Phosphate 
Potassium 
Sodium 
Urea (nitrogen) 
Uric acid 
Hematology 
Hematocrit 
Hemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential count 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
Prothrombin Complex International Normalized Ratio (PK[INR]) 
Urinalysis (dip stick) 
Bilirubin 
Blood 
Erythrocytes 
Glucose 
Ketones 
Leucocytes 
Nitrites 
pH 
Albumin 
Pregnancy test  
Urine pregnancy test at screening1 
1 Females of child-bearing potential only 
11.3 Assessments related to secondary endpoints 
An independent neurologist or the treating physician will rate patients at each clinical site. At 
each applicable visit (Visits 2, 6 and 7), the same rater (if possible) will conduct efficacy 


 
 
 
 
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assessments beginning 30 minutes after the patient has taken 150% of his or her regular 
L-DOPA dose, when the patient is ON and experiencing typical dyskinesia. 
Efficacy in treating LID, as well as other non-motor symptoms of PD, will be assessed with 
the UDysRS, UPDRS, CGI-S, CGI-C, PDQ39, and a PD Home Dyskinesia Diary (electronic). 
Dyskinesia will also be monitored using a wearable dyskinesia assessment device. In addition, 
2 exploratory scales, the KPPS and the ICIQ-OAB will assess potential treatment effects on 
various types of pain and on overactive bladder, respectively, and one assessment of sleep 
(the ESS) will be used to evaluate sleep quality, sleep disturbances and sleepiness while 
engaged in 8 activities. 
The details of the rating scales, the patient diary, and the wearable dyskinesia assessment 
device are presented below. 
 L-DOPA challenge  
The patient will take 150% of their normal L-DOPA dose 30 minutes prior to the start of 
efficacy assessments (UDysRS) at Day 1 (Visit 2), Day 28 (Visit 6) and Day 42 (Visit 7), see 
Table 8.1-1 and Section 11.3.2.  
The challenge should be performed approximately 2 to 2.5 hours after the patient’s morning 
dose (which is also generally around 150%).  
Patients who use continuous intestinal levodopa infusion (Duodopa or Lecigon) should 
instead stop the infusion for 15-30 minutes before the administration of an oral levodopa dose 
equivalent to 300% of their hourly infusion levodopa equivalent dose (LED*). The time of the 
day and the time between stopping the pump and administering the oral dose should be the 
same on all assessments. 
*) 100 mg Duodopa = 111 mg LED, 100 mg Lecigon = 148 mg LED 
The maximum L-DOPA dose to be given is 250 mg. 
The UDysRS (Parts III and IV) will be repeated 3 times after each L-DOPA challenge, 
30 minutes apart, and will hence be performed approximately 30, 60 and 90 minutes after 
each challenge.  
Should the Investigator consider it medically warranted to reduce the L-DOPA challenge in a 
specific patient for safety or tolerability reasons, this should be approved by the Sponsor prior 
to implementation. It is critical that the same dose is given at all visits with L-DOPA 
challenges for a given patient. 
 Unified Dyskinesia Rating Scale (UDysRS) 
The UDysRS is a rating instrument designed to assess the core features of dyskinesia in 
Parkinson's Disease. The UDysRS consists of 4 parts: 
• Part I, historical disability with regard to the patient's perceptions of the impact on 
activities of ADL of on-dyskinesia. 
• Part II, historical disability with regard to the patient's perceptions of the impact on 
ADL of off-dystonia. 
• Part III, objective impairment, which assesses severity of dyskinesia, affected body 
parts, and type of impairment (choreic vs. dystonic). 


 
 
 
 
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• Part IV, objective disability, based on an evaluation of Part III activities. 
Each item in the UDysRS is scored from 0 to 4, with a possible maximum total score of 104. 
The UDySRS assessment will be performed at baseline (Day 1, Visit 2), Day 28 and Day 42 
(Visits 6 and 7), see Table 8.1-1, starting approximately 30 minutes after the L-DOPA 
challenge on these days. The UDysRS (Parts III and IV) will be repeated 3 times after each 
L-DOPA challenge, 30 minutes apart, and will hence be performed approximately 30, 60 and 
90 minutes after each challenge.  
The data for all 3 assessments performed at each visit will be entered in the eCRF and the 
Investigator will highlight which of the assessments, corresponding to the assessment where 
the patient had most severe dyskinesia, that will be used in the descriptive summaries of data.  
The UDysRS assessments will be videotaped at Visits 2, 6 and 7. The video recordings are 
planned to be used as a backup to the standard investigator rating; for example, to ensure 
consistency between assessments in case several assessors are involved, or if other issues 
arise. It may be possible that all video recordings are assessed by a common central rater..  
 PD Home Dyskinesia Diary 
A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver 
with concordance in ON time with dyskinesia between study staff and patient. The diary is 
integrated in the Kinesia 360 wearable dyskinesia assessment system (Section 11.3.6) and is 
based on the PD Home Diary developed by Hauser et al 2004 [26]. The diary will be used to 
score 5 different conditions in 30-minute time intervals during 2x24 hours prior to Visit 2, 
Visit 6 and Visit 7:  
• ASLEEP; 
• OFF; 
• ON (i.e., adequate control of PD symptoms) without dyskinesia; 
• ON with non-troublesome dyskinesia; 
• ON with troublesome dyskinesia. 
 Unified Parkinson’s Disease Rating Scale (UPDRS) 
The UPDRS is one of the most widely-used rating scales employed in the assessment of 
Parkinson's disease. The UPDRS consists of 4 parts: 
• Part I assesses non-motor experiences of daily living, such as cognitive impairment and 
depressed mood. 
• Part II assesses motor experiences of daily living, such as speech and eating tasks. 
• Part III is a motor examination conducted by the clinician, including assessments of 
symptoms such as rigidity and tremor. 
• Part IV is an assessment of motor complications, such as time spent with dyskinesia 
and functional impact of dyskinesias. 
Each item in the UPDRS is scored from 0 to 4, and the individual scores are summed to give a 
total score that indicates the severity of the disease, with a score of 0 indicating no disability 
and a score of 199 being the most severe (indicating total disability). 


 
 
 
 
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For timing of assessments, refer to Table 8.1-1. 
 Clinical Global Impression of Severity and Change (CGI-S, CGI-C) 
The CGI-C is a clinician-oriented scale that assesses the total improvement in the patient's 
condition relative to the clinical global impression of severity (CGI-S) scale conducted at 
baseline. The CGI-C rates the patient's condition from 0 to 7, with a rating of 0 indicating "no 
assessment'', a rating of 1 indicating "very much better", and a rating of 7 indicating "very 
much worse".  
For timing of assessments, refer to Table 8.1-1. 
 Wearable dyskinesia assessment device  
The Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment 
system will be used to monitor dyskinesias. Wearable data collection of dyskinesias will take 
place during a 2-day period prior to the baseline visit (Visit 2) and a 2-day period prior to the 
clinic visits on Days 28 and 42 (Visits 6 and 7, respectively).  
The Kinesia 360 motor assessment system provides low burden method for remote, 
continuous measurement of patient symptoms. Sensors worn on the wrist and ankle combined 
with a mobile application continuously record data for assessment of tremor, slowness, 
dyskinesia and mobility. Data from the motion sensors is uploaded to the Kinesia Web Portal 
and algorithms are used to detect symptoms and calculate severity scores every 2 minutes on a 
scale shown to be highly correlated with clinician ratings. Sensors record data all day and 
recharge overnight for extended home use. 
Each patient will be trained and provided with a user guide in Swedish, sensors and a 
smartphone that is preloaded with the Kinesia 360 software app. The app guides patients 
through daily use and includes electronic diaries for capturing patient-reported outcomes (see 
Section 11.3.3) and a medication diary. The system also includes mobile device management 
to ensure that the software is always current.  
Motion and diary data are transmitted to a secure cloud via mobile broadband for processing 
and storage in a 21 CFR Part 11 compliant database. Clinicians and researchers can access 
reports via the Kinesia web portal and view real-time patient compliance.  
Each site will be trained by the manufacturer.  
11.4 Assessments related to exploratory endpoints  
 King’s Parkinson’s Disease Pain Scale (KKPS) 
The KPPS is a rater-interview-based scale conducted with the patient and caregiver (if 
available). It is a 14-item scale covering 7 domains of pain: 
• Musculoskeletal pain 
• Chronic pain 
• Fluctuation-related pain 
• Nocturnal pain 
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• Edema/swelling; discoloration 
• Radicular pain 
Each item is scored by severity (0 - 3; none to very severe) multiplied by frequency (0 - 4; 
never to all the time), for an item sub score of 0-12, resulting in a total score from 0 to 168. 
Ratings are based on the previous month, or in the case of this study, the intervening period 
since the previous clinic visit (about 3 weeks). Treatment effects will be analyzed as change 
from baseline for total score and for individual pain domains. 
For timing of assessments, refer to Table 8.1-1. 
 Parkinson’s Disease Questionnaire (PDQ39) 
The PDQ39-item patient reported outcome of health status and quality of life and is the most 
frequently used disease-specific health status measure for PD. The questionnaire assesses how 
often people affected by PD experience difficulties across 8 dimensions of daily living. The 
standard PDQ39 assesses quality of life over the previous month. In this study the initial time 
period assessed at the Baseline Visit will be the previous month, with subsequent assessments 
for the intervening period since the last clinic visit (about 3 weeks). 
The 8 quality of life dimensions covered in the questionnaire are: 
• Mobility (10 items #1-10) 
• ADL (6 items #11-16) 
• Emotional Well Being (6 items #17-22) 
• Stigma (4 items #23-26) 
• Social Support (3 items #27-29) 
• Cognition (4 items #30-33) 
• Communications (3 items #34-36) 
• Bodily Discomfort (3 items #37-39) 
Individual items are rated by the patient on a scale of 0 to 5. Dimension scores are calculated 
on a scale of 0 to 100. The total score and individual dimension scores will be assessed for 
change from baseline. 
For timing of assessments, refer to Table 8.1-1. 
 Hospital Anxiety Depression Scale (HADS) 
The HADS is used to determine the levels of anxiety and depression that a person is 
experiencing. The questionnaire consists of 7 items related to anxiety and 7 related to 
depression. Each item on the questionnaires is scored from 0-3, which means that a person 
can score between 0 and 21 for either anxiety or depression.  
For timing of assessments, refer to Table 8.1-1. 
 International Consultation on Incontinence Questionnaire Overactive Bladder 
Module (ICIQ-OAB) 


 
 
 
 
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The ICIQ-OAB provides a brief and robust measure to assess the impact of symptoms of 
overactive bladder on quality of life and outcome of treatment. It is a 4-item patient reported 
outcome covering 4 domains of bladder function: frequency, nocturia, urgency, and urge 
urinary incontinence. Each item is scored by frequency of 0 - 4, for a total score of 0 - 16. 
Ratings will be based on the previous month or since the last clinic visit. Efficacy will be 
assessed as change from the baseline total score.  
For timing of assessments, refer to Table 8.1-1. 
 Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, 
on a 4-point scale (0 - 3), their usual chances of dozing off or falling asleep while engaged in 
8 different activities. The ESS score (the sum of 8 item scores, 0 - 3) can range from 0 to 24. 
Ratings are based on the previous month, or in the case of this study, the intervening period 
since the previous clinic visit (about 3 weeks). 
For timing of assessments, refer to Table 8.1-1. 
 Plasma concentration of NLX-112 
Should it be deemed necessary by the Sponsor, the NLX-112 plasma concentration will be 
analyzed using blood taken at visits specified in Table 8.1-1. These plasma level checks may 
serve as a rough measure of compliance with the study medication. 
Blood samples (5 mL) will be collected into tubes containing K2 EDTA and will be 
centrifuged at approximately 2000xg for 10 minutes at +4 °C. The resultant plasma will be 
transferred into 2 clean, labeled 2 mL tubes. All plasma samples will be stored in a - 20 °C 
freezer until shipment. 
A samples will be transferred to the bioanalysis laboratory on dry ice. B samples will be 
shipped to the bioanalysis laboratory, upon instruction from the Sponsor, if they are required 
for repeat analysis. 
11.5 Appropriateness of measurements 
Methods used for safety assessments are commonly used in standard medical care and in 
clinical studies as are methods used for the preliminary assessment of efficacy.  
12 PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 Sample collection  
The sample collection procedure for plasma concentration analysis of NLX-112 is described 
in Section 11.4.6. 
Safety laboratory samples will be collected according to standard procedures. 
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The anticipated volume of blood samples collected during the study from each patient will be 
approximately 100 mL, which is significantly less than volume drawn during a regular blood 
donation (450 mL). 
12.3 Handling, storage and destruction of laboratory samples 
Safety laboratory samples will be analyzed shortly after sample collection and these samples 
will not be stored. Any remains from the safety laboratory samples will be disposed of after 
analyses.  
Samples collected for potential NLX-112 plasma concentration analysis are included in a 
biobank and will be stored at <-20°C until analyzed. The A samples will be destroyed by the 
bioanalysis lab and the B samples will be destroyed at each site after finalization of the CSR. 
12.4 Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
Each investigator keeps full traceability of collected biological samples from the patients 
while in storage at the research clinic until shipment and keeps documentation of receipt of 
arrival.  
The sample receiver (the analytical laboratory) keeps full traceability of the samples while in 
their storage and during use until used or disposed of.  
The Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.  
12.5 Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of biological samples donated, the samples will be 
disposed of /destroyed, if not already analyzed and documented.  
The Principal Investigator will ensure that:  
• Patient withdrawal of informed consent is notified immediately to Sponsor.  
• Biological samples from the patient, if stored at the research clinic, are immediately 
identified, disposed of/destroyed and the action is documented.  
The Sponsor has to ensure that the laboratory(ies) holding the samples is/are informed about 
the withdrawn consent immediately and that samples are disposed of/destroyed or returned to 
the research clinic and the action is documented. 
13 QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL 
13.1 Quality management: critical process, system and data identification 
During CSP development, the Sponsor will identify those processes, systems (facilities, 
computerized systems) and data that are critical to ensure human subject protection and the 


 
 
 
 
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reliability of trial results according to applicable SOPs and International Council for 
Harmonisation (ICH) E6 (R2) guidelines. 
Identified risks, including risks associated with the Covid-19 (Coronavirus) pandemic, will be 
categorized separately from the CSP. 
Sponsor oversight responsibilities, such as monitoring, AE reporting, safety monitoring, 
changes in investigators and key study team staff and quality assurance (QA) activities may 
need to be reassessed in relation to the Covid-19 pandemic and temporary, alternative 
proportionate mechanisms of oversight may be required. 
13.2 Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining QA and quality control (QC) 
systems with written SOPs with regards to management of identified risks, CSP compliance, 
good clinical practice (GCP) compliance and applicable regulatory requirements.  
The Sponsor is responsible for securing agreements with involved subcontractors and to 
perform regular subcontractor oversight to ensure CSP compliance, GCP compliance and 
compliance with applicable regulatory requirements.  
The Sponsor is responsible for implementing a risk-based validated electronic data capture 
(EDC) system and maintain SOPs for the whole life cycle of the system. 
QC should be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 
The Sponsor has delegated the responsibilities outlined above to CTC AB whilst maintaining 
overall study oversight. 
14 ETHICAL AND REGULATORY REQUIREMENTS  
14.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [27] and are consistent with ICH E6 (R2) GCP guidelines, EU 
Clinical Trials Directive, and applicable local regulatory requirements. 
14.2 Ethics and regulatory review 
The Principal Investigator is responsible for submission of the CSP, the patient information 
and ICF, any other written information to be provided to the patients and any advertisements 
used for recruitment of patients to applicable IEC for approval.  
The Sponsor has delegated to CTC AB the responsibility to submit study documents to the 
applicable CA according to local regulatory requirements. 
Approval must be obtained in writing from both IEC and CA before the first patient can be 
recruited. 


 
 
 
 
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The Sponsor will provide the CA, IEC and Principal Investigators with safety updates/reports 
according to local requirements. Progress reports and notifications of SUSARs will be 
provided to the IEC according to local regulations and guidelines. 
14.3 Patient information and consent 
It is the responsibility of the Investigator or an authorized associate to give each potential 
study patient (or the patient’s legally acceptable representative and/or witness, as applicable) 
adequate verbal and written information before any study specific assessments are performed. 
The information will include the objectives and the procedures of the study as well as any 
risks or inconvenience involved. It will be emphasized that participation in the study is 
voluntary and that the patient may withdraw from participation at any time and for any 
reason, without any prejudice. All patients will be given the opportunity to ask questions 
about the study and will be given sufficient time to consider participation before signing the 
ICF. 
Before performing any study-related procedures the ICF must be signed and personally dated 
by the patient and by the Investigator. A copy of the patient information including the signed 
ICF will be provided to the patient. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the eCRF. The patient information sheet and the signed ICF 
should be filed by the Investigator for possible future audits and/or inspections.  
The final approved version of the patient information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC.  
14.4 Patient information card 
The patient will be provided with a Patient Information Card including the following 
information:  
• That he/she is participating in a clinical study 
• Patient study ID  
• That he/she is treated with an IMP 
• The name and phone number of the Investigator  
• Name and address of the Sponsor 
14.5 Patient data protection 
The ICF includes information that data will be recorded, collected and processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the 
General Data protection Regulation (GDPR) (EU) 2016/679, the data will not identify any 
persons taking part in the study. 
The potential study patient (or the patient’s legally acceptable representative and/or witness, 
as applicable) should be informed that by signing the ICF he/she approves that authorized 
representatives from Sponsor and CTC AB, the concerned IEC and CA have direct access to 


 
 
 
 
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his/her medical records for verification of clinical study procedures. For further details on the 
patient information and ICF process, refer to Section 14.3. 
The patient has the right to request access to his/her personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with GDPR (EU) 
2016/679 and the request will be raised to the Principal Investigator.  
The Investigator must file a Patient Identification List which includes sufficient information 
to link records, i.e. the eCRF and clinical records. This list should be preserved for possible 
future inspections/audits but must not be made available to the Sponsor except for monitoring 
or auditing purposes. 
Personal data that are collected in the study such as health information and ethnicity are 
considered as sensitive personal data. This data will be pseudoanonymized, i.e. personally 
identifiable information (PII) will be removed and replaced by a unique patient ID and will be 
processed by the Sponsor and other involved parties during the study. After the study end, 
only anonymized data, i.e. aggregated data sets, can be used.  
For this study, the Sponsor is the data controller of all data processed during the study (e.g. 
TMF, study reports) and CTC AB is the data processor. For data that are processed at the 
clinic(s) (e.g. medical records and ISF), each site is the data controller. Any subcontractors 
used in the study are data processors.  
14.6 Changes to the approved clinical study protocol  
Any proposed change to the approved final CSP (including appendices) will be documented 
in a written and numbered clinical protocol amendment. All substantial amendments to the 
protocol must be approved by the appropriate IEC and/or CA before implementation 
according to applicable regulations. 
14.7 Audits and inspections 
Authorized representatives of Sponsor, a CA, or an IEC may perform audits or inspections at 
the research clinic, including source data verification (SDV). The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH E6 (R2)GCP guidelines and 
any applicable regulatory requirements. The Investigator will contact the Sponsor 
immediately if contacted by a CA about an inspection at the center. 
14.8 Insurance 
Patients will be covered under Neurolixis’ insurance policy through the Swedish 
Pharmaceutical Insurance (Läkemedelsförsäkringen). The certificate of insurance and an 
information leaflet containing essential information about the insurance coverage can be 
provided upon request. The participating patients are also protected in accordance with 
national regulations, as applicable.  


 
 
 
 
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15 STUDY MANAGEMENT 
15.1 Training of study site personnel 
Before enrolment of the first study patient, a Sponsor representative or delegate will perform a 
study initiation visit at the research clinic. The requirements of the CSP and related 
documents will be reviewed and discussed, and the investigational staff will be trained in any 
study specific procedures and system(s) utilized. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study and have a detailed knowledge of and 
training in the procedures that are to be executed by them. Any new information of relevance 
to the performance of this study must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the study together with their 
function and study related duties delegated. A Curriculum Vitae will be available for all staff 
to whom study-specific duties are delegated.  
 
15.2 Clinical monitoring  
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all study related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities.  
As defined in the risk-based monitoring (RBM) plan, approved by the Sponsor and provided 
separately, the responsible Monitor will periodically visit the study site at times agreed upon 
by the Investigator and the Monitor. Adaptations related to the on-site monitoring plan, when 
it is impossible or inappropriate to follow due to the Covid-19 pandemic, may be required 
such as supplementation with (additional/increased) centralized monitoring and central review 
of data if considered possible and meaningful. Results of adjusted monitoring/review 
measures should be reported to the Sponsor in monitoring reports and in the CSR. At the time 
of each monitoring visit, the role of the Monitor is (but not limited to) to: 
• provide information and support to the investigational team. 
• confirm that facilities and resources remain acceptable. 
• confirm that the investigational team is adhering to the CSP, applicable SOPs, 
guidelines, manuals and regulatory requirements.  
• verify that data are being accurately and timely recorded in the eCRFs and that IMP 
accountability checks are being performed. 
• verify that data in the eCRF are consistent with the clinical records (SDV) in 
accordance with the RBM plan.  
• verify that the correct informed consent procedure has been adhered to for participating 
patients.  
 


 
 
 
 
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• ensure that withdrawal of informed consent to the use of the patient’s biological 
samples will be reported and biological samples are identified and disposed 
of/destructed accordingly, and that this action is documented and reported to the 
patient. 
• verify that AEs are recorded and reported in a timely manner and according to the CSP. 
• raise and escalate any serious quality issues, serious GCP breach and any data privacy 
breach to the Sponsor.  
Centralized monitoring will also be performed continuously by study team members at CTC 
AB in accordance with the RBM plan.  
When the study has been completed and all queries have been resolved and the database has 
been locked, the Monitor will perform a close-out visit. 
15.3 Source data documents 
A separate Origin of Source Data List will be generated for each site before start of 
enrolment, specifying the location of the source of derived information appearing in the 
eCRF. This document must be signed by the Principal Investigator and the Monitor to confirm 
agreement before start of recruitment. 
Source documents are all documents used by the Investigator or hospital that relate to the 
patient’s medical history, that verifies the existence of the patient, the inclusion and exclusion 
criteria, and all records covering the patient’s participation in the trial. They include 
laboratory notes, memoranda, material dispensing records, patient files, etc. The eCRF may 
constitute source data if clearly defined in the Origin of Source Data List.  
The Investigator should guarantee access to source documents to the Monitor, CAs and the 
IECs, if required. 
15.4 Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement for this study. 
Agreements between Sponsor and CTC AB and site contracts must be in place before any 
study-related procedures can take place, or patients are be enrolled. 
15.5 Study timetable and end of study 
The study is expected to start in Q3 2021 and to be completed by Q4 2022. 
A patient is considered to have completed the study if he/she has completed all visits in the 
study including. 
The end of the study is defined as the date of the last visit of the last patient in the study. 


 
 
 
 
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15.6 Criteria for site termination 
A specific site maybe terminated due to the following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled at that site. 
• The Investigator does not meet an acceptable enrollment rate. 
• The Investigator is not adhering to the protocol requirements. 
If there are patients still active at a site that is being terminated, efforts will be made to 
transfer the patients to another participating site if feasible. 
15.7 Termination of the study 
The study may be terminated if evidence indicates that there is an unacceptable risk to the 
patients or if circumstances arise that make it impossible for the study to continue. If it is 
necessary to terminate the study, Neurolixis will formulate and communicate to the 
Investigators the plan for study termination and close out. Neurolixis may decide to delay or 
terminate the study at any time, or for any reason. 
The IEC and CA should be informed promptly. Conditions that may warrant study 
termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study or potential study patients; or 
• A decision by the Sponsor to suspend or discontinue development of the IMP. 
• If the CA obtains information that raises doubts about the safety or scientific validity 
of the clinical study, the CA can suspend or prohibit the study. Before the CA reaches 
its decision, it shall, except where there is imminent risk, ask the Sponsor and/or the 
Investigator for their opinion, to be delivered within one week (Directive 2001/20/EC, 
Article 12, Section 1).  
If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the study patients and should assure appropriate follow-up for the 
patients. 
15.8 Reporting and publication 
 Clinical study report  
A summarizing report must be submitted to the applicable CA and IEC within 12 months after 
completion of the study (in accordance with LVFS 2011:19, Chapter 9). 
A CSR, in compliance with ICH-E3 guidelines, describing the conduct of the study, any 
statistical analyses performed and the results obtained, will be prepared by CTC AB. The 
report will be reviewed and approved by, as a minimum, the Coordinating Investigator, the 
Statistician and the Sponsor. The study results will be reported in the EudraCT database per 
applicable regulations within 12 months after completion of the study. Any work created in 
connection with performance of the study and contained in the data that can benefit from 


 
 
 
 
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copyright protection (except any publication by the Investigator as provided for below) shall 
be the property of Neurolixis as author and owner of copyright in such work. 
 Annual safety report 
If the study duration exceeds one year, the Sponsor must submit development safety update 
report (DSUR) to the CA and to the IEC. The report shall summarize all pertinent safety 
information collected during the reporting period and contain an update of the risk-benefit 
evaluation if there has been any change since the approval of the clinical study. 
 Confidentiality and ownership of study data 
Any confidential information relating to the IMP or the study, including any data and results 
from the study, will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the study are responsible for protecting the confidentiality of this 
proprietary information belonging to the Sponsor.   
 Publication 
All information, including but not limited to information regarding NLX-112 or the 
operations of Neurolixis, (e.g., patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, and formulation information) supplied by Neurolixis to the 
Investigator and not previously published, and any data generated as a result of this study, is 
considered confidential and remains the sole property of Neurolixis. The Investigator agrees 
to maintain this information in confidence and use this information only to accomplish this 
study, and will not use it for other purposes without the prior written consent of Neurolixis. 
The Investigator understands that the information developed in the clinical study will be used 
by Neurolixis. in connection with the continued development of NLX-112, and thus may be 
disclosed as required to other clinical investigators or government regulatory agencies. To 
permit the information derived from the clinical studies to be used, the Investigator is 
obligated to provide Neurolixis with all data obtained in the study.  
Neurolixis shall have the right to publish data and information without approval from the 
Investigator. If an Investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to Neurolixis for review before submission for publication or 
presentation. Expedited reviews will be arranged for abstracts, poster presentations, or other 
materials. If requested by Neurolixis in writing, the Investigator will withhold any publication 
to allow for fi1ing of a patent application. Authorship of publications resulting from this study 
will be based on generally accepted criteria for major medical journals. 
15.9 Archiving  
The Principal Investigator is responsible for maintaining essential documents, (as defined in 
ICH E6 (R2) GCP guidelines, Section 8) for 10 years after finalization of the CSR. This 
includes any original source documents related to the study, the Patient Identification List 
(providing the sole link between named patient source records and anonymous eCRF data), 
the original signed ICFs and detailed records of disposition of IMP.  
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 


 
 
 
 
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The Sponsor will archive the TMF in accordance with ICH E6 (R2) GCP guidelines, 
Section 8 and applicable regulatory requirements. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the clinic and 
filed in the Investigator Study File for archiving for 10 years after finalization of the CSR. 
The completed eCRFs are the sole property of the Sponsor and should not be made available 
in any form to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from the Sponsor.  
16 DATA MANAGEMENT 
The data management routines include procedures for handling of the eCRF, database set-up 
and management, data entry and verification, data validation, QC of the database, and 
documentation of the performed activities including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the CSP. 
Data validation/data cleaning procedures are designed to assure validity and accuracy of 
clinical data. These procedures consist of computerized online edit checks identifying e.g. 
data values that are outside the allowed range and SAS-programmed batch checks on data 
exports. All study-specific and standard data validation programming will be tested prior to 
being used on final data. 
Detailed information on data management will be described in a study-specific Data 
Management Plan (DMP). 
16.1 The web-based eCRF 
Clinical data will be entered into a 21 CFR Part 11-compliant eCRF (Viedoc™) provided by 
Viedoc Technologies AB. The eCRF includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents or at bedside 
(if the eCRF data constitutes source data). Source data are to be defined at the site before 
inclusion of the first patient (Section 15.3). 
Authorized site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorized trial site personnel prior to the trial being initiated and any data being entered into 
the system for any study patient. 
16.2 The entering of data into the eCRF 
All entries, corrections, and alterations are to be made by the Investigator or designee. Neither 
the Monitor nor any other study team member besides site staff can enter data in the eCRF. 
All data should be entered in English. The eCRFs should be completed as soon as possible 
during or after the patient’s visit. The Investigator must verify that all data entries in the 
eCRFs are accurate and correct. If some assessments are not done, or if certain information is 
not available, not applicable or unknown, the Investigator or assigned clinical staff should 
record such information in the eCRF. The Investigator will be required to electronically sign 


 
 
 
 
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off the clinical data. This will be performed by means of the Investigator’s unique User ID 
and password; date and time stamps will be added automatically at time of electronic 
signature. 
16.3 The query process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Data in the eCRF will be compared with the respective source documents to ensure that there 
are no discrepancies for critical data as described in the RBM plan.  
If corrections are needed, queries will be raised within the eCRF, either as a result of built-in 
edit checks or manually raised by the monitor. An appropriate member of the site staff will 
answer the queries in the eCRF either by correcting the data or by entering a response to the 
query. The monitor will either approve the answer/correction or re-issue the query. 
16.4 Audit trail 
All entries in the eCRF will be fully recorded in a protected audit trail. Once clinical data 
have been saved, corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who made the change, together with time and date will be 
logged. 
16.5 External data 
External data consists of data that are not recorded in the eCRF. External data must be 
received in electronic format. Key variables are defined in order to uniquely identify each 
sample record. File and data formats are agreed with the external data provider.  
External data in the current study include safety laboratory data, wearable data, electronic 
diary data and (if performed) NLX-112 plasma concentration data.  
16.6 Medical coding 
Medical coding will be performed by trained personnel at CTC AB. AEs and 
medical/psychiatric history verbatim terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA; latest version available at eCRF setup). Prior and 
concomitant medications will be coded according to the World Health Organization (WHO) 
Anatomical Therapeutic Chemical (ATC) classification system. All coding will be approved 
by Sponsor prior to database lock. 
16.7 Database lock 
When all data have been entered and discrepancies solved, clean file will be declared, the 


 
 
 
 
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database will be locked, the code will be broken and the data will be analyzed.  
17 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
The principal features of the statistical analysis to be performed are described in this section. 
A more technical and detailed elaboration of the principal features will be presented in a 
separate Statistical Analysis Plan (SAP), which will be signed and approved prior to database 
lock. All analyses will be performed by CTC AB. 
17.1 General 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic 
mean, standard deviation (SD), median, minimum and maximum value.  
Categorical data will be presented as counts and percentages. When applicable, summary data 
will be presented by treatment, and by assessment time. Individual patient data will be listed 
by patient number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or 
later (SAS Institute, Inc., Cary, NC). 
Baseline will be defined as the last non-missing data point prior to the first administration of 
IMP. 
The primary objective of this study is to evaluate the safety and tolerability of NLX-112. The 
secondary objective is to evaluate preliminary efficacy endpoints, hence, statistical tests of 
efficacy outcomes will be for descriptive purposes and no adjustment for multiple tests will be 
performed.  
No imputation of missing data will be performed. 
All data will be listed by treatment and patient. 
17.2 Determination of sample size 
No formal sample size calculation has been performed. The sample size of 24 patients is 
considered sufficient to evaluate the primary objective and to allow for a preliminary efficacy 
evaluation. 
17.3 Analysis populations 
 Safety analysis set 
The safety analysis set will comprise all patients who received at least one dose of the IMP.  
 Full analysis set 
The full analysis set (FAS) will comprise all randomized patients who were dosed and who 
provided at least one post-baseline assessment of the UDysRS. 


 
 
 
 
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 Per protocol set 
The per protocol set (PPS) will consist of all patients included in the FAS population who do 
not have any major protocol violations assessed to compromise the analysis of study data. All 
protocol violations will be judged as major or minor prior to database lock. 
17.4 Description of study population 
 Demographics and baseline characteristics 
Descriptive statistics for demographics, weight and height will be presented by treatment. 
 Medical/psychiatric history and prior/concomitant medication 
Medical/psychiatric history will be presented by system organ class (SOC) and preferred term 
(PT) by treatment. Prior/concomitant medications will be presented by ATC level 1, 3 and 5 
by treatment. 
 Treatment compliance 
The number of patients treated in each treatment period and their individual dose will be 
listed. 
Compliance will be presented using summary statistics per treatment (1-[number of study 
drugs returned/number of study drug delivered]). 
17.5 Analysis of primary endpoints 
The safety analyses will be based on the safety dataset.  
 Adverse events  
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented by treatment. Incidence of AEs and SAEs will be summarized by SOC and PT by 
treatment. Separate tables will be provided, if relevant, for serious AEs (SAEs) or events 
leading to withdrawal from study.   
All AE data will be listed by patient and include the verbatim term entered by the 
Investigator. 
 Physical examination 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by patient and summarized by treatment. 
Changes over time will be presented using shift tables, if considered appropriate.  
 Vital signs 
Vital signs (systolic/diastolic blood pressure, orthostatic blood pressure, pulse, respiratory rate 
and body temperature) will be summarized by treatment. Data will be presented with absolute 
and percent change from baseline. 


 
 
 
 
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 12-lead ECG 
All ECGs will be categorized as ”normal”, ”abnormal, not clinically significant”, or 
”abnormal, clinically significant” (as judged by the Investigator) and summarized by 
treatment using frequency tables.  
Changes over time will be presented using shift tables, if considered appropriate. 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS data will be listed by patient and visit and summarized by treatment. 
Changes over time will be presented using shift tables, if considered appropriate. 
 Safety laboratory analyses 
Safety laboratory data will be summarized by treatment with absolute and percent change 
from baseline at each visit. 
Abnormal, clinically significant values will be summarized separately, if considered 
appropriate.  
17.6 Analysis of secondary endpoints 
The efficacy analyses will be performed separately on both the FAS and PPS if deemed 
appropriate. 
 Unified Dyskinesia Rating Scale (UDysRS) total score 
Change from baseline in the UDysRS total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. A Wilcoxon signed-rank test will 
be used to assess statistically significant differences between active treatment and placebo for 
each time point. The same analysis will be done for UDysRS total objective score Part III and 
IV only. 
 ON Time Without Troublesome Dyskinesia 
Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without 
Dyskinesia plus ON With Non-troublesome Dyskinesia) based on a PD Home Dyskinesia 
Diary (see Section 11.3.3) will be summarized using descriptive statistics for all assessment 
time points. A Chi-Square test will be used to assess statistically significant differences 
between active treatment and placebo for the whole study period. 
 Unified Parkinson’s Disease Rating Scale (UPDRS)  
Change from baseline in UPDRS combined scores (Parts I, II, III and IV) to Visit 6 (Day 28) 
and Visit 7 (Day 42) respectively will be summarized using descriptive statistics. A Wilcoxon 
signed-rank test will be used to assess statistically significant differences between active 
treatment and placebo for each time point. The same analysis will be done for UPDRS Part III 
only. 


 
 
 
 
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 Clinical Global Impression of Change (CGI-C) in overall PD symptoms 
Change from baseline in CGI-C in overall PD symptoms to Visit 6 (Day 28) and Visit 7 (Day 
42) respectively will be summarized using descriptive statistics. A Wilcoxon signed-rank test 
will be used to assess statistically significant differences between active treatment and 
placebo for each time point. 
 Dyskinesia scores measured by a wearable dyskinesia assessment device 
Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes 
Neurotechnologies, Inc) wearable dyskinesia assessment system to Visit 6 (Day 28) and 
Visit 7 (Day 42) respectively will be summarized using descriptive statistics. A Wilcoxon 
signed-rank test will be used to assess statistically significant differences between active 
treatment and placebo for each time point. 
17.7 Analysis of exploratory endpoints  
 King’s Parkinson’s Disease Pain Scale (KPPS) total score 
Change from baseline in the KPPS total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. A Wilcoxon signed-rank test will 
be used to assess statistically significant differences between active treatment and placebo for 
each time point. 
 Parkinson’s Disease Questionnaire (PDQ39) total score 
Change from baseline in the PDQ39 total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. A Wilcoxon signed-rank test will 
be used to assess statistically significant differences between active treatment and placebo for 
each time point. 
 Hospital Anxiety Depression Scale (HADS) 
Change from baseline in the HADS to Visit 6 (Day 28) and Visit 7 (Day 42) respectively will 
be summarized using descriptive statistics. A Wilcoxon signed-rank test will be used to assess 
statistically significant differences between active treatment and placebo for each time point. 
 International Consultation on Incontinence Questionnaire Overactive Bladder 
Module (ICIQ-OAB) total score 
Change from baseline in the ICIQ-OAB total score to Visit 6 (Day 28) and Visit 7 (Day 42) 
respectively will be summarized using descriptive statistics. A Wilcoxon signed-rank test will 
be used to assess statistically significant differences between active treatment and placebo for 
each time point. 
 Epworth Sleepiness Scale (ESS) 
Change from baseline in the ESS to Visit 6 (Day 28) and Visit 7 (Day 42) respectively will be 
summarized using descriptive statistics. A Wilcoxon signed-rank test will be used to assess 
statistically significant differences between active treatment and placebo for each time point. 


 
 
 
 
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Movement Disorder Society, 2010. 25(11): p. 1646-51. 
6. Rahman, S., H.J. Griffin, N.P. Quinn, and M. Jahanshahi, Quality of life in Parkinson's 
disease: the relative importance of the symptoms. Movement disorders : official journal of 
the Movement Disorder Society, 2008. 23(10): p. 1428-34. 
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19 SIGNATURES 
19.1 Principal Investigator statement 
I have read and understood this CSP and agree to conduct the study accordingly and to 
comply with the Investigator obligations stated in this CSP, GCP and applicable regulatory 
requirements.  
 
Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
Name 
 
Signature 
 
Date 
 
 
 
 
 
Site