Conditions: Restless Legs Syndrome
Keywords: RLS Rotigotine Neupro
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate the efficacy of rotigotine against placebo in adolescent subjects with idiopathic Restless Legs Syndrome (RLS) over a 12-week maintenance period and to investigate the safety and tolerability of rotigotine in adolescent subjects with idiopathic RLS.

Detailed description:

Arms:
arm 1: Subjects randomized to this arm will be initiated on 1 milligram (mg)/24 hours (h) rotigotine and up-titrated to a maximum of 2 mg/24 h rotigotine, which is the assigned dose level throughout the 12-week Maintenance Period. arm 2: Subjects randomized to this arm will be initiated on 1 milligram (mg)/24 hours (h) rotigotine and up-titrated to a maximum of 3 mg/24 h rotigotine (1 mg/24 h patch + 2 mg/24 patch at the same time), which is the assigned dose level throughout the 12-week Maintenance Period. arm 3: Subjects randomized to this arm will receive matching placebo patches to maintain the blinding.

Interventions: intervention 1: Rotigotine 1 milligram/24 hours intervention 2: Rotigotine 2 milligram/24 hours intervention 3: Placebo
Intervention descriptions: intervention 1: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: Application of rotigotine transdermal patch with 1 milligram (mg)/24 hours (h) (5 square centimeter (cm\^2) patch size). intervention 2: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: Application of rotigotine transdermal patch with 2 milligram (mg)/24 hours (h) (10 square centimeter (cm\^2) patch size). intervention 3: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: not applicable

Protocol document:
Prot_000.pdf: 
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PROTOCOL SP1006 AMENDMENT 3 
A REMOTE, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED STUDY OF ROTIGOTINE TRANSDERMAL 
SYSTEM IN ADOLESCENT SUBJECTS WITH IDIOPATHIC 
RESTLESS LEGS SYNDROME 
PHASE 3 
 
IND Number: 063902 
 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
02 Feb 2018 
Not applicable 
Protocol Amendment 1 
19 Mar 2019 
Substantial 
Protocol Amendment 2 
05 Feb 2020 
Non-substantial 
Protocol Amendment 3 
29 Apr 2021 
Non-substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SRL, Allée de la Recherche 60, 1070, Brussels, BELGIUM 
Principal/Coordinating Investigator 
Name: 
David Kudrow, 
 
Affiliation: 
Science 37 
Address: 
600 Corporate Pointe, 
 
Culver City, CA 90230-7600 
USA 
Phone: 
 
 
Sponsor Study Physician 
Name: 
 
Address: 
UCB Biosciences Inc.  
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
 
 
Clinical Project Manager 
Name: 
  
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
  
 
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Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
 
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
  
 
Clinical Monitoring Contract Research Organization 
Name: 
PAREXEL International (IRL) Limited-Ireland 
Address: 
Ireland Limited at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland 
Phone: 
 
Fax: 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com  
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 12 
3 
STUDY OBJECTIVES .................................................................................................... 13 
4 
STUDY VARIABLES ..................................................................................................... 14 
4.1 
Efficacy variables......................................................................................................... 14 
4.1.1 
Primary efficacy variable ..................................................................................... 14 
4.1.2 
Secondary efficacy variables ............................................................................... 14 
4.1.3 
Other efficacy variables ....................................................................................... 14 
4.2 
Safety variables ............................................................................................................ 14 
4.2.1 
Primary safety variables ...................................................................................... 14 
4.2.2 
Other safety variables .......................................................................................... 14 
4.3 
Other variables ............................................................................................................. 15 
5 
STUDY DESIGN ............................................................................................................. 15 
5.1 
Study description ......................................................................................................... 15 
5.1.1 
Study duration per subject ................................................................................... 16 
5.1.2 
Planned number of subjects and sites .................................................................. 16 
5.1.3 
Anticipated regions and country .......................................................................... 16 
5.2 
Schedule of study assessments..................................................................................... 16 
5.3 
Schematic diagram ....................................................................................................... 20 
5.4 
Rationale for study design and selection of dose ......................................................... 21 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 21 
6.1 
Inclusion criteria .......................................................................................................... 21 
6.2 
Exclusion criteria ......................................................................................................... 23 
6.3 
Withdrawal criteria ...................................................................................................... 24 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 25 
7 
STUDY TREATMENTS ................................................................................................. 26 
7.1 
Description of investigational medicinal products ...................................................... 26 
7.2 
Treatments to be administered ..................................................................................... 26 
7.2.1 
Titration Period .................................................................................................... 26 
7.2.1.1 
Maintenance Period ................................................................................... 27 
7.2.1.2 
Taper Period .............................................................................................. 27 
7.2.1.3 
Safety Follow-Up Period ........................................................................... 27 
7.2.2 
Application instructions ....................................................................................... 27 
7.2.3 
Removal instructions ........................................................................................... 28 
7.2.4 
General instructions ............................................................................................. 28 
7.3 
Packaging ..................................................................................................................... 29 
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7.4 
Labeling ....................................................................................................................... 29 
7.5 
Handling and storage requirements ............................................................................. 29 
7.6 
Drug accountability ...................................................................................................... 30 
7.7 
Procedures for monitoring subject compliance ............................................................ 30 
7.8 
Concomitant medications/treatments ........................................................................... 31 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 31 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 31 
7.8.3 
Rescue medication ............................................................................................... 31 
7.9 
Blinding........................................................................................................................ 32 
7.9.1 
Procedures for maintaining and breaking the treatment blind ............................. 32 
7.9.1.1 
Maintenance of study treatment blind ....................................................... 32 
7.9.1.2 
Breaking the treatment blind in an emergency situation ........................... 32 
7.10 
Randomization and numbering of subjects .................................................................. 32 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 33 
8.1 
Screening Period .......................................................................................................... 33 
8.1.1 
Visit 1 (Day -28 to Day -1) .................................................................................. 33 
8.2 
Titration Period ............................................................................................................ 34 
8.2.1 
Visit 2 (Baseline) ................................................................................................. 34 
8.2.2 
Visit 3 (Day 1) ..................................................................................................... 35 
8.2.3 
Visit 4 (Day 8) and Visit 5 (Day 15) ................................................................... 35 
8.3 
Maintenance Period ..................................................................................................... 36 
8.3.1 
Visit 6 (Day 22) ................................................................................................... 36 
8.3.2 
Visit 7 (Day 50) and Visit 8 (Day 78) ................................................................. 37 
8.3.3 
Visit 9 (Day 106)/End of Maintenance ................................................................ 37 
8.4 
Taper Period (Day 106 to Day 110) ............................................................................. 38 
8.5 
Safety Follow-Up Visit (if applicable) ........................................................................ 39 
8.6 
Withdrawal Visit .......................................................................................................... 39 
8.7 
Unscheduled Visit ........................................................................................................ 39 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 40 
9.1 
International Restless Legs Rating Scale (IRLS) ......................................................... 41 
9.2 
Clinical Global Impressions ......................................................................................... 42 
9.3 
RLS-6 ........................................................................................................................... 42 
9.4 
Subject Quality of Life Questionnaire ......................................................................... 43 
10 ASSESSMENT OF PHARMACOKINETIC VARIABLES ........................................... 43 
10.1 
Blood sampling for the determination of rotigotine plasma concentrations ................ 43 
10.2 
Shipment procedures .................................................................................................... 43 
10.3 
Bioanalytical method ................................................................................................... 43 
11 ASSESSMENT OF SAFETY .......................................................................................... 43 
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11.1 
Adverse events ............................................................................................................. 44 
11.1.1 
Definitions ........................................................................................................... 44 
11.1.1.1 
Adverse event ............................................................................................ 44 
11.1.1.2 
Serious adverse event ................................................................................ 44 
11.1.1.3 
Adverse events of special interest ............................................................. 45 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 46 
11.1.2.1 
Description of adverse events .................................................................... 46 
11.1.2.2 
Rule for repetition of an adverse event...................................................... 46 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 46 
11.1.3 
Follow up of adverse events ................................................................................ 47 
11.2 
Pregnancy ..................................................................................................................... 47 
11.3 
Suspected transmission of an infectious agent............................................................. 48 
11.4 
Overdose of investigational medicinal product ........................................................... 48 
11.5 
Safety signal detection ................................................................................................. 48 
11.6 
Laboratory measurements ............................................................................................ 49 
11.6.1 
Evaluation of PDILI ............................................................................................ 51 
11.6.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 54 
11.6.1.2 
Immediate action: determination of IMP discontinuation ......................... 54 
11.6.1.3 
Testing: identification/exclusion of alternative etiology ........................... 54 
11.6.1.4 
Follow-up evaluation ................................................................................. 56 
11.7 
Other safety measurements .......................................................................................... 56 
11.7.1 
12-lead electrocardiogram values ........................................................................ 56 
11.7.2 
Vital signs ............................................................................................................ 56 
11.7.3 
Physical and neurological examinations .............................................................. 56 
11.7.4 
Hormone status .................................................................................................... 57 
11.7.5 
Modified Minnesota Impulsive Disorders Interview ........................................... 57 
11.7.6 
Menstrual function ............................................................................................... 57 
11.7.7 
Assessment of suicidal ideation and behavior ..................................................... 57 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 58 
12.1 
Adherence to protocol .................................................................................................. 58 
12.2 
Monitoring ................................................................................................................... 58 
12.2.1 
Definition of source data ..................................................................................... 58 
12.2.2 
Source data verification ....................................................................................... 59 
12.3 
Data handling ............................................................................................................... 59 
12.3.1 
Case Report form completion .............................................................................. 59 
12.3.2 
Database entry and reconciliation ........................................................................ 59 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 59 
12.4 
Termination of the study .............................................................................................. 60 
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12.5 
Archiving and data retention ........................................................................................ 60 
12.6 
Audit and inspection .................................................................................................... 60 
12.7 
Good Clinical Practice ................................................................................................. 61 
13 STATISTICS ................................................................................................................... 61 
13.1 
Definition of analysis sets ............................................................................................ 61 
13.2 
General statistical considerations ................................................................................. 61 
13.3 
Planned efficacy analyses ............................................................................................ 61 
13.3.1 
Analysis of the co-primary efficacy variables ..................................................... 61 
13.3.2 
Analysis of the secondary efficacy variable ........................................................ 62 
13.3.3 
Other efficacy variables ....................................................................................... 62 
13.4 
Planned safety and other analyses................................................................................ 62 
13.4.1 
Safety analyses ..................................................................................................... 63 
13.4.2 
Other analyses ...................................................................................................... 63 
13.5 
Handling of protocol deviations................................................................................... 63 
13.6 
Handling of dropouts or missing data .......................................................................... 63 
13.7 
Planned interim analysis and data monitoring ............................................................. 64 
13.8 
Determination of sample size ....................................................................................... 65 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 65 
14.1 
Informed consent ......................................................................................................... 65 
14.2 
Subject identification cards .......................................................................................... 66 
14.3 
Institutional Review Boards and Independent Ethics Committees .............................. 66 
14.4 
Subject privacy............................................................................................................. 67 
14.5 
Protocol amendments ................................................................................................... 68 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 68 
16 REFERENCES ................................................................................................................ 69 
17 APPENDICES ................................................................................................................. 70 
17.1 
Protocol Amendment 1 ................................................................................................ 70 
17.2 
Protocol Amendment 2 ................................................................................................ 91 
17.3 
Protocol Amendment 3 ................................................................................................ 92 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 98 
19 SPONSOR DECLARATION .......................................................................................... 99 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of assessments .................................................................................. 17 
Table 7‒1: 
Investigational medicinal product .................................................................... 26 
Table 7‒2: 
Dose titration schedule ..................................................................................... 26 
Table 7‒3: 
Dose down titration schedule ........................................................................... 27 
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Table 11‒1: 
Anticipated serious adverse events for the RLS population ............................ 45 
Table 11‒2: 
Laboratory measurements ................................................................................ 50 
Table 11‒3: 
Required investigations and follow up for PDILI............................................ 52 
Table 11‒4: 
PDILI laboratory measurements ...................................................................... 54 
Table 11‒5: 
PDILI information to be collected ................................................................... 55 
Table 13‒1: 
Decision rules at the interim analysis .............................................................. 64 
 
LIST OF FIGURES 
Figure 5‒1: 
Schematic diagram ........................................................................................... 20 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance  
ADHD 
attention deficit hyperactivity disorder 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CDMS 
clinical data management system 
CGI 
Clinical Global Impressions  
CI 
confidence interval 
CPM 
Clinical Project Manager 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
eCRF 
electronic Case Report form 
ECG 
electrocardiogram 
EoM 
End of Maintenance 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICD 
impulse control disorder 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRLS 
International Restless Legs Rating Scale  
IRT 
interactive response technology 
ISF 
investigator site file 
LOCF 
last observation carried forward 
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LS 
least square 
MAO 
monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMIDI 
Modified Minnesota Impulsive Disorder Interview 
PD 
pharmacodynamic 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic 
PLATFORM 
Science 37 Platform 
PPS 
Per Protocol Set 
PS 
Patient Safety 
PT 
preferred term 
RLS 
Restless Legs Syndrome  
RLS-QoL 
Restless Legs Syndrome-Quality of Life 
RLS-6  
Restless Legs-6 Rating Scales 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WMP 
Where’s My Patch 
 
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1 
SUMMARY 
This is a Phase 3, remote, double-blind, randomized, adaptive, placebo-controlled study of fixed 
dose administration of rotigotine transdermal system in adolescent subjects, 13 to 17 years of 
age, with idiopathic Restless Legs Syndrome (RLS). Subjects will be randomized to 1 of 
3 treatment groups: placebo, 2mg/24h rotigotine, or 3mg/24h rotigotine.  
The total study duration per subject will be up to 24 weeks including a 4-week Screening Period, 
a 3-week Titration Period, 12-week Maintenance Period, a Taper Period of 4 days (with 
de-escalation by 1 dose step every 2 days), and a 30-day Safety Follow-Up Period (for subjects 
not participating in the open-label, long-term follow-up study). The end of the study is defined as 
the last visit of the last subject in the study. 
A total of 138 subjects are planned to be randomized during the study. A single remote site in the 
USA is planned to be included in the study. This model integrates telemedicine technology into 
the clinical research process and supports management of research activities, including data 
collection.  
The primary objective of this study is to demonstrate the efficacy of rotigotine against placebo in 
adolescent subjects with idiopathic RLS over a 12-week Maintenance Period. The secondary 
objectives are to investigate the efficacy, safety, and tolerability of rotigotine in adolescent 
subjects. 
The co-primary efficacy variables are change from Baseline to the end of the Maintenance 
Period in International Restless Legs Rating Scale (IRLS) sum score and change from Baseline 
to the end of the Maintenance Period in Clinical Global Impressions (CGI) Item 1 score. 
Other efficacy variables are change from Baseline by visit in IRLS sum score and 
Restless Legs-6 Rating Scales (RLS-6). 
Safety variables are adverse events (AEs), withdrawals due to AEs, physical and neurological 
examination findings, changes from Baseline in 12-lead electrocardiograms (ECGs), vital signs, 
laboratory data, hormone status, body weight, height, body mass index (BMI), and Modified 
Minnesota Impulsive Disorder Interview (mMIDI). 
2 
INTRODUCTION 
Restless Legs Syndrome, also known as Willis-Ekbom disease, is a common pediatric neurologic 
condition affecting 2% to 4% of school-aged children and adolescents, with about 25% to 50% 
of pediatric cases having moderate-to-severe symptoms. Restless Legs Syndrome has a 
significant impact on sleep, mood, cognition, and function, particularly sleep disturbance. 
Impairment is often manifested in behavioral and educational domains (Pichietti et al, 2013). 
Genetic factors, dopamine dysfunction, and low-iron stores may play a role in the 
pathophysiology of RLS (Simakajornboon et al, 2009). Current evidence supports relative iron 
deficiency and renal failure as potential aggravating factors for pediatric RLS. Periodic limb 
movements in sleep and a family history of RLS among first-degree relatives are supportive of 
pediatric RLS (Pichietti et al, 2013). 
The pediatric RLS diagnostic criteria were published in 2003 based on the consensus at a 
National Institutes of Health workshop (2002) sponsored in part by the International RLS Study 
Group. These diagnostic criteria were updated in 2013 by the International RLS Study Group 
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(Picchietti et al, 2013). Ruling out RLS mimics was integrated as an essential element for RLS 
diagnosis. 
Dopaminergic agents are the first-choice treatment for RLS in adults; however, to date, no 
treatment for RLS has been approved for children. Small published reports suggest that 
dopamine agonists are effective in the management of RLS in children (Simakajornboon et al, 
2009; Cortese et al, 2009; Muhle et al, 2008; Mohri et al, 2008; Konofal et al, 2005; 
Guilleminault et al, 2003).  
The investigational medicinal product (IMP) is a transdermal formulation of the dopamine 
agonist rotigotine. The patch is applied to the skin and provides constant plasma concentrations. 
It was first approved by the European regulatory authorities for use in patients with Parkinson’s 
disease in March 2006, and by the US Food and Drug Administration (FDA) in May 2007. 
Rotigotine transdermal system was approved by the FDA as a treatment for adult patients with 
RLS in April 2012. 
The tolerability of rotigotine transdermal system appears to be within the range of what is known 
and expected from other dopamine agonists, except for application site reactions, which appear 
to be mild to moderate in the majority of cases (Perez-Lloret et al, 2013). 
UCB has completed a Phase 2 pharmacokinetic (PK)/pharmacodynamic (PD) study in adolescent 
subjects 13 to 17 years of age, which showed a PK profile similar to that in adult subjects. 
Although the study was open-label and the sample size was small, the efficacy of rotigotine 
transdermal system in adolescent subjects also appeared similar to efficacy in adults. 
Improvements were observed in most efficacy parameters, including the IRLS, CGI Items 1 
through 3, and RLS-6, indicating improvements in RLS symptoms and sleep. The purpose of this 
study is to further investigate the efficacy, safety, and tolerability of rotigotine in adolescent 
subjects 13 to 17 years of age. 
A remote study model will be used to conduct this study. This model integrates telemedicine 
technology into the clinical research process and supports management of research activities, 
including data collection. As part of this model, study visits are completed using the unique 
technology platform called Science 37 Platform, or PLATFORM, which is the backbone of the 
studies conducted via this model. PLATFORM is the software interface that connects 
subjects/legal representatives to their investigators/study teams through a study-issued 
smartphone. This technology will be used in combination with visits from mobile study 
personnel to subjects’/legal representatives’ homes. 
3 
STUDY OBJECTIVES 
The primary objective of this study is to demonstrate the efficacy of rotigotine against placebo in 
adolescent subjects with idiopathic RLS over a 12-week Maintenance Period. The secondary 
objectives are to investigate the safety and tolerability of rotigotine in adolescent subjects with 
idiopathic RLS. 
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4 
STUDY VARIABLES 
4.1 
Efficacy variables 
4.1.1 
Primary efficacy variable 
The co-primary efficacy variables are change from Baseline to the end of the Maintenance 
Period in IRLS sum score and change from Baseline in CGI Item 1 to the end of the Maintenance 
Period. 
4.1.2 
Secondary efficacy variables 
Secondary efficacy variables include: 
• Change from Baseline in RLS-6 Rating Scales to the end of the Maintenance Period 
4.1.3 
Other efficacy variables 
• Change from Baseline in CGI Item 1 by visit*  
• Change from Baseline in RLS-6 Rating Scales by visit* 
• Change from Baseline in IRLS sum score by visit* 
• IRLS Responder: A responder is defined as a subject with a decrease of ≥50% in IRLS sum 
score from Baseline 
• IRLS Remitter: Two definitions for IRLS remitter will be used in the study; a remitter is 
defined as a subject with an IRLS sum score ≤10 points or a subject who is symptom free (ie, 
IRLS sum score of 0 points) 
• CGI Item 1 Responder: A responder is defined as a subject with a decrease of ≥50% in CGI 
Item 1 
*For the IRLS, CGI, and RLS-6, the End of Maintenance (EoM) Visit is already covered under 
primary and secondary variables. 
4.2 
Safety variables 
4.2.1 
Primary safety variables 
• Occurrence of TEAEs 
• TEAEs leading to withdrawals 
4.2.2 
Other safety variables 
• Changes from Baseline (Visit 1) in 12-lead ECGs  
• Changes from Baseline (Visit 1) in vital signs (including assessment of orthostasis)  
• Changes from Baseline (Visit 1) in laboratory data (hematology, blood chemistry, and 
urinalysis)  
• Changes from Baseline (Visit 1) in hormone status  
• Changes from Baseline (Visit 1) in body weight, height, and BMI  
• Changes in mMIDI 
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• Changes in menstrual function for all female subjects 
4.3 
Other variables 
Other variables include: 
• Plasma concentrations of unconjugated rotigotine 
• Subject Quality of Life Questionnaire 
5 
STUDY DESIGN 
5.1 
Study description 
This is a Phase 3, remote, double-blind, randomized, adaptive placebo-controlled study of fixed 
dose administration of the rotigotine transdermal system. The study will be conducted in 
adolescent subjects, 13 to17 years of age, with idiopathic RLS. Subjects will be randomized to 
1 of 3 treatment groups: placebo, 2mg/24h rotigotine, or 3mg/24h rotigotine. 
The study will be conducted using the remote study model, which uses telemedicine technology 
(ie, PLATFORM, see Section 2 for an overview) for interactions between the investigator/study 
staff and study subjects/legal representatives. Mobile study personnel will visit subjects’/legal 
representatives’ homes to complete certain study procedures (eg, neurological exams, physical 
exams, ECGs, lab collections, and vital signs). 
The study will also utilize a reminder app to help maximize retention of study subjects and limit 
dropouts. The app, located on the study smartphone, called Where’s My Patch (WMP) will help 
encourage subject adherence to study medication administration by reminding them to place 
patches at their prespecified time each day. It also provides a body map to record daily patch 
locations as a visual reminder of where patches have already been placed over the past 14 days 
and to facilitate patch site rotation. Patch location data will only be retained locally on the 
smartphone and then automatically deleted after 14 days. Subject use of the MWP app will be 
encouraged, but not required. 
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists or taking L-dopa must discontinue the 
therapy at least 7 days prior to Visit 2/Baseline. Discontinuation of therapy must be driven by the 
subject’s medical need and not undertaken for the purpose of making a potential subject eligible 
for the study. 
The Screening Period will be followed by the Titration Period. Subjects will receive their first 
dose of study medication at Visit 3/Day 1. Subjects will be initiated either on placebo or 
1mg/24h rotigotine. The dose of rotigotine taken by subjects randomized to rotigotine will then 
be up-titrated on a weekly basis by 1mg/24h at a time to 2mg/24h or 3mg/24h, depending on the 
subject’s assigned dose level. 
Subjects will be administered study medication according to the dose titration schedule in 
Section 7.2.1. 
Subjects will be allowed to back-titrate 1 dose level during the Titration Period. Subjects are to 
complete the Titration Period at the back-titrated dose level and remain at this dose level for the 
duration of the Maintenance Period. If AEs occur during the Titration Period that are thought to 
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be the result of excessive dopaminergic stimulation (eg, intolerable nausea/vomiting), subjects 
should be back-titrated to their previous dose level and commence the Maintenance Period 
immediately. Subjects who do not tolerate the assigned dose in the first week (placebo or 
1mg/24h) will be withdrawn from the study. If subjects withdraw due to lack of efficacy, they 
are eligible to roll over to the open-label study, RL0007, after the 3 weeks of the Titration Period 
are completed. 
The Titration Period will be followed by a 12-week Maintenance Period. Subjects will remain at 
the assigned (or back-titrated) dose level throughout the Maintenance Period. At the end of the 
Maintenance Period, subjects will enter a Taper Period lasting up to a maximum of 4 days 
(de-escalation of study medication), followed by a 30-day Safety Follow-Up Period. 
Visits will be scheduled every week during the Titration Period. During the Maintenance Period, 
visits will be scheduled every 4 weeks. There is a 4-day interval until the end of the Taper 
Period, followed by a 30-day interval (±5 days) until the Safety Follow-Up Visit. Details are 
provided in the schedule of study assessments in Section 5.2.  
Plasma concentration of unconjugated rotigotine will be summarized by dose levels and visit. 
Plasma samples will be collected at Visit 6 and Visit 9. 
An interim analysis for futility (for the primary outcome measures only), with the possibility of 
stopping the study early, stopping a dose arm, or continuing the study as planned, will be 
performed with approximately 33% of the planned number of evaluable subjects; recruitment 
will not be stopped for the interim analysis. The futility criteria are defined in Section 13.7.  
An overview of the study activities is given in Table 5‒1 and Figure 5‒1. 
5.1.1 
Study duration per subject 
The total study duration per subject will be up to 24 weeks, including a 4-week Screening Period, 
a 3-week Titration Period, a 12-week Maintenance Period, a Taper Period of 4 days (with 
de-escalation by 1 dose step every 2 days), and a 30-day Safety Follow-Up Period (for subjects 
not participating in the open-label, long-term follow-up study). 
The end of the study is defined as the last visit of the last subject in the study. 
5.1.2 
Planned number of subjects and sites 
A total of 138 subjects are planned to be randomized during the study. A remote clinical study 
model in the USA is planned to be utilized in the study. 
5.1.3 
Anticipated regions and country 
This study will be conducted in the USA. 
5.2 
Schedule of study assessments 
The schedule of study assessments is provided in Table 5‒1. 
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Table 5‒1: 
Schedule of assessments  
Screening 
Period 
(+1 day) 
Rand 
(+3 
days) 
Titration Perioda  
(±1 day) 
 
 
 
EOT/ 
SOM 
 
Maintenance Perioda 
(±2 days) 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Assessment 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Withdrawal criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
General medical/ 
procedures history 
X 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle 
X 
 
 
 
 
 
 
 
 
 
 
 
Reproductive 
potential and birth 
control 
X 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Neurological 
examination 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc  
Vital signs 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Body weight, height, 
and BMI  
X 
 
 
 
 
X 
 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Safety laboratory 
tests 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy 
Testd (hCG) 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
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Table 5‒1: 
Schedule of assessments  
Screening 
Period 
(+1 day) 
Rand 
(+3 
days) 
Titration Perioda  
(±1 day) 
 
 
 
EOT/ 
SOM 
 
Maintenance Perioda 
(±2 days) 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Assessment 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
Hormone status 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
PK samplinge 
 
 
 
 
 
X 
 
 
X 
 
 
 
IRLS 
X 
Xf 
 
 
 
X 
X 
X 
X 
 
 
 
CGI 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
RLS-6  
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
mMIDI 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Menstrual functiond 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Subject Quality of 
Life Questionnaire 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Recording of 
medication and 
procedures 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse event 
assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact IRT 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
Dispense study 
medication 
 
 
Xg 
 
 
Xg 
Xg 
Xg 
Xg 
 
 
X 
Return unused study 
medication 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
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Table 5‒1: 
Schedule of assessments  
Screening 
Period 
(+1 day) 
Rand 
(+3 
days) 
Titration Perioda  
(±1 day) 
 
 
 
EOT/ 
SOM 
 
Maintenance Perioda 
(±2 days) 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Assessment 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
BL=Baseline; BMI=body mass index; CGI=Clinical Global Impressions; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
eCRF=electronic Case Report form; EOT=End of Titration; hCG=human chorionic gonadotropin; IRLS=International Restless Legs Scale; IRT=interactive 
response technology; mMIDI=Modified Minnesota Impulsive Disorder Interview; PK=pharmacokinetic; Rand=randomization; RLS=Restless Legs Syndrome; 
SOM=Start of Maintenance; V=Visit; WD=withdrawal 
Note: The date of informed consent may be prior to screening assessments and study procedures. 
Note: Rescreening is allowed with the permission of the Study Physician or representative. 
Note: For Visit 2, there is a visit window of +3 days to allow for direct-to-subject shipment of study medication. Visit 3/Day 1 is the first day of study medication 
exposure. All subsequent visits are calculated based on Visit 3/Day 1. 
Note: Visit 6 is the end of the Titration Period and start of the Maintenance Period. Visit 9 is the end of the Maintenance Period and start of the Taper Period.  
Note: All visits are via telemedicine calls, with the exception of Visit 1, Visit 6, Visit 9, and SFU. Unscheduled visits are at the discretion of the investigator and 
may be telemedicine calls.  
a The visit window for Titration Visits is ±1 day per visit relative to Visit 3 (day of first dose). The visit window for visits during the Maintenance Period, 
including the End of Maintenance Visit, is ±2 days per visit. The Taper Period, which will last up to a maximum of 4 days, will start on the day after the End of 
Maintenance Visit. The visit window for Safety Follow-Up Period is 30 days±5 days relative to the end of the Taper Period. Following dose de-escalation, 
subjects may be eligible to participate in the open-label, long-term follow-up study (RL0007) at any time prior to the Safety Follow-Up Visit (see Section 5). 
The Safety Follow-Up Visit is for subjects not entering RL0007. 
b Assessments to be performed are at the investigator's discretion. 
c C-SSRS is required if the Unscheduled Visit is conducted due to safety or efficacy reasons. 
d Pregnancy test and menstrual function for all female subjects; serum pregnancy test at Screening and urine pregnancy test at all other visits. A positive urine 
pregnancy test must be confirmed by a serum pregnancy test. 
e At the time of PK sampling, sampling time, time of application of study medication, and application site of study medication should be recorded in the eCRF. 
f At Baseline, subjects must score ≥15 on the IRLS Rating Scale (indicating moderate-to-severe RLS) and must score ≥4 points on the CGI Item 1. 
g Study medication to be shipped to subject’s home to be available no later than this date. 
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5.3 
Schematic diagram 
Subjects will be randomized to 1 of 3 treatment groups: 
Figure 5‒1: Schematic diagram 
 
 
• Subjects will remain at the assigned dose level throughout the 12-week Maintenance Period. 
• Subjects will be allowed to back-titrate 1 dose level during the Titration Period. See Section 5.1.  
• Subjects will complete the Titration Period at the back-titrated dose level and remain at this dose level for the duration of the 
Maintenance Period. 
Screening
Titration
Maintenance
Taper
Day -28 to 
Day -1
Days
1-7
Days
8-14
Days
15-21
Days 22-105
Days
106-109
3mg/24h
2mg/24h
Placebo*
0 mg
0 mg
0 mg
* Two patch sizes will be used: 5cm2 and 10cm2. Placebo patches will be identical in size and appearance to active patches.
1 mg
2 mg
3 mg
1 mg
2 mg
2 mg
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5.4 
Rationale for study design and selection of dose 
SP1006 is a Phase 3, remote, double-blind, randomized, placebo-controlled study of fixed dose 
administration of the rotigotine transdermal system, designed to investigate the efficacy, safety, 
and tolerability of rotigotine in adolescent subjects 13 to 17 years of age. The study design is 
based on the FDA’s request to conduct a study in adolescents with RLS. The fixed dose levels of 
2mg/24h and 3mg/24h were chosen based on the results of the SP1004 PK/PD study in a similar 
population.  
The PK results of SP1004 were similar compared with those obtained in adults. Rotigotine 
plasma clearance was similar as compared to adults, although the mean value appeared to be 
somewhat higher; however, given the high variability, the meaning of this is negligible. Mean 
volume of distribution, AUC, and Cmax were similar to results obtained in adults earlier. 
In terms of safety, the rotigotine transdermal system was well tolerated at doses of up to 
3mg/24h in adolescent subjects with idiopathic RLS. No safety issues were identified in SP1004. 
A similar number of subjects reported treatment-emergent adverse events (TEAEs) in the 
0.5mg/24h, 1mg/24h, and 2mg/24h dose steps during the study, with fewer subjects reporting 
TEAEs in the 3mg/24h dose step. Overall, 62.5% reported TEAEs, and 45.8% reported 
drug-related TEAEs. The most frequently reported TEAEs (and drug-related TEAEs) were in the 
system organ class (SOC) of Gastrointestinal disorders, with nausea the most frequently reported 
TEAE by preferred term (PT). All of the TEAEs in this study were mild or moderate in intensity. 
No deaths, serious adverse events (SAEs), or TEAEs leading to discontinuation were reported 
during the study.  
Fourteen subjects from SP1004 were rolled over to open-label extension study SP1005 and were 
treated for up to 2 years. Overall, rotigotine was well tolerated with long-term use. 
Augmentation, defined as an increase in the severity of symptoms beyond baseline levels, 
represents the main complication of long-term dopaminergic treatment. Augmentation did not 
occur in SP1004; however, the study was too short to trigger augmentation with less than 
5 weeks of treatment in total. 
The 2mg/24h and 3mg/24h rotigotine doses chosen for testing in this protocol, SP1006, were 
selected by balancing the potential need for higher doses with the risk of augmentation as seen in 
adults receiving doses higher than 3mg/24h. Previous studies have indicated that the incidence of 
augmentation with rotigotine is low during 6 months and 1 year of treatment. Following an 
open-label extension study of the long-term safety and efficacy of rotigotine transdermal patch in 
adult patients with moderate-to-severe idiopathic RLS, a retrospective systematic analysis was 
conducted in order to investigate the 5-year incidence of augmentation. In this study, the dose 
was titrated in weekly increments (up to 4 weeks) from 0.5mg/24h to a maximum of 4mg/24h, 
followed by up to 5 years of maintenance at the optimum dose. Clinically significant 
augmentation was recorded in 8% of adult patients receiving rotigotine at doses of 4mg/24h 
compared with 5% of patients receiving rotigotine doses of ≤3mg/24h (Oertel et al, 2011). 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
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1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject or by the parent(s) or legal 
representative. The Informed Consent form or a specific Assent form, where required, will be 
signed and dated by minors. 
2. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete questionnaires), visit schedule, and medication intake 
according to the judgment of the investigator. 
3. Subject is male or female, and is ≥13 and <18 years of age at Baseline. 
4. Subject weighs ≥40kg. 
5. Deleted. 
6. Subject meets the diagnosis of RLS based on all of the following features according to the 
2013 Revised International RLS Group Diagnostic Criteria (Pichietti et al, 2013): 
− An urge to move the legs usually, but not always, accompanied by or felt to be caused by 
uncomfortable and unpleasant sensations in the legs (sometimes the urge to move the legs 
is present without the uncomfortable sensations and sometimes the arms or other parts of 
the body are involved in addition to the legs. For children, the description of these 
symptoms should be in the child’s own words.). 
− The urge to move the legs and any accompanying unpleasant sensations begin or worsen 
during periods of rest or inactivity such as lying down or sitting. 
− The urge to move the legs and any accompanying unpleasant sensations are partially or 
totally relieved by movement, such as walking or stretching, at least as long as the 
activity continues (when symptoms are very severe, relief by activity may not be 
noticeable but must have been previously present). 
− The urge to move the legs and any accompanying unpleasant sensations during rest or 
inactivity only occur or are worse in the evening or night than during the day (when 
symptoms are very severe, the worsening at night may not be noticeable but must have 
been previously present). 
− The occurrence of the above features is not solely accounted for as symptoms primary to 
another medical or behavioral condition (eg, myalgia, venous stasis, leg edema, arthritis, 
leg cramps, positional discomfort, habitual foot tapping). 
7. Subject’s RLS symptoms cause significant daytime symptoms or significant distress or 
impairment in social, occupational, educational, or other important areas of functioning by 
the impact on sleep, energy/vitality, daily activities, behavior, cognition or mood. 
8. At Baseline, subject has a score of ≥15 on the IRLS Rating Scale (indicating 
moderate-to-severe RLS). 
9. At Baseline, subject scores ≥4 points on the CGI Item 1 assessment (indicating at least 
moderately ill). 
10a. Subjects who are receiving supplemental iron have been on a stable dose for at least 1 
month prior to Screening. Subjects previously treated with supplemental iron must have a 
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washout period of at least 1 month prior to Screening. No supplemental iron administration 
or iron dose adjustment will be allowed while in study, unless medically necessary. 
11. Female subjects must be surgically incapable of childbearing, or effectively practicing an 
acceptable method of contraception (oral/parenteral/implantable hormonal contraceptives, 
intrauterine device, or barrier and spermicide). Abstinence is an acceptable method. Subjects 
must agree to use adequate contraception during the study and for 4 weeks after their final 
dose of study medication. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has previously participated in this study or subject has received previous treatment 
with rotigotine. 
2. Subject has participated in another study of an IMP or a medical device within the last 3 
months prior to Visit 1/Screening or is currently participating in another study of an IMP or a 
medical device. 
3. Subject has clinically relevant renal dysfunction (serum creatinine >1.5mg/dL) at 
Visit 1/Screening. 
4a. Subject has a serum ferritin level below the lower limit of normal at Visit 1/Screening. 
5. Subject has a hemoglobin level below the lower limit of normal at Visit 1/Screening. 
6. Subject has had previous treatment with dopamine agonists or L-dopa within 7 days prior to 
Visit 2/Baseline. 
7. Subject has any medical or psychiatric condition, which in the opinion of the investigator, 
would jeopardize or compromise the subject’s well-being or ability to participate in this 
study. 
8. Subject is pregnant or nursing. 
9. Subject is not willing to abstain from caffeine after 4pm each evening within 7 days prior to 
Visit 2/Baseline and for the duration of the study. 
10. Subject has a QTc interval of ≥500ms at Visit 1/Screening. Bazett’s correction method must 
be used for the correction of the QT interval. 
11. At Visit 1/Screening, subject has symptomatic orthostatic hypotension with a decrease of 
blood pressure (BP) from supine to standing position of ≥20mmHg in systolic blood pressure 
(SBP) or of ≥10mmHg in diastolic blood pressure (DBP) taken from the 5 minute supine and 
1 and/or 3 minute standing measurements. 
12. Subject has a known hypersensitivity to any of the components of the study medication, such 
as a history of significant skin hypersensitivity to adhesives, known hypersensitivity to other 
transdermal medications or has unresolved contact dermatitis or eczema. 
13. Subject has secondary RLS (eg, due to renal insufficiency [uremia], iron deficiency, or 
rheumatoid arthritis). 
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14. Subject has a lifetime history of suicide attempts (including actual attempt, interrupted 
attempt, or aborted attempt), or had suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS at Screening 
(Visit 1). 
15. Subject is taking a prohibited concomitant medication (see Section 7.8.2). Prohibited 
concomitant medication must have been discontinued at least 2 weeks prior to Screening 
(Visit 1). 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Subjects should be withdrawn from the study if any of the following events occur: 
1. Subject develops a physical or mental illness or AE that would interfere with his/her 
continued participation. 
2. Subject is noncompliant with the study procedures or medications in the opinion of the 
investigator. 
3. The investigator feels that it is in the subject’s best interest to withdraw from the study. 
4. Subject is unwilling to manage the application and removal of patches at any time during the 
study. 
5. The subject develops clinically relevant symptomatic orthostatic hypotension. 
6. The subject develops a clinically relevant ECG abnormality that is confirmed by a repeat 
ECG performed at least 1 hour later. If abnormalities are still present, the subject is to be 
withdrawn from the study. 
7. The subject has a QTc interval ≥500ms and/or a QTc interval which has increased by ≥60ms 
as compared to the QTc interval taken at Visit 1/Screening. Bazett’s method must be used for 
correction of QT intervals. 
8. Subject or parent(s)/legal representative withdraws his or her consent. 
9. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
10. The sponsor or a regulatory agency requests withdrawal of the subject. 
11. Subject has active suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study. 
Investigators/designated study staff should attempt to obtain information on subjects in the case 
of withdrawal or discontinuation. For subjects considered as lost to follow up, the 
investigator/designated study staff should make an effort (at least 1 phone call and 1 written 
message to the subject), and document his/her effort (date and summary of the phone call and 
copy of the written message in the source documents), to complete the final evaluation. All 
results of these evaluations and observations, together with a narrative description of the 
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reason(s) for removing the subject, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal or discontinuation. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subjects with either of the following: 
− ALT or AST ≥ 5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume IMP 
administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 11.6.1.2 are followed. 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator.  
• Subjects with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated as described in Section 11.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
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7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
Table 7‒1 provides summary information regarding the products that will be used in this study. 
Table 7‒1: 
Investigational medicinal product 
International Non-Proprietary Name 
Rotigotine 
Dosage form 
Silicone patch containing rotigotine in an adhesive matrix 
Content 
Nominal Dose (mg/24h) 
Patch size (cm2) 
1 
5 
2 
10 
Placebo patches do not contain drug, but are identical in size and appearance to rotigotine 
patches.  
7.2 
Treatments to be administered 
7.2.1 
Titration Period 
The study will begin with a 3-week Titration Period, during which subjects will receive 
rotigotine patches in escalating weekly doses (from 1mg/24h to 2mg/24h for subjects 
randomized to 2mg/24h and from 1mg/24h to 2mg/24h to 3mg/24h for subjects randomized to 
3mg/24h) until the randomized dose level (or matching placebo) is achieved (Table 7‒2). During 
the Maintenance Period, the subject will continue as per the assigned treatment arm. Following 
the Maintenance Period, subjects will be de-escalated over 4 days. 
Table 7‒2: 
Dose titration schedule 
 
Rotigotine Nominal Dose 
(mg/24h) 
Patch surface area 
(cm2) 
Week 1 (Days 1 to 7) 
1 
1 x 5cm2 Active 
OR 
1 x 5cm2 Placebo 
Week 2 (Days 8 to 14) 
2 
1 x 10cm2 Active 
OR 
1 x 10cm2 Placebo 
Week 3 (Days 15 to 21) 
3 
1 x 5cm2 Placebo + 1 x 10cm2 Active 
OR 
1 x 5cm2 Active + 1 x 10cm2 Active 
OR 
1 x 5cm2 Placebo + 1 x 10cm2 Placebo 
Subjects will be allowed to back-titrate 1 dose level during the Titration Period. Subjects are to 
complete the Titration Period at the back-titrated dose level and remain at this dose level for the 
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duration of the Maintenance Period. If AEs occur during the Titration Period that are thought to 
be the result of excessive dopaminergic stimulation (eg, intolerable nausea/vomiting), subjects 
should be back-titrated to their previous dose level and commence the Maintenance Period 
immediately. Visits will be scheduled every week during the Titration Period. If subjects 
withdraw due to lack of efficacy, they are eligible to roll over to the open-label study, RL0007, 
after the 3 weeks of the Titration Period are completed. 
7.2.1.1 
Maintenance Period 
The Titration Period will be followed by a 12-week Maintenance Period. Subjects will maintain 
doses achieved at Visit 6 (end of the Titration Period) throughout the Maintenance Period. 
During the Maintenance Period, visits will be scheduled every 4 weeks for 3 visits. 
7.2.1.2 
Taper Period 
At the end of the Maintenance Period, subjects will enter a Taper Period lasting up to a 
maximum of 4 days (de-escalation of study medication) (Table 7‒3). Subjects in the 2mg/24h 
arm and the 3mg/24h arm will taper down to 1mg/24h by the end of the Taper Period. Subjects 
in the placebo arm will continue placebo throughout the 4-day Taper Period. At the end of the 
Taper Period, subjects will be contacted by telemedicine call. 
Table 7‒3: 
Dose down titration schedule 
Rotigotine nominal dose 
(mg/24h) 
Days 
Patch surface area 
(cm2) 
Placebo 
107 and 108 
1 x 5cm2 Placebo + 1 x 10cm2 Placebo 
109 and 110 
1 x 5cm2 Placebo + 1 x 10cm2 Placebo 
1 
107 and 108 
1 x 5cm2 Active + 1 x 10cm2 Placebo 
109 and 110 
1 x 5cm2 Active + 1 x 10cm2 Placebo 
2 
107 and 108 
1 x 5cm2 Active + 1 x 10cm2 Placebo 
109 and 110 
1 x 5cm2 Active + 1 x 10cm2 Placebo 
3 
107 and 108 
1 x 5cm2 Placebo + 1 x 10cm2 Active 
109 and 110 
1 x 5cm2 Active + 1 x 10cm2 Placebo 
7.2.1.3 
Safety Follow-Up Period 
The Taper Period is followed by a 30-day interval (±5 days) until the Safety Follow-Up Visit. 
Details are provided in the schedule of study assessments in Section 5.2. 
7.2.2 
Application instructions 
Following are instructions for patch application: 
• The patch should be applied immediately after removing it from the protective pouch. 
• Subjects, with the assistance of a legal representative (ie, parent/guardian) as needed, should 
apply the patch at approximately the same time each day. 
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• The patch should be worn continuously for 24 hours. After 24 hours, the patch should be 
removed and a new one applied immediately. The WMP app on the study smartphone 
provides a reminder to place patches at a subject’s prespecified time each day (see Section 5 
for an overview). 
• The patch should be applied to an area of clean, dry, and healthy skin on the stomach, thigh, 
hip, flank (side of the body between the ribs and the pelvis), shoulder, or upper arm. 
• Each patch should be applied to a different place on the skin each day, for example, from the 
right side to the left side and from the upper body to the lower body. The patch should not be 
applied to the same application site more than once every 14 days. The WMP app on the 
study smartphone provides a body map to record daily patch location and a visual reminder 
of where patches have been placed over the past 14 days (see Section 5 for an overview). 
• When applied, the patch should be pressed firmly into place with the palm of the hand for 
30 seconds to make sure there is good contact with the skin, especially around the edges. 
• If it is necessary to apply the patch to a hairy area, the area should be clipped at least 3 days 
prior to applying the patch. 
• The patch should not be applied to areas where it could be rubbed by tight clothing or under a 
waistband. 
• Avoid applying the patch on skin folds or body areas of increased sweating. 
• Do not apply the patch to skin that is red, irritated, or injured. 
• Creams, lotions, ointments, oils, and powders should not be applied to the skin area where 
the patch will be placed. 
• Subjects and legal representatives (ie, parents/guardians) should wash their hands with soap 
and water immediately after handling the patch. 
7.2.3 
Removal instructions 
Following are instructions for patch removal: 
• Slowly and carefully peel off the used patch which still contains some of the drug. 
• Carefully fold it in half (sticky sides together) and throw it in the trash. 
• Gently wash the area with warm water and mild soap to remove any adhesive that stays on 
the skin. Baby oil may also be used to remove any excess residue. Alcohol or other solvents, 
such as nail polish remover, may cause skin irritation and should not be used. 
• Subjects may see mild redness at the site when a patch is removed. This redness should 
disappear over time. If uncomfortable irritation or excessive itchiness continues, subjects 
and/or their parent/guardian should tell their investigator. 
7.2.4 
General instructions 
Following are general instructions: 
• Contact with water while bathing, showering, swimming will not change the way that 
rotigotine works; however, these activities could loosen the patch. If a patch falls off, 
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re-apply a new patch for the remainder of the day. A new patch should be applied the next 
day on the subject’s regular schedule. The location of a replacement patch can be recorded in 
the WMP app on the study smartphone (see Section 5 for an overview). 
• If the subject forgets to apply a patch at the usual time, the subject should remove the patch 
he/she is currently wearing and put a new patch on a different area of skin. Then apply a new 
patch the next day on the subject’s regular schedule. 
• Avoid applying heating pads or other sources of external heat to the patch. Avoid exposing 
the patch to direct sunlight. 
• If the subject develops a skin rash or irritation from the patch, avoid direct sunlight on the 
area until the skin heals because this exposure could lead to changes of skin color. 
• Subjects should not reduce the dosage or stop applying a patch without first talking with their 
investigator. 
• Do not cut or damage the patch. 
• After 24 hours, the patches should be removed and new ones applied right away to a different 
area of skin. 
• To avoid potential burns, the patch should be removed before undergoing cardioversion or a 
diagnostic procedure known as magnetic resonance imaging. 
• The patches should be stored according to the labeling on the clinical trial supply packaging. 
Do not store the patch outside pouch. 
7.3 
Packaging 
The IMP will be packaged and labeled by UCB according to current Good Manufacturing 
Practice (GMP) guidelines and the applicable laws and guidelines. The sponsor will provide site 
boxes containing complete study medication. The site boxes will be packaged in such a way as to 
protect the product from deterioration during transport and storage. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language. 
7.5 
Handling and storage requirements 
Rotigotine transdermal patches should be stored in the original pouch. Rotigotine should be 
stored according to the labeling on the clinical trial supply packaging. The investigator (or 
designee) is responsible for the safe and proper storage of rotigotine at the site. Rotigotine stored 
by the investigator (or designee) is to be kept in a secured area with limited access according to 
the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlled room temperature or by 
completion of a temperature log in accordance with local requirements on a regular basis 
(eg, once a week), showing minimum and maximum temperatures reached over the time interval. 
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In case an out-of-range temperature is noted, it must be immediately communicated to the 
Sponsor’s designee in accordance with the Pharmacy Manual. The investigator (or designee) will 
instruct the subject to store the IMP following the instructions on the label. Detailed information 
on handling the IMP will be given in the Pharmacy Manual. 
As part of the remote study model, the study site’s depot/pharmacy will provide study 
medication and all required supplies via direct-to-subject shipments. Once eligibility is 
confirmed, the study site will contact the interactive response technology (IRT) for 
randomization assignment, and shipments will be prepared and sent out for delivery to the 
subject’s/legal representative’s home/preferred address. Shipments will be confirmed as 
delivered by the study staff, with appropriate documentation in the subject’s study records. The 
study medication will be confirmed as received in good condition and within the acceptable 
temperature range (ie, fit for use). A telemedicine call will be completed to instruct the 
subject/legal representative on the correct storage and administration of the study medication, 
which will also be documented as part of subject’s study record. 
7.6 
Drug accountability 
At the designated timepoints during the study, subjects/legal representatives will return to the 
study site’s depot/pharmacy the unused study medication patches remaining as part of the 
medication kits, along with the kit itself, via the return shipment materials provided. A Drug 
Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, disposed of at the study site’s 
depot/pharmacy, or returned to the sponsor or designee must also be recorded on the appropriate 
forms. All supplies and drug accountability documentation must be made available throughout 
the study for UCB (or designee) to review. 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site’s depot/pharmacy to an appropriate designee. 
The investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) and unused IMP containers must be reconciled and returned to UCB (or designee), 
preferably in their original package. Investigational medicinal product intended for the study 
cannot be used for any other purpose than that described in this protocol. 
7.7 
Procedures for monitoring subject compliance 
At the designated visits (see Table 5‒1), subjects/legal representatives will return all unused IMP 
and empty IMP containers, using the return shipment supplies provided to them by the study 
staff. Upon receipt of the returned medication at the study site’s depot/pharmacy, the designated 
study staff will review drug accountability with the subject/legal representative via a telephone 
or a telemedicine call in order to obtain explanations regarding any discrepancies in compliance 
with the dosing regimen. 
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If a subject is found to be persistently noncompliant (defined as ≤85% or ≥115% compliant with 
dosing schedule), the sponsor, in conjunction with the investigator, will make a decision as to 
whether the subject should be withdrawn from the study. 
7.8 
Concomitant medications/treatments 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
If nausea or vomiting occurs during the study, antiemetic therapy with Ondansetron (Zofran®, 
GlaxoSmithKline, Philadelphia, PA) is allowed. Ondansetron (Zofran) is not to be used 
prophylactically. 
Use of a topical anesthetic (eg, EMLA®, AstraZeneca, Wilmington, DE) is permitted to treat the 
venous puncture or indwelling venous catheter site prior to the needle stick. 
If medication is medically indicated, the subject must inform the investigator immediately. 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(ie, eCRF and source document). 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
• Neuroleptics  
• Antidepressants  
• Anxiolytic drugs  
• Opioids or opioid agonists  
• MAO inhibitors 
• Sedative antihistamines 
• Benzodiazepines 
• Hypnotics 
• Anticonvulsants  
• Central alpha-adrenergic agonists 
• Melatonin 
• Psychostimulant therapy, eg, for ADHD 
Therapy that becomes necessary, in the investigator’s opinion, during the course of the study 
must not be refused to a subject. The subject’s participation in this study may be discontinued in 
such a case. 
7.8.3 
Rescue medication 
Not applicable. 
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7.9 
Blinding 
This is a double-blind, placebo-controlled study. Subjects will be treated with either rotigotine 
transdermal patches or matching placebo patches. 
7.9.1 
Procedures for maintaining and breaking the treatment blind 
7.9.1.1 
Maintenance of study treatment blind 
All subject treatment details (ie, subject-related information about assigned kit numbers as listed 
in the randomization schedule) will be allocated and maintained by the IRT. 
UCB personnel, as well as contract research organization (CRO) personnel involved in the study 
for clinical monitoring, will be blinded to the treatment assignment with the following 
exceptions: 
• Sponsor Clinical Study Supplies Coordinator and personnel directly involved in 
manufacturing/packaging of the IMP 
• Bioanalytical personnel involved in the bioanalytical analysis of the PK samples 
• Sponsor pharmacovigilance personnel reporting SAEs to regulatory authorities 
• IRT services personnel 
7.9.1.2 
Breaking the treatment blind in an emergency situation 
In the event of an emergency, it will be possible to determine to which treatment arm and dose 
the subject has been allocated by contacting the IRT. The study site will be provided with details 
of how to contact the system for code breaking at the start of the study. The Medical Monitor or 
equivalent should be consulted prior to unblinding, whenever possible. 
The clinical project manager (CPM) will be informed immediately via the IRT when a code is 
broken, but will remain blinded to specific treatment information. Any unblinding of the IMP 
performed by the investigator must be recorded in the source documents and on the Study 
Termination eCRF page. 
An emergency envelope (or equivalent) containing the randomization code will be printed for 
each subject in a double-blind study and must not be broken, except for emergency situations.  
7.10 
Randomization and numbering of subjects 
An IRT will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by UCB (or 
designee). The IRT will generate individual assignments for subject kits of study drug, as 
appropriate, according to the visit schedule. 
To enroll a subject (Visit 1), the investigator or designee will contact the IRT and provide brief 
details about the subject to be enrolled. Each subject will receive a 5-digit number assigned at 
screening that serves as the subject identifier throughout the study. The subject number will be 
required in all communication between the investigator or designee and the IRT regarding a 
particular subject. Subject numbers and kit numbers will be tracked via the IRT.  
To randomize a subject (Visit 2/Baseline), the investigator or designee will contact the IRT and 
provide brief details about the subject to be randomized. The IRT will automatically inform the 
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investigator or designee of the subject’s randomization number. The IRT will allocate kit 
numbers to the subject based on the subject number during the course of the study. 
For Visit 2, there is a visit window of +3 days to allow for direct-to-subject shipment of study 
medication. Visit 3/Day 1 is the first day of study medication exposure. 
8 
STUDY PROCEDURES BY VISIT  
8.1 
Screening Period 
Prior to any study activities, subjects will be asked to read and sign an Informed Consent form 
and/or Assent form that has been approved by an IRB/IEC and which complies with regulatory 
requirements. See Section 14.1 for a description of the informed consent process for the remote 
study model. 
Subjects will be given adequate time to consider any information concerning the study, given to 
them by the investigator or designee. As part of the Informed Consent procedure, subjects will be 
given the opportunity to ask the investigator any questions regarding potential risks and benefits 
of participation in the study. 
Once consented, study supplies, including screening lab kits and study instructions, will be 
shipped out to the subject/legal representative. The initial shipment of study supplies will include 
the study-issued smartphone which subjects/legal representatives will utilize throughout the 
study to communicate with the study team and to complete various study procedures, such as 
questionnaires. The telemedicine functionality of PLATFORM (see Section 2 for an overview) 
may also be used for the designated study visits. Subject/legal representative will return the 
smartphone to the study site once study participation is completed. Additional supplies will be 
sent to the subject/legal representative as needed throughout the study. 
Subjects who have been screened but not randomized may be rescreened with the permission of 
the Study Physician or representative. 
8.1.1 
Visit 1 (Day -28 to Day -1) 
The following assessments will be performed: 
• Obtain informed consent. See Section 14.1 for a description of the informed consent process 
for the remote study model. 
• Demographics 
• Eligibility criteria 
• General medical/procedures history 
• Lifestyle: caffeine, alcohol use, and smoking 
• Reproductive potential and birth control 
The assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
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• Neurological examination 
• 12-lead ECG 
For lab collections listed below, mobile study personnel will be sent to the subject’s/legal 
representative’s home for sample collections. Samples will be prepared and sent to the central 
laboratory for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine drug screen 
• Serum pregnancy test for all female subjects 
• Hormone status 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Baseline/Screening version) 
• IRLS 
• CGI  
• mMIDI 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. Medications and procedures will be reviewed with 
the subject/legal representative by the investigator/designated study staff via a telephone or 
telemedicine call and noted as part of the subject’s study record. 
• AE assessment. All AEs will be assessed and reviewed throughout the study, starting after 
signing the consent documents. 
• Contact IRT. During the Screening Period, the IRT will be contacted to obtain an individual 
study identifier that will serve as the subject’s ID throughout the study. 
8.2 
Titration Period 
The visit window for Titration Visits is ±1 day per visit relative to Visit 3 (Day 1).  
8.2.1 
Visit 2 (Baseline) 
The following assessments will be performed via telemedicine call. The visit window for 
Visit 2/Baseline is +3 days.  
Information and procedures listed below will be collected/completed by the investigator and/or 
study staff, as appropriate, via a telephone or telemedicine call with the subject/legal 
representative. Eligibility may only be confirmed once all the procedures noted for screening are 
completed, and results are obtained and reviewed. 
• Eligibility criteria 
• Withdrawal criteria 
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• Menstrual function for all female subjects 
Assessments listed below will be completed by either the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
• IRLS (at Baseline, subjects must score ≥15 on the IRLS Rating Scale [indicating moderate-
to-severe RLS])  
• CGI (at Baseline, Subjects must score ≥4 points on the CGI Item 1 assessment [indicating at 
least moderately ill])  
• RLS-6  
• Subject Quality of Life Questionnaire 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. Medications and procedures will be reviewed with 
the subject/legal representative by the investigator/designated study staff via a telephone or 
telemedicine call and noted as part of the subject’s study record. 
• AE assessment. All AEs will be assessed and reviewed throughout the study. 
• Contact IRT. Once eligibility is confirmed (see above), the IRT will be contacted to obtain 
the assigned randomization number and study medication kit numbers for the Titration 
Period.  
• Once randomization is completed, study medication for the Titration Period will be assigned 
and shipped to the subject/legal representatives home for receipt on Day 1. See Section 7.5 
for a description of the direct-to-subject shipment process for the remote study model. 
8.2.2 
Visit 3 (Day 1) 
Visit 3/Day 1 is the first day of study medication exposure. All subsequent visits are calculated 
based on Visit 3/Day 1.  
The following assessments will be performed. 
• Withdrawal criteria 
• C-SSRS (Since Last Visit version) 
The subject will apply their first patch during the visit under the supervision of the investigator 
(or designee) via a telemedicine call. 
8.2.3 
Visit 4 (Day 8) and Visit 5 (Day 15) 
Subjects will be contacted via telemedicine call. The following assessments will be performed. 
• Withdrawal criteria 
• C-SSRS (Since Last Visit version) 
• Recording of medication and procedures 
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• AE assessment 
8.3 
Maintenance Period 
The visit window for visits during the Maintenance Period is ±2 days per visit. 
8.3.1 
Visit 6 (Day 22) 
The following assessments will be performed. 
Information and procedures listed below will be collected/completed by the investigator and/or 
study staff, as appropriate, via a telephone or telemedicine call with the subject/legal 
representative.  
• Withdrawal criteria 
• Menstrual function for all female subjects 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Vital signs 
• Body weight, height, and BMI 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
• IRLS 
• CGI 
• RLS-6  
• mMIDI 
• Subject Quality of Life Questionnaire 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. See Section 8.2.1. 
• AE assessment. See Section 8.2.1. 
• Contact IRT. The IRT will be contacted to obtain study medication kit numbers for the 
Maintenance Period. 
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• Dispense study medication. Study medication for the Maintenance Period will be distributed. 
See Section 7.5 for a description of the direct-to-subject shipment process for the remote 
study model. 
• Return any unused study medication. Subjects/legal representatives will return the unused 
study medication patches remaining as part of the medication kits, along with the kit itself. 
Upon receipt of this return, designated study staff will review drug accountability with the 
participant via a telephone or telemedicine call to obtain explanations regarding any 
discrepancies in compliance with the dosing regimen. 
8.3.2 
Visit 7 (Day 50) and Visit 8 (Day 78) 
The following assessments will be performed at Visit 7 and Visit 8 via telemedicine call. 
Information and procedures listed below will be collected/completed by the investigator and/or 
study staff, as appropriate, via a telemedicine call with the subject/legal representative.  
• Withdrawal criteria 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
• IRLS 
• CGI 
• RLS-6  
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. See Section 8.2.1.  
• AE assessment. See Section 8.2.1.  
• Contact IRT. The IRT will be contacted to obtain study medication kit assignments.  
• Dispense study medication. Study medication for the Maintenance Period will be distributed 
See Section 7.5 for the description of the direct-to-subject shipment process for the remote 
study model. 
• Return any unused study medication. See Section 8.3.1.  
8.3.3 
Visit 9 (Day 106)/End of Maintenance 
The following assessments will be performed. 
Information and procedures listed below will be collected/completed by the investigator and/or 
study staff, as appropriate, via a telephone or telemedicine call with the subject/legal 
representative.  
• Withdrawal criteria 
• Menstrual function for all female subjects 
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Assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
• IRLS 
• CGI 
• RLS-6  
• mMIDI 
• Subject Quality of Life Questionnaire 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures: See Section 8.2.1.  
• AE assessment: See Section 8.2.1.  
• Contact IRT: The IRT will be contacted to obtain study medication kit numbers for the Taper 
Period. 
• Dispense study medication for the Taper Period. See Section 7.5 for the description of the 
direct-to-subject shipment process for the remote study model. 
• Return any unused study medication 
8.4 
Taper Period (Day 106 to Day 110) 
The Taper Period, which will last up to a maximum of 4 days, will start on the day after Visit 9 
and will consist of a telemedicine call. The de-escalation study medication to be taken during the 
Taper Period will be dispensed at Visit 9. 
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8.5 
Safety Follow-Up Visit (if applicable) 
The visit window for Safety Follow-Up Period is 30 days±5 days relative to the end of the Taper 
Period. Following dose de-escalation, subjects may be eligible to participate in the open-label, 
long-term follow-up study (RL0007) at any time prior to the Safety Follow-Up Visit (see 
Section 5). The Safety Follow-Up Visit is for subjects not entering RL0007. 
Information listed below will be collected by the investigator and/or study staff, as appropriate, 
via a telephone or telemedicine call with the subject/legal representative. 
• Menstrual function for all female subjects 
The assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. See Section 8.2.1.  
• AE assessment. See Section 8.2.1.  
• Contact IRT. The IRT is contacted to process the subject’s completion of the study. 
• Return unused study medication. See Section 8.3.1. 
8.6 
Withdrawal Visit 
Procedures for a withdrawal visit are the same as for Visit 9. 
8.7 
Unscheduled Visit 
Assessments to be performed at an Unscheduled Visit are at the investigator’s discretion. 
Information listed below will be collected/completed by the investigator and/or study staff, as 
appropriate, via a telephone or telemedicine call with the subject/legal representative.  
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• Withdrawal criteria 
• Menstrual function for female subjects 
The assessments listed below will be completed by mobile study personnel at the 
subject/subject’s/legal representative’s home and records of the procedures will be obtained, with 
information noted as part of the subject’s study record. 
• Brief physical examination 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home for sample collections. Samples will be prepared and sent 
to the central laboratory for processing and analysis, and results will be provided to the study 
site. 
• Vital signs 
• Safety laboratory tests 
• Urine drug screen 
• Urine pregnancy test for female subjects 
• Hormone status 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) (required if the Unscheduled Visit is conducted due to 
safety or efficacy reasons) 
• mMIDI 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. See Section 8.2.1. 
• AE assessment. See Section 8.2.1. 
• Contact IRT. The IRT is contacted to process the subject’s completion of the study, if 
applicable. 
• Dispense study medication (Taper Period de-escalation study medication will be dispensed at 
this visit). See Section 7.5 for a description of the direct-to-subject shipment process for the 
remote study model. 
• Return any unused study medication. See Section 8.3.1. 
9 
ASSESSMENT OF EFFICACY 
Refer to Table 5‒1 for timings of all efficacy assessments. 
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9.1 
International Restless Legs Rating Scale (IRLS) 
The IRLS will be performed at Screening, Baseline (Visit 2), Visit 6, Visit 7, Visit 8, and Visit 9. 
The IRLS should also be performed in the event that a subject is prematurely withdrawn from the 
study (Withdrawal Visit). 
The IRLS was developed by the International RLS Study Group and was validated in a 
large-scale study (Walters et al, 2003). The IRLS is intended to evaluate, in a standardized way, 
the subjective intensity of major symptoms of RLS and, in 2 items (9 and 10), the impact of the 
disease on subjects’ functioning in daytime activities by use of a 5-point scale for each of a total 
of 10 items: 
1. Discomfort in arms and legs due to RLS 
2. Urge to move 
3. Relief of symptoms by movement 
4. Sleep disturbances due to RLS 
5. Fatigue and somnolence during the day due to RLS  
6. Global severity rating of RLS 
7. Frequency of symptoms 
8. Severity of symptoms (if present) during an average day (24 hours) 
9. Impact of symptoms on daytime activities (family, home, social, job) 
10. Impact of symptoms on mood (eg, angry, depressed, sad, anxious, irritable) 
Each item is scored by the subject. Investigators or clinic personnel can assist the subject if 
he/she has difficulty understanding the items or locating the appropriate score. Scores for each 
item range from 0 (not present) to 4 (very severe). A sum score of all 10 items is calculated for 
analysis. The sum score ranges from 0 (no RLS symptoms present) to 40 (maximum severity in 
all symptoms).  
The following ranges are used to determine severity categories: 
• 0=none 
• 1 to 10=mild 
• 11 to 20=moderate 
• 21 to 30=severe 
• 31 to 40=very severe 
A minimum score of 15 points (moderate) is typically required for inclusion in a study at 
Baseline.  
Subjects should answer each item in reference to the 7 days prior to their visit. If the timeframe 
since the last visit is <7 days (eg, in the event of premature discontinuation), the subject should 
answer each item in reference to the days since their last visit. 
Subjects will be classified into the following categories: 
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• IRLS responder: A relative reduction in IRLS total score in percentage points at the end of 
maintenance compared to Baseline. This categorization will be carried out for a reduction of 
at least 50% (that is a percentage relative change for less than or equal to -50%), 
• IRLS remitter: Two types of IRLS remitter are defined: 1) an IRLS total score of 10 or less 
(remitter criterion 1) and 2) an IRLS total score of 0 (remitter criterion 2). 
9.2 
Clinical Global Impressions 
The CGI Item 1 will be performed at Screening, Baseline (Visit 2), and Visit 6 through Visit 9 
(Guy and Bonato, 1970). 
Item 1 (Severity of Illness): Scores range from 0 to 7 as follows: 0=not assessed, 1=normal, not 
ill at all, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=among 
the most extremely ill.  
The CGI Item 1 is to be completed during an interview between the subject and the investigator 
or designee. 
Note that at Baseline a minimum CGI Item 1 score of 4 points (indicating at least moderately ill) 
is typically required for inclusion in RLS studies. 
Subjects will be classified into the following category: 
• CGI Item 1 responder: A relative reduction in CGI Item 1 (severity of illness) in percentage 
points of at least 50% at the respective visit compared to Baseline (ie, a percentage relative 
change for less than or equal to –50%) 
CGI is validated in mental diseases only; but it is widely used. 
9.3 
RLS-6 
The RLS-6 will be performed at Baseline (Visit 2) and at Visit 6 through Visit 9. The RLS-6 
should also be performed in the event that a subject is prematurely withdrawn from the study 
(Withdrawal Visit). 
The RLS-6 Rating Scales is designed to assess the severity of RLS (Kohnen et al, 2003) and 
consists of 6 subscales. The subscales assess severity of symptoms at the following times of the 
day/evening: falling asleep, during the night, during the day at rest, and during the day when 
engaged in daytime activities. In addition, the subscales assess satisfaction with sleep and 
severity of daytime tiredness/sleepiness. 
Scores for each of the 6 subscales range from 0 (completely satisfied) to 10 (completely 
dissatisfied). 
Each subscale item should be scored by the subject. Investigators or clinic personnel can assist 
the subject if he/she has difficulty understanding the subscale. Subjects should answer each 
subscale in reference to the 7 days prior to their visit. If the timeframe since the last visit is <7 
days (eg, in the event of premature discontinuation), the subject should answer each subscale in 
reference to the days since their last visit. 
The change from baseline will be derived for each of the 6 subscales. 
No sum score will be calculated. 
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Post-baseline missing values will not be imputed. 
9.4 
Subject Quality of Life Questionnaire 
The RLS-QoL will be performed at Visit 2, Visit 6, and Visit 9. The RLS-QoL should also be 
performed in the event that a subject is prematurely withdrawn from the study (Withdrawal 
Visit). 
The RLS-QoL (Kohnen et al, 2002) will be used to evaluate quality of life at these visits. This 
disease-specific instrument consists of 12 items. The most relevant item is a global rating of 
quality of life “all in all”. 
Further items are related to consequences of the RLS symptoms on sleep, activities of daily 
living, mood, and social interactions, to the consequences of disturbed sleep on everyday life and 
to those of tiredness during the day on mood; furthermore, consequences of pain and side effects 
of treatments on daily activities are to be evaluated. A final section of the questionnaire asks for 
evaluation of coping behavior (effort of measures to get relief from the symptoms, avoidance of 
social situations, changes in life style). The main outcome parameter is a total score which is 
calculated from all items. 
10 
ASSESSMENT OF PHARMACOKINETIC VARIABLES 
10.1 
Blood sampling for the determination of rotigotine plasma 
concentrations 
For the determination of unconjugated rotigotine, 5.5mL of blood will be drawn prior to patch 
removal by venous puncture or indwelling venous catheter into lithium heparinized tubes at 
Visit 6 and Visit 9 (refer to Table 5‒1 for timing of PK assessments). The sampling time should 
be recorded on the eCRF when PK samples are to be taken. The application site and time of last 
application of the study medication prior to the PK assessment will also be collected. 
Treatment of the venous puncture or indwelling venous catheter site with a topical anesthetic 
(eg, EMLA) prior to the needle stick is permissible. 
Details can be found in the study lab manual. 
10.2 
Shipment procedures 
Details can be found in the study lab manual. 
10.3 
Bioanalytical method 
Plasma concentrations of requested analytes will be determined with validated bioanalytical 
methods. After the sample preparation step, the target compounds are separated by a reversed-
phase liquid chromatography and detected by electrospray ionization tandem mass spectrometry 
using multiple reaction monitoring in positive-ion mode. 
11 
ASSESSMENT OF SAFETY 
Refer to Table 5‒1 for timings of all safety assessments. In addition to the AE assessments 
completed at the designated study visits (see Table 5‒1 and Section 8), the subjects/legal 
representatives are also able to contact study staff at any time via the study-issued smartphone to 
discuss their condition, ask questions, and/or report AEs/SAEs. All AEs and SAEs will be 
evaluated and reported as noted below. Based on the investigator’s evaluation of the AE/SAE, 
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appropriate medical intervention/support measures will be instituted as necessary (ie, urgent care 
services, etc) and documented as part of the subject’s study record. 
11.1 
Adverse events 
11.1.1 
Definitions 
11.1.1.1 
Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that 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 (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
investigator from the subject’s history or the Baseline Period.  
11.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
• Significant or persistent disability/incapacity 
• Congenital anomaly/birth defect (including that occurring in a fetus) 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 11.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
• Initial inpatient hospitalization or prolongation of hospitalization 
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(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criterion for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, ecg]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
11.1.1.2.1 
Anticipated serious adverse events 
The following Anticipated SAEs are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure.  
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 11.1.2.3. 
Table 11‒1: Anticipated serious adverse events for the RLS population 
MedDRA system organ class 
MedDRA preferred term 
Gastrointestinal disorders 
Diarrhoea 
Infections and infestations 
Upper respiratory tract infection 
Bronchitis 
Urinary tract infection 
Psychiatric disorders 
Depression 
MedDRA=Medical Dictionary for Regulatory Activities; RLS=Restless Legs Syndrome 
11.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
subject. 
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11.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
11.1.2.1 
Description of adverse events 
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines. 
11.1.2.2 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
11.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE Report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database. 
An Investigator SAE Report form will be provided to the investigator. The Investigator SAE 
Report form must be completed in English.  
It is important for the investigator, when completing the SAE Report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form. 
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The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the investigator of any SAE within this period. Serious AEs that the 
investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study. 
Upon receipt of the SAE Report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure. 
11.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up. This follow-up 
requirement applies to AEs, SAEs, and AEs of special interest; further details regarding follow 
up of PDILI events is provided in Section 11.6.1.4.  
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. The follow up will usually be continued for 30 days 
days after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
11.2 
Pregnancy 
If an investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol). The subject should be withdrawn from the study 
as soon as pregnancy is known (by positive pregnancy test), and the following should be 
completed: 
• An early discontinuation visit should be conducted. 
• The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the early discontinuation visit.  
• A Safety Follow-Up Visit should be scheduled 30 days ±5 days after the subject has 
discontinued her IMP. 
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
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circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the investigator site file (ISF). In case of questions about the consent process, the 
investigator may contact the UCB/CRO contract monitor for the study. The investigator will 
complete the Pregnancy Report and Outcome form and send it to UCB’s PS department (for 
contact details see Serious Adverse Event reporting information at the beginning of this protocol) 
only after the partner has agreed that additional information can be captured and has provided the 
signed Partner Pregnancy Consent form. UCB’s PS department is also the primary contact for 
any questions related to the data collection for the partner pregnancy, eventual birth, and follow 
up. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
11.3 
Suspected transmission of an infectious agent 
With respect to the rotigotine transdermal patch, it is not likely that transmission of an infectious 
agent will occur in clinical practice. For the purposes of reporting, any suspected transmission of 
an infectious agent via a medicinal product should be considered as an SAE; such cases must be 
reported immediately, recorded in the AE module of the eCRF, and followed as any other SAE. 
Any organism, virus, or infectious particle (eg, prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
11.4 
Overdose of investigational medicinal product 
With respect to the rotigotine transdermal patch, it is not likely that significant overdosing will 
occur in clinical practice unless subjects forget to remove the previous day’s patch; subjects 
should be warned against this possibility. 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
11.5 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
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The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
11.6 
Laboratory measurements 
A central laboratory will perform routine hematology, clinical chemistry, and hormone analyses. 
It is recommended that subjects be scheduled for morning appointments to complete these 
procedures. However, if morning appointments are not feasible, then subjects should continue to 
be scheduled at approximately the same time of day as all other visits. 
Treatment of the venous puncture or indwelling venous catheter site with a topical anesthetic (eg, 
EMLA) prior to the needle stick is permissible. 
Urinalyses are performed locally using urine dipsticks. If the dipstick results are abnormal and of 
clinical concern, a repeat sample will be sent to the central laboratory for evaluation. 
The laboratory parameters listed in Table 11‒2 will be measured. 
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Table 11‒2: Laboratory measurements 
Hematology 
Endocrine 
Urinalysis 
Red blood cell count 
Estradiola 
Color 
Hematocrit 
FSH 
Appearance 
Hemoglobin 
IGF-1 
Glucose 
Platelet count 
LH 
Protein 
White blood cell countb  
Progesteronea 
Blood 
RBC indices 
MCH 
MCV 
MCHC 
RDW 
Prolactin 
Ketones 
Testosteronec 
Pregnancy testa 
T3 
 
T4 
 
TSH 
 
Chemistry 
 
ALT 
Glucose 
 
AST 
Phosphorus 
 
Albumin 
LDH 
 
Alkaline phosphatase 
Potassium 
 
Bicarbonate 
Serum iron 
 
BUN 
Sodium 
 
Calcium 
Total cholesterol 
 
Chloride 
Total bilirubin 
 
Creatinine 
Total protein 
 
Ferritin 
Transferrin 
 
GGT 
Uric acid 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; GGT=gamma-glutamyl transferase; IGF-1=insulin-like growth factor-1; LDH=lactate 
dehydrogenase; LH=luteinizing hormone; MCH=mean corpuscular hemoglobin; MCHC= mean corpuscular 
hemoglobin concentration; MCV=mean cell volume; RBC=red blood cell; RDW=red cell distribution width; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone 
a Females only. Serum pregnancy test at Screening and urine pregnancy test at all other visits. A positive urine 
pregnancy test must be confirmed by a serum pregnancy test. 
b With differential. 
c Males only. 
 
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11.6.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 11.1.1.3), and, if applicable, also reported as an 
SAE (see Section 11.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.6.1.4). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings.  
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The table below summarizes the approach to investigate PDILI. 
 
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Table 11‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or AST 
Total bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology 
consult.c 
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.6.1.3. 
Monitoring of 
liver chemistry 
values at least 
twice per week 
until values 
normalize, 
stabilize, or return 
to within baseline 
values.d 
 
≥8xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥3xULN (and ≥2x 
baseline) and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that 
allows for IMP 
continuation is 
met. 
Further 
investigation – 
immediate IMP 
discontinuation 
not required (see 
Section 11.6.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
≥5xULN (and ≥2x 
baseline)  
<2xULN 
No 
Discussion with 
Medical Monitor 
required. 
Immediate, 
permanent IMP 
discontinuation. 
 
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
(see 
Section 11.6.1.3). 
Monitoring of 
liver chemistry 
values at least 
twice per week 
until values 
normalize, 
stabilize, or return 
to within baseline 
values.d 
 
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Table 11‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or AST 
Total bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; IMP=investigational medicinal 
product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 11.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
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11.6.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 11.6.1.3) and SAE report (if applicable). 
11.6.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒3 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
11.6.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒4 (laboratory measurements) and Table 11‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
Table 11‒4: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
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Table 11‒4: PDILI laboratory measurements 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; 
hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative cause). 
The following additional information is to be collected: 
Table 11‒5: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty liver 
disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel  
• 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, should 
not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
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Table 11‒5: PDILI information to be collected 
New or updated information 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
11.6.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 11‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
11.7 
Other safety measurements 
11.7.1 
12-lead electrocardiogram values 
If a subject develops a clinically relevant ECG abnormality that is confirmed by a repeat ECG 
performed at least 1 hour later, the subject should be excluded from the study. Bazett’s formula 
must be used for correction of QT intervals. 
The ECGs will be centrally read. The investigator will confirm the computerized measurements 
of PR, QRS, QT, and QT interval corrected for heart rate using Bazett’s formula (QTcB) 
intervals (assessed as the mean of 3 to 5 beats). 
11.7.2 
Vital signs 
Vital sign assessments include supine and standing BP measurements and pulse rate. At each 
visit, vital signs will be assessed. The assessment should be taken as follows: The subject should 
initially rest for 2 minutes. While the subject is supine, the BP and pulse rate should be measured 
after 1 minute and then again after 5 minutes (ie, 4 minutes between the 2 measurements). The 
subject should then be asked to stand and the BP and pulse rate should be taken 1 minute and 3 
minutes post standing (ie, 2 minutes between measurements). 
Assessment of orthostatic reaction will be performed at all visits as follows: After the 5-minute 
measurement in supine position, the subject is asked to stand up; BP and pulse rate are measured 
1 and 3 minutes after standing. The 5-minute BP supine values will be compared with the values 
after standing. A drop in systolic BP of ≥20mmHg and/or a drop of ≥10mmHg in diastolic BP 
after 1 and/or 3 minutes in standing position is indicative of orthostatic hypotension. 
Subjects who develop clinically relevant symptomatic hypotension during the course of the study 
should be withdrawn (see Section 6.3). 
11.7.3 
Physical and neurological examinations 
A brief physical examination of all body systems will be performed. 
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The neurological examination may include assessment of mental status, cranial nerves, plantar 
reflexes, deep tendon reflexes, muscle strength, gait, coordination/balance, involuntary 
movements, and sensory perception. 
11.7.4 
Hormone status 
It is recommended that subjects be scheduled for morning appointments to assess hormone status 
(beta-17-estradiol [females only], progesterone [females only], follicle-stimulating hormone 
[FSH], luteinizing hormone [LH], prolactin, triiodothyronin [T3], thyroxine [T4], thyroid-
stimulating hormone [TSH], testosterone [males only], and insulin-like growth factor-1 [IGF-1]). 
However, if morning appointments are not feasible, then subjects should continue to be 
scheduled at approximately the same time of day as all other visits. 
11.7.5 
Modified Minnesota Impulsive Disorders Interview 
The mMIDI has been previously used in Parkinson’s subjects to monitor for development of 
ICDs (Christenson et al, 1994). The mMIDI is applicable for both initial identification of a 
potential ICD and for monitoring ICDs during a clinical study. This mMIDI focuses on the 5 
most common ICDs which may be associated with dopamine agonist use: compulsive buying, 
compulsive gambling, compulsive eating, hypersexuality, and punding (nonsense repetitive 
behavior). The mMIDI will be used only to identify potential impulsive control AEs. The 
mMIDI will be completed according to the schedule of study procedures (Table 5‒1).  
For each of the 5 modules, a gateway question is asked (eg, Do you gamble?). If a gateway 
question is answered “no”, that module ends. Any positive answer after a gateway question 
would affirm the ICD and the subject would move to the next step, which is formal diagnosis 
(referral for a structured clinical interview such as the Structured Clinical Interview for DSM-IV 
Axis II Personality Disorders or other applicable structured clinical interview for the diagnosis of 
ICDs). The instrument should be administered by a physician or a clinical psychologist trained to 
administer the instrument. 
If the subject has a positive mMIDI and a positive structured clinical interview or if the subject 
refuses the structured clinical interview, it would be up to the investigator to determine if the 
subject should be withdrawn from the study. Positive findings from the structured interview must 
be recorded as AEs, and monitored for degree of changes during the study. 
If the subject was referred for a structured clinical interview previously during the study, the 
investigator may use his/her discretion regarding the need to refer the subject for a further 
structured interview. 
11.7.6 
Menstrual function 
Questions regarding changes in menstrual function in females will be asked. 
11.7.7 
Assessment of suicidal ideation and behavior 
Suicidal ideation and behavior will be assessed by trained study personnel using the C-SSRS. 
This scale will be used for screening as well as to assess suicidal ideation and behavior that may 
occur during the study. The C-SSRS will be completed according to the tabular schedule of study 
assessments (see Table 5‒1). 
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12 
STUDY MANAGEMENT AND ADMINISTRATION  
12.1 
Adherence to protocol 
The investigator should not deviate from the protocol. However, the investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the investigator must notify the CPM of the sponsor 
within 24 hours and follow any local regulatory requirements. 
12.2 
Monitoring 
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the CRO’s monitoring Standard Operating Procedures (SOPs), ICH-GCP guideline, and 
applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are 
adequate.  
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities’ regulations, and investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
For the remote study model, a remote monitoring option is available. All study materials, 
including the ISF, drug accountability records, electronic source documentation, etc will be 
available for remote monitoring with view-only access, with training provided prior to access 
being granted, Study staff will be available to meet via telephone call or telemedicine call. 
12.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording and should not be 
obscured. Photocopies and/or printouts of eCRFs are not considered acceptable source 
documents.  
Source documents, whether paper or electronic, are original records in which raw data are first 
recorded. These may include hospital/clinic/general practitioner records, charts, diaries, x-rays, 
laboratory results, printouts, drug accountability records, care records, ECG or other printouts, 
completed scales, or quality of life questionnaires, for example. Source documents should be 
kept in a secure, limited access area. 
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Source documents that are computer generated and stored electronically must be available for 
review by the monitor (eg, ECG reports). The technology platform used in this study 
(PLATFORM, see Section 2 for an overview) has multiple levels of functionality, including 
electronic source documentation. All information and data collected in PLATFORM is kept 
securely, with the required privacy measures in place per regulations. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
12.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject records, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory reports). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 12.2.1. 
12.3 
Data handling 
12.3.1 
Case Report form completion 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
12.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person. 
The data are entered into the eCRFs once and are subsequently verified if the study is performed 
using electronic data capture. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded as part of the Subject Screening and 
Enrollment log. 
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject. 
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The subject’s consent and enrollment in the study must be recorded as part of the subject’s study 
record. These data should identify the study and document the dates of the subject’s 
participation. 
12.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
12.5 
Archiving and data retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (Committee for Proprietary Medicinal Products [CPMP]/ICH/135/95, 2002 
[Section 4.9.5]). The investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the sponsor’s study master file. 
12.6 
Audit and inspection 
The investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH-GCP, and applicable regulatory 
requirements. 
The investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the investigator will immediately 
inform UCB (or designee). 
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12.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
13 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
13.1 
Definition of analysis sets 
The following analysis sets will be defined: 
• Enrolled Set (ES): all subjects with a signed informed consent form and demographic data. 
• Randomized Set (RS): all subjects from the ES who have been randomized. 
• Safety Set (SS): all subjects from the RS who have at least 1 patch (rotigotine or placebo) 
applied. This population will be used for all safety analyses. 
Full Analysis Set (FAS): all subjects from the SS who have a valid IRLS score and a valid CGI 
Item 1 score at Baseline and a valid post-Baseline IRLS score and a valid post-Baseline CGI 
Item 1 score. This population is the primary population for efficacy analysis.  
• Per Protocol Set (PPS): all subjects from the FAS with no important protocol deviations (as 
specified in the data evaluation meeting) that could affect the co-primary variables and hence 
the efficacy evaluation. This population is the secondary population for efficacy analysis. 
13.2 
General statistical considerations 
Datasets will be analyzed using SAS version 9.4 or higher. 
A complete set of raw data listings containing both, all documented data and all calculated data 
(eg, difference from Baseline) will be generated. In general, summary statistics (n [number of 
available measurements], arithmetic mean, standard deviation [SD], median, minimum, and 
maximum) for quantitative variable and frequency tables for qualitative data will be presented by 
treatment. 
13.3 
Planned efficacy analyses 
13.3.1 
Analysis of the co-primary efficacy variables 
Mean changes from Baseline to the end of the Maintenance Period in IRLS sum score and CGI 
(Item 1) in the 2 rotigotine arms (2mg/24h and 3mg/24h) will be compared with placebo to 
demonstrate superior efficacy of rotigotine. 
The primary analysis of each co-primary variable will be based on a mixed model repeated 
measures (MMRM) analysis of covariance (ANCOVA) that includes terms for treatment group, 
visit, the respective Baseline score, and the interaction between treatment group and visit. The 
model will define patient as a random effect and utilize an unstructured covariance pattern. From 
this MMRM ANCOVA, treatment least-square (LS) means (with 95% confidence intervals [CI]) 
will be calculated and 1-sided 2 sample t-test will be performed (significance level 0.025) to test 
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the superiority of the rotigotine dose levels versus placebo, starting with 3mg/24h. The 
corresponding p-values will also be calculated. 
The null hypotheses at each dose level are (H0): rotigotine is not superior compared to placebo. 
The alternative hypotheses are (H1): rotigotine is superior to placebo. Both co-primary endpoints 
must demonstrate significant results (at significance level 0.025) to demonstrate superiority of 
this dose level of rotigotine over placebo. 
If the 3mg/24h dose is successful, the 2mg/24h dose level will be tested in the same way. Since 
both hypotheses have to be rejected in order to continue, multiplicity adjustment is not needed 
for the 2 hypotheses at each dose level. The multiplicity based on the two dose levels will be 
covered by applying the hierarchical approach (closed test procedure). 
For subjects who prematurely withdraw for any reason before end of Maintenance, data collected 
during the Withdrawal Visit will be used to impute measurements at the next consecutive visit. 
IRLS or CGI-1 measurements must be performed no longer than 1 day after the last patch 
removal to be utilized for analysis (valid measurements). 
The above analyses will be performed on the FAS and the PPS. The primary analysis will be 
considered the analysis on the FAS. 
13.3.2 
Analysis of the secondary efficacy variable 
For the secondary variables change from Baseline to end of the Maintenance Period in CGI Item 
1 and RLS-6 an ANCOVA will be performed as described for the analysis of the primary 
variable, however PPS analyses will not be performed.  
13.3.3 
Other efficacy variables 
The other efficacy variables listed will be analyzed in a descriptive manner. Summary statistics 
will be provided, statistical tests comparing rotigotine arms with placebo will be performed and 
the corresponding p-values will be provided for descriptive purposes only. 
• Change from Baseline in CGI Item 1 by visit*  
• Change from Baseline in RLS-6 Rating Scales by visit* 
• Change from Baseline in IRLS sum score by visit* 
• IRLS Responder by visit 
• IRLS Remitter by visit and by definition (see previous) 
• CGI scale Item 1 Responder 
• *For the IRLS, CGI, and RLS-6 the EoM Visit is already covered under primary and 
secondary variables.  
13.4 
Planned safety and other analyses 
All analyses for safety and other non-efficacy variables will be performed using the subjects in 
the SS. 
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13.4.1 
Safety analyses 
Adverse events will be reported in frequency tables as the number and percentage of subjects 
reporting TEAEs by treatment group. Additionally, frequency tables for serious TEAEs, non-
serious TEAEs, TEAEs leading to discontinuation of study medication, TEAEs by intensity and 
TEAEs by relationship to treatment will be provided by treatment group. 
Descriptive statistics on change from Baseline in laboratory data, including hormone status, will 
be summarized by visit and treatment group. Post-Baseline clinical significant abnormalities will 
be presented by treatment group. 
Vital signs variables and their change from Baseline will be presented using descriptive statistics 
by visit and treatment group. The number and percentage of subjects meeting orthostatic 
hypotension criteria will also be presented. 
ECG and its change from Baseline will be presented using descriptive statistics by visit and 
treatment group. The number and percentage of subjects with post-Baseline clinical significant 
abnormalities will be presented by treatment group. 
Body weight, height, and BMI and their change from Baseline will be presented using 
descriptive statistics by visit and treatment group. Clinically significant values will be reported. 
13.4.2 
Other analyses 
Prior and concomitant medication as well as medical history will be summarized using frequency 
tables. Demographic and baseline characteristics will be summarized using descriptive statistics. 
Plasma concentration of unconjugated rotigotine will summarized by dose levels and visit. In 
addition, these concentrations may be used for population PK-PD analyses. 
Summary statistics for Subject Quality of Life Questionnaire will be provided. 
13.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy, key safety, or PK/PD outcomes 
(if applicable) for an individual subject. The criteria for identifying important protocol deviations 
will be defined within the appropriate protocol-specific document. Important protocol deviations 
will be reviewed as part of the ongoing data cleaning process and data evaluation. All important 
deviations will be identified and documented prior to unblinding to confirm exclusion from 
analysis sets. 
13.6 
Handling of dropouts or missing data 
Rules for imputation of missing data will be detailed in the SAP. 
No imputation will be implemented for missing values in other efficacy variables or safety 
variables. However, rules for date imputations to allow the derivation of variables (eg, age and 
TEAEs) will be implemented. 
Dropouts will not be replaced during the course of the study. 
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13.7 
Planned interim analysis and data monitoring 
An interim analysis for futility will be performed with approximately 33% of the planned 
number of evaluable subjects; recruitment will not be stopped for the interim analysis. The 
interim analysis will have three possible outcomes: 
• Stop the study early for futility because rotigotine treatment at 3mg/24h meets the futility 
criteria (ie, no demonstrated benefit between active treatment and placebo to be expected at 
final analysis) regarding the primary objective of the study 
• Stop recruitment into the rotigotine 2mg/24h arm for futility because rotigotine treatment at 
2mg/24h seems futile regarding the primary objective of the study, 
• Continue the study as planned. 
No further changes to the protocol (eg, sample size adjustment) will be made as a result of the 
interim analysis. 
The interim analysis will be conducted as soon as the end of the Maintenance/Premature 
Withdrawal Visit has been documented for 45 evaluable patients. The interim analysis will be 
performed on the data for the primary efficacy variable IRLS only and CGI Item 1 will not be 
considered. In case futility is achieved for the IRLS, this would also hold true for the CGI, since 
a lower effect size index for CGI is anticipated. 
In the interim analysis, the change from Baseline to the end of the Maintenance Period in the 
score of the IRLS will be investigated. Estimates of treatment effect will be obtained separately 
for the two active treatment arms and Placebo from an MMRM ANCOVA model as described in 
Section 13.3.1. Furthermore, the conditional power under the anticipated effect (anticipated 
effect and standard deviation will be utilized) according to Lan and Wittes (Siu and Lan, 2001) 
will be calculated for each of the treatment arms. The conditional power under the anticipated 
effect refers to the probability of concluding a positive result on the IRLS at the end of the study, 
assuming that the assumptions for the sample size estimation holds true. 
The continuation criterion for each treatment arm is defined as applying both of the following 
conditions regarding the change from Baseline to the end of the Maintenance Period in the score 
of the IRLS: 
• Treatment difference between the respective active group and placebo ≥2.0 points  
• Conditional power under anticipated effect ≥60 % 
If at least 1 of these conditions fails, the continuation criterion is not met. Table 13‒1 shows the 
possible outcomes of the interim results and the corresponding decision rules. 
Table 13‒1: Decision rules at the interim analysis  
Interim result 
Decision 
Failed continuation criterion for the 3mg/24h arm 
Stop the study early 
Met continuation criterion for the 3mg/24h arm 
Failed continuation criterion for the 2mg/24h arm 
Remove the 2mg/24h arm and continue the study 
with the 3mg/24h arm and the placebo arm 
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Table 13‒1: Decision rules at the interim analysis  
Interim result 
Decision 
Met continuation criterion for the 3mg/24h arm 
Met continuation criterion for the 2mg/24harm 
Continue the study as planned (with 3mg/24h and 
2mg/24h arms plus placebo) 
The interim analysis will be performed by an independent unblinded statistician not involved in 
any other study activity. Access to the interim results will be restricted to the statistician 
performing the analysis. 
The study team will remain blinded and will be informed of the decision (stop the study early, 
stop a dose arm or continue the study as planned) without any supporting information. Details of 
the analysis will only be disclosed to the sponsor after study unblinding and will be provided in 
the clinical study report. 
13.8 
Determination of sample size 
The sample size estimate is based on the efficacy results observed in the adult RLS Phase 3 
confirmatory study SP792, which was conducted in the USA. In this study, a range of rotigotine 
doses were compared to placebo. 
The sample size calculation assumes that adolescent and adult patients will show a similar effect 
of rotigotine with respect to IRLS score and CGI (item 1) changes from Baseline in comparison 
to placebo, with a similar proportion of patients not included in the primary analysis. 
In the adult study, the observed difference between the 3mg/24h rotigotine group and placebo in 
the change from Baseline to end of the 3-month Maintenance Period in IRLS sum score was 5.9. 
Already a difference between rotigotine and placebo of 4.0 points can be considered as clinically 
relevant. The common Standard Deviation (SD) estimate in the adult study was 7.9. For the CGI 
(Item 1), the difference between 3mg/24h rotigotine group and placebo was 0.6 with a SD of 1.2. 
With these assumptions, a sample size of 45 evaluable patients in each group will provide a 
power of 93% for the IRLS endpoint, and a power of 87% for the CGI (Item 1) endpoint in the 
3mg/24h dose. Assuming independence of the 2 endpoints will result in a power of 80% for the 
analysis of the co-primary variables. Since it is known that the 2 endpoints will have a relatively 
high correlation (approximately 0.7), the calculated 80% is a conservative estimator for the 
power. 
Assuming similar effects for the 2mg/24h dose group, the conditional power for the 2mg/24h 
dose group is also 80% with an overall power for the study >60%. To obtain 135 evaluable 
subjects (ie, FAS), 138 patients have to be randomized (assuming approximately 2% of the 
randomized subjects cannot be utilized). 
14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
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Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator. 
For those subjects who are assessed as preliminarily eligible per the IRB-approved prescreening 
script, contact information will be collected, including a valid email address of the subject/legal 
representative (eg, parent or guardian). A secure link to the eConsent web portal will be sent via 
email, along with unique login credentials. The subject/legal representative will receive a prompt 
to change the temporary assigned password upon first login. The informed consent materials will 
be presented in the eConsent portal through an electronic rendition of the IRB-approved consent 
documents. The study investigator and/or designated staff will complete the informed consent 
process with the subject/legal representative by telephone. Subjects who agree to take part in the 
study will provide their handwritten signature using a computer mouse, touchscreen, or stylus on 
a computer or tablet in the designated signature block; the legal representative will complete the 
handwritten signature in the same manner; and the consenter will countersign. If a legal 
representative agrees for the adolescent to take part in the study, but the adolescent does not wish 
to participate, then he or she cannot be enrolled. 
The subject or his/her legal representative must receive a copy of the signed and dated Informed 
Consent form. As part of the consent process, each subject must consent to direct access to 
his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory 
inspection. 
If the Informed Consent form is amended during the study, the investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form. 
All studies conducted in the United States must include the use of a Health Insurance Portability 
and Accountability Act Authorization form. 
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. An eCRF 
must not be started, nor may any study specific procedure be performed for a given subject, 
without having obtained his/her written consent to participate in the study. 
14.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with him/her at all times. 
14.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
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The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
14.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
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14.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
15 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable. 
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16 
REFERENCES 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Christenson GA, Faber RJ, de Zwaan M, Raymond NC, Specker SM, Ekern MD, et al. 
Compulsive buying: descriptive characteristics and psychiatric comorbidity. J Clin Psychiatry. 
1994;55:1-11. 
Cortese S, Konofal E, Lecendreux M. Effectiveness of ropinirole for RLS and depressive 
symptoms in an 11-year-old girl. Sleep Med. 2009;10:259–61. 
Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in 
prepubertal children: what triggers them? Pediatrics. 2003;111:e17-e25. 
Guy W, Bonato RR, editors. Manual for the EDCEU Assessment Battery. 2nd revised ed. Chevy 
Chase: National Institute for Mental Health; 1970.  
Kohnen R, Benes H, Heinrich B, Kurella B. Development of the disease-specific restless legs 
syndrome quality of life (RLS-QoL) questionnaire [abstract]. Mov Disord. 2002;17 Suppl 5:232. 
Kohnen R, Oertel WH, Stiasny-Kolster K, Benes H, Trenkwalder C. Severity rating of RLS: 
review of ten years experienced with the RLS-6 scales in clinical trials [abstract]. Sleep. 2003;26 
Abstract suppl: A342. 
Konofal E, Arnulf I, Lecendreux M, Mouren MC. Ropinirole in a child with Attention-Deficit 
Hyperactivity Disorder and Restless Legs Syndrome. Pediatr Neurol. 2005;32:350-1.  
Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Tachibana N, Ozone K, Taniike M. [Restless-
Leg Syndrome – possible unrecognized cause for insomnia and irritability in children]. No To 
Hattatsu. 2008;40:473-7. Japanese. 
Muhle H, Neumann A, Lohmann-Hedrich K, Lohnau T, Lu Y, Winkler S, et al. Childhood-onset 
Restless Legs Syndrome: clinical and genetic features of 22 families. Mov Disord. 
2008;23:1113-21. 
Oertel W, Trenkwalder C, Beneš H, Ferini-Strambi L, Högl B, Poewe W, et al. Long-term safety 
and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic Restless Legs 
Syndrome: a 5-year open-label study. Lancet Neurol. 2011;10:710-20. 
Perez-Lloret S, Rey MV, Ratti PL, Rascol O. Rotigotine transdermal patch for the treatment of 
Parkinson's Disease. Fundam Clin Pharmacol. 2013;27:81-95. 
Pichietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens JA, et al. Pediatric Restless 
Legs Syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study 
Group. Sleep Med. 2013;14:1253-9. 
Simakajornboon N, Kheirandish-Gozal, L, Gozal D. Diagnosis and management of Restless 
Legs Syndrome in children. Sleep Med Rev. 2009;13:149-56. 
Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the 
International Restless Legs Syndrome Study Group rating scale for Restless Legs Syndrome. 
Sleep Med. 2003;4:121-32. 
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17 
APPENDICES 
17.1 
Protocol Amendment 1 
Rationale for the amendment 
The main purpose of this substantial amendment was to change the ferritin level at 
Visit 1/Screening from <50ng/mL to below the lower limit of normal.  
Other changes included in this amendment are as follows: 
• Sponsor contact information has been updated. 
• Added headings for primary and other safety variables. Clarified that AEs are treatment 
emergent. Categorized occurrence of TEAEs and TEAEs leading to withdrawal as primary 
safety variables. The remaining safety variables were categorized as other.  
• Changed the eC-SSRS to the C-SSRS. 
• Addition of urine drug screen at Unscheduled Visits. 
• Clarified that the smartphone technology will be used in combination with visits from mobile 
study personnel to subjects’/legal representatives’ homes. Visits to local health care providers 
or Patient Service Centers will not be conducted during this study. 
• Clarified that a serum pregnancy test is to be performed in females at Screening and urine 
pregnancy test at all other visits. A positive urine pregnancy test must be confirmed by a 
serum pregnancy test. 
• Added a description of the Where’s My Patch (WMP) app. 
• Removed BMI of <95th percentile for his or her age group, according to the Child and Teen 
BMI calculator as Inclusion Criterion #5. 
• Clarified that the washout period for supplemental iron is 1 month prior to Baseline in 
Exclusion Criterion #10a. 
• Added secondary RLS (eg, due to renal insufficiency [uremia], iron deficiency, or 
rheumatoid arthritis as Exclusion Criterion #13. 
• Added a lifetime history of suicide attempts or suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS at 
Screening as Exclusion Criterion #14. 
• Added taking a prohibited concomitant medication and the washout period as Exclusion 
Criterion #15. 
• Clarified that subjects who have been screened but not randomized may be rescreened with 
the permission of the Study Physician or representative. 
• Added RBC indices (mean corpuscular hemoglobin; mean corpuscular hemoglobin 
concentration; mean cell volume; cell distribution width) to the laboratory measurements. 
• Typographic errors and changes of an editorial nature were made. 
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Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
• Changed the eC-SSRS to the C-SSRS. 
Specific changes 
Change #1 
Page 2, STUDY CONTACT INFORMATION: 
Sponsor Study Physician 
Name: 
, 
 
Address: 
UCB BIOSCIENCES GmbH  
Alfred-Nobel-Strasse 10, 40789 Monheim, Germany 
Phone: 
 
Email: 
 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH  
Alfred-Nobel-Strasse 10, 40789 Monheim, Germany 
Phone: 
 
Email: 
 
 
Change #2 
Page 2, STUDY CONTACT INFORMATION: 
Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB BIOSCIENCES GmbH  
Alfred-Nobel-Strasse 10, 40789 Monheim, Germany 
Phone: 
 
Email: 
 
 
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Has been changed to: 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Celltech 
216 Bath Road, Slough SL1 3WE, UK 
Phone: 
 
Email: 
 
Change #3 
Section 2, INTRODUCTION 
Last paragraph, last sentence 
This technology will be used in combination with visits from mobile study personnel to 
subjects’/legal representatives’ homes, subjects’/legal representatives’ visits to their local 
healthcare provider, and/or subjects’/legal representatives’ visits to national Patient Service 
Centers for various lab collections and designated study procedures. Patient Service Center 
locations are available across the country and provide standardized collection and processing of 
various laboratory samples and other standard procedures, such as collection of vital signs, etc.  
Has been changed to: 
This technology will be used in combination with visits from mobile study personnel to 
subjects’/legal representatives’ homes. 
Change #4 
Section 4.2, Safety variables 
Safety variables include: 
• AEs 
• Withdrawals due to AEs  
• Changes from Baseline in 12-lead ECGs  
• Changes from Baseline in vital signs (including assessment of orthostasis)  
• Changes from Baseline in laboratory data (hematology, blood chemistry, and urinalysis)  
• Changes from Baseline in hormone status  
• Changes from Screening in body weight, height, and BMI  
• Changes from Baseline in mMIDI 
• Changes in menstrual function for all female subjects 
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Has been changed to: 
4.2.1 Primary safety variables 
• Occurrence of TEAEs 
• TEAEs leading to withdrawals 
4.2.2 Other safety variables 
• Changes from Baseline in 12-lead ECGs  
• Changes from Baseline in vital signs (including assessment of orthostasis)  
• Changes from Baseline in laboratory data (hematology, blood chemistry, and urinalysis)  
• Changes from Baseline in hormone status  
• Changes from Screening in body weight, height, and BMI  
• Changes from Baseline in mMIDI 
• Changes in menstrual function for all female subjects 
Change #5 
Section 5.1, Study description 
Second, third, and fourth paragraphs 
The study will be conducted using the remote study model, which uses telemedicine technology 
(ie, NORA, see Section 2 for an overview) for interactions between the investigator/study staff 
and study subjects/legal representatives. Additionally, subjects/legal representatives will visit 
local healthcare facilities, such as local healthcare provider’s offices/clinics and local Patient 
Service Centers, to complete designated study procedures (eg, neurological exams, physical 
exams, and ECGs with local healthcare providers; lab collections and vital signs at Patient 
Service Centers). As an alternative option to Patient Service Centers, mobile study personnel 
may visit subjects’/legal representatives’ homes to complete certain study procedures. 
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists must discontinue therapy at least 14 days 
prior to Visit 2/Baseline. Subjects taking L-dopa must discontinue therapy at least 7 days prior to 
Visit 2/Baseline. 
The Screening Period will be followed by the Titration Period. Subjects will receive their first 
dose of study medication following Baseline at Visit 3/Day 1. Subjects will be initiated either on 
placebo or 1mg/24h rotigotine. The dose of rotigotine taken by subjects randomized to rotigotine 
will then be up-titrated on a weekly basis by 1mg/24h at a time to 2mg/24h or 3mg/24h, 
depending on the subject’s assigned dose level. 
Has been changed to: 
The study will be conducted using the remote study model, which uses telemedicine technology 
(ie, NORA, see Section 2 for an overview) for interactions between the investigator/study staff 
and study subjects/legal representatives. Mobile study personnel may visit subjects’/legal 
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representatives’ homes to complete certain study procedures (eg, neurological exams, physical 
exams, ECGs, lab collections, and vital signs). 
The study will also utilize a reminder app to help maximize retention of study subjects and limit 
dropouts. The app, located on the study smartphone, called Where’s My Patch (WMP) will help 
encourage subject adherence to study medication administration by reminding them to place 
patches at their prespecified time each day. It also provides a body map to record daily patch 
locations as a visual reminder of where patches have already been placed over the past 14 days 
and to facilitate patch site rotation. Patch location data will only be retained locally on the 
smartphone and then automatically deleted after 14 days. Subject use of the MWP app will be 
encouraged, but not required. 
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists must discontinue the therapy at least 14 days 
prior to Visit 2/Baseline. Subjects taking L-dopa must discontinue the therapy at least 7 days 
prior to Visit 2/Baseline. Discontinuation of therapy must be driven by the subject’s medical 
needs and not undertaken with the purpose of making a potential subject eligible for this study. 
The Screening Period will be followed by the Titration Period. Subjects will receive their first 
dose of study medication at Visit 3/Day 1. Subjects will be initiated either on placebo or 
1mg/24h rotigotine. The dose of rotigotine taken by subjects randomized to rotigotine will then 
be up-titrated on a weekly basis by 1mg/24h at a time to 2mg/24h or 3mg/24h, depending on the 
subject’s assigned dose level. 
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Change #6 
Section 5.2, Schedule of assessments 
Table 5‒1: 
Schedule of Assessments  
Assessment 
Screening 
Period 
Rand Titration Perioda  
 
Maintenance Perioda 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Testd (hCG) 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Dispense study 
medication 
 
 
Xg 
 
 
Xg 
 
 
Xg 
 
 
 
Return unused study 
medication 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
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Table 5‒1: 
Schedule of Assessments  
Assessment 
Screening 
Period 
Rand Titration Perioda  
 
Maintenance Perioda 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
BL=Baseline; BMI=body mass index; CGI=Clinical Global Impressions; ECG=electrocardiogram; eCRF=electronic Case Report form; eC-SSRS=electronic 
Columbia-Suicide Severity Rating Scale; hCG=human chorionic gonadotropin; IRLS=International Restless Legs Scale; IRT=interactive response technology; 
mMIDI=Modified Minnesota Impulsive Disorder Interview; PK=pharmacokinetic; Rand=randomization; RLS=Restless Legs Syndrome; V=Visit; 
WD=withdrawal 
Note: For Visit 2, there is a visit window of +3 days to allow for direct-to-subject shipment of study medication. Visit 3/Day 1 is the first day of study medication 
exposure. All subsequent visits are calculated based on Visit 3/Day 1. 
Note: Visit 5 is the end of the Titration Period and start of the Maintenance Period. Visit 8 is the end of the Maintenance Period and start of the Taper Period.  
Note: All visits are via telemedicine calls, with the exception of Visit 1, Visit 6, Visit 9, SFU, and unscheduled visits. 
a The visit window for Titration Visits is ±1 day per visit relative to Visit 3 (day of first dose). The visit window for visits during the Maintenance Period, 
including the End of Maintenance Visit, is ±2 days per visit. The Taper Period, which will last up to a maximum of 4 days, will start on the day after the End of 
Maintenance Visit. Note that there are no planned visits during the Taper Period. The visit window for Safety Follow-Up Period is 30 days±5 days relative to 
the end of the Taper Period. Following dose de-escalation, subjects may be eligible to participate in the open-label, long-term follow-up study (RL0007) at any 
time prior to the Safety Follow-Up Visit (see Section 5). The Safety Follow-Up Visit is for subjects not entering RL0007. 
b Assessments to be performed are at the investigator's discretion. 
c eC-SSRS is required if the Unscheduled Visit is conducted due to safety or efficacy reasons. 
d Urine pregnancy test and menstrual function for all female subjects. 
e At the time of PK sampling, sampling time, time of application of study medication, and application site of study medication should be recorded in the eCRF. 
f At Baseline, subjects must score ≥15 on the IRLS Rating Scale (indicating moderate-to-severe RLS) and must score ≥4 points on the CGI Item 1. 
g Study medication to be shipped to subject’s home to be available no later than this date. 
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Has been changed to: 
Table 5‒1: 
Schedule of Assessments  
Assessment 
Screening 
Period 
(+1 day) 
Rand 
(+3 
days) 
Titration 
Perioda  
(±1 day) 
 
EOT/ 
SOM 
 
Maintenance Perioda 
(±2 days) 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/ 
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy 
Testd (hCG) 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
Dispense study 
medication 
 
 
Xg 
 
 
Xg 
Xg 
Xg 
Xg 
 
 
X 
Return unused study 
medication 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
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Table 5‒1: 
Schedule of Assessments  
Assessment 
Screening 
Period 
(+1 day) 
Rand 
(+3 
days) 
Titration 
Perioda  
(±1 day) 
 
EOT/ 
SOM 
 
Maintenance Perioda 
(±2 days) 
 
Taper Period (4 days)a 
Safety 
Follow-
Upa 
(30 ±5 
days) 
Un- 
scheduled 
Visitb  
End of 
Maintenancea/ 
WD Visit 
End of 
Taper  
 
Telemedicine Calls 
 
Telemedicine Calls 
 
 
Telemedicine 
Call 
V1 
V2/BL V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day -28 
to Day -1 
Day  
0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
50 
Day 
78 
Day 
106 
Day  
110 
BL=Baseline; BMI=body mass index; CGI=Clinical Global Impressions; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
eCRF=electronic Case Report form; EOT=End of Titration; hCG=human chorionic gonadotropin; IRLS=International Restless Legs Scale; IRT=interactive 
response technology; mMIDI=Modified Minnesota Impulsive Disorder Interview; PK=pharmacokinetic; Rand=randomization; RLS=Restless Legs Syndrome; 
SOM=Start of Maintenance; V=Visit; WD=withdrawal 
Note: Informed consent must be obtained prior to Screening assessments and study-specific procedures. 
Note: Rescreening is allowed with the permission of the Study Physician or representation. 
Note: For Visit 2, there is a visit window of +3 days to allow for direct-to-subject shipment of study medication. Visit 3/Day 1 is the first day of study medication 
exposure. All subsequent visits are calculated based on Visit 3/Day 1. 
Note: Visit 6 is the end of the Titration Period and start of the Maintenance Period. Visit 9 is the end of the Maintenance Period and start of the Taper Period.  
Note: All visits are via telemedicine calls, with the exception of Visit 1, Visit 6, Visit 9, and SFU. Unscheduled visits are at the discretion of the investigator and 
may be telemedicine calls. 
a The visit window for Titration Visits is ±1 day per visit relative to Visit 3 (day of first dose). The visit window for visits during the Maintenance Period, 
including the End of Maintenance Visit, is ±2 days per visit. The Taper Period, which will last up to a maximum of 4 days, will start on the day after the End of 
Maintenance Visit. The visit window for Safety Follow-Up Period is 30 days±5 days relative to the end of the Taper Period. Following dose de-escalation, 
subjects may be eligible to participate in the open-label, long-term follow-up study (RL0007) at any time prior to the Safety Follow-Up Visit (see Section 5). 
The Safety Follow-Up Visit is for subjects not entering RL0007. 
b Assessments to be performed are at the investigator's discretion. 
c C-SSRS is required if the Unscheduled Visit is conducted due to safety or efficacy reasons. 
d Pregnancy test and menstrual function for all female subjects; serum pregnancy test at Screening and urine pregnancy test at all other visits. A positive urine 
pregnancy test must be confirmed by a serum pregnancy test. 
e At the time of PK sampling, sampling time, time of application of study medication, and application site of study medication should be recorded in the eCRF. 
f At Baseline, subjects must score ≥15 on the IRLS Rating Scale (indicating moderate-to-severe RLS) and must score ≥4 points on the CGI Item 1. 
g Study medication to be shipped to subject’s home to be available no later than this date. 
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Change #7 
Section 6.1, Inclusion Criteria 
Inclusion criterion #5 has been removed. 
5. Subject’s BMI is less than the 95th percentile for his or her age, according to Child and Teen 
BMI calculator at www.cdc.gov/healthyweight/assessing/bmi/. 
Change #8 
Section 6.1, Inclusion Criteria, criterion #10 
10. If subject is receiving supplemental iron, subject has been on a stable dose for at least 
3 months prior to Screening. 
Has been changed to: 
10a. Subjects who are receiving supplemental iron have been on a stable dose for at least 
1 month prior to Screening. Subjects previously treated with supplemental iron must have a 
washout period of at least 1 month prior to Screening. No supplemental iron administration 
or iron dose adjustment will be allowed while in study, unless medically necessary. 
Change #9 
Section 6.2, Exclusion Criteria, criterion #5 
4. Subject has a serum ferritin level <50ng/mL at Visit 1/Screening. 
Has been changed to: 
4a. Subject has a serum ferritin level below the lower limit of normal at Visit 1/Screening. 
Change #10 
Section 6.2, Exclusion Criteria 
Exclusion criteria #13, #14, and #15 were added.  
13. Subject has secondary RLS (eg, due to renal insufficiency [uremia], iron deficiency, or 
rheumatoid arthritis). 
14. Subject has a lifetime history of suicide attempts (including actual attempt, interrupted 
attempt, or aborted attempt), or had suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 at the C-SSRS at Screening 
(Visit 1). 
15. Subject is taking a prohibited concomitant medication (see Section 7.8.2). Prohibited 
concomitant medication must be discontinued at least 2 weeks prior to Screening (Visit 1). 
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Change #11 
Section 7.1, Description of investigational medicinal products 
Table 7-1: 
Investigational medicinal product 
International Non-Proprietary Name 
Rotigotine 
Dosage form 
Silicone patch containing rotigotine in an adhesive matrix 
Content 
Nominal Dose (mg/24h) 
Patch size (cm2) 
1 
5 
2 
10 
Supplier 
UCB BIOSCIENCES GmbH Germany 
Has been changed to: 
Table 7-1: 
Investigational medicinal product 
International Non-Proprietary Name 
Rotigotine 
Dosage form 
Silicone patch containing rotigotine in an adhesive matrix 
Content 
Nominal Dose (mg/24h) 
Patch size (cm2) 
1 
5 
2 
10 
Change #12 
Section 7.2.2, Application instructions 
Bullet #3 
• The patch should be worn continuously for 24 hours. After 24 hours, the patch should be 
removed and a new one applied immediately. 
Has been changed to: 
• The patch should be worn continuously for 24 hours. After 24 hours, the patch should be 
removed and a new one applied immediately. The WMP app on the study smartphone 
provides a reminder to place patches at a subject’s prespecified time each day (see Section 5 
for an overview). 
Change #13 
Section 7.2.2, Application instructions 
Bullet #5 
• Each patch should be applied to a different place on the skin each day, for example, from the 
right side to the left side and from the upper body to the lower body. The patch should not be 
applied to the same application site more than once every 14 days. 
Has been changed to: 
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• Each patch should be applied to a different place on the skin each day, for example, from the 
right side to the left side and from the upper body to the lower body. The patch should not be 
applied to the same application site more than once every 14 days. The WMP app on the 
study smartphone provides a body map to record daily patch location and a visual reminder 
of where patches have been placed over the past 14 days (see Section 5 for an overview). 
Change #14 
Section 7.2.4, General instructions 
Bullet #1 
• Contact with water while bathing, showering, swimming will not change the way that 
rotigotine works; however, these activities could loosen the patch. If a patch falls off, 
re-apply a new patch for the remainder of the day. A new patch should be applied the next 
day on the subject’s regular schedule. 
Has been changed to: 
• Contact with water while bathing, showering, swimming will not change the way that 
rotigotine works; however, these activities could loosen the patch. If a patch falls off, 
re-apply a new patch for the remainder of the day. A new patch should be applied the next 
day on the subject’s regular schedule. The location of a replacement patch can be recorded in 
the WMP app on the study smartphone (see Section 5 for an overview). 
Change #15 
Section 8.1, Screening Period 
The following paragraph was added: 
Subjects who have been screened but not randomized may be rescreened with the permission of 
the Study Physician or representative. 
Change #16 
Section 8.1.1, Visit 1 (Day -28 to Day -1) 
Assessments listed below will be completed by the subject/subject’s/legal representative’s local 
healthcare provider and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections listed below, subjects/legal representatives will either visit their local Patient 
Service Center or mobile study personnel will be sent to the subject’s/legal representative’s 
home for sample collections. Samples will be prepared and sent to the central laboratory for 
processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests (rescreening is allowed with the permission of the medical monitor) 
• Urine drug screen 
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• Urine pregnancy test for all female subjects 
• Hormone status 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• eC-SSRS (Screening version) 
• IRLS 
• CGI 
• mMIDI 
Has been changed to: 
Assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections listed below, mobile study personnel will be sent to the subject’s/legal 
representative’s home for sample collections. Samples will be prepared and sent to the central 
laboratory for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine drug screen 
• Serum pregnancy test for all female subjects 
• Hormone status 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Baseline/Screening version) 
• IRLS 
• CGI  
• mMIDI 
Change #17 
Section 8.2, Titration Period 
The visit window for Titration Visits is ±1 day per visit relative to Visit 2/Baseline.  
Has been changed to: 
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The visit window for Titration Visits is ±1 day per visit relative to Visit 3 (Day 1).  
Change #18 
Section 8.2.1, Visit 2 (Baseline) 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. Medications and procedures will be reviewed with 
the subject/legal representative by the investigator/designated study staff via a telephone or 
telemedicine call and noted as part of the subject’s study record. 
• AE assessment. All AEs will be assessed and reviewed throughout the study. 
• Contact IRT. Once eligibility is confirmed (see above), the IRT will be contacted to obtain 
the assigned randomization number and study medication kit numbers for the Titration 
Period.  
• Dispense study medication. Once randomization is completed, study medication for the 
Titration Period will be distributed. See Section 7.5 for a description of the direct-to-subject 
shipment process for the remote study model. 
Has been changed to: 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. Medications and procedures will be reviewed with 
the subject/legal representative by the investigator/designated study staff via a telephone or 
telemedicine call and noted as part of the subject’s study record. 
• AE assessment. All AEs will be assessed and reviewed throughout the study. 
• Contact IRT. Once eligibility is confirmed (see above), the IRT will be contacted to obtain 
the assigned randomization number and study medication kit numbers for the Titration 
Period.  
• Once randomization is completed, study medication for the Titration Period will be assigned 
and shipped to the subject/legal representatives home for receipt on Day 1. See Section 7.5 
for a description of the direct-to-subject shipment process for the remote study model. 
Change #19 
The following sentence was moved from Section 8.2.1, Visit 2 (Baseline) to Section 8.2.2, Visit 3 
(Day 1). 
The subject will apply their first patch during the visit under the supervision of the investigator 
(or designee) via a telemedicine call. 
Change #20 
Section 8.3.1, Visit 6 (Day 22) 
For lab collections and procedures listed below, subjects/legal representatives will either visit 
their local Patient Service Center or mobile study personnel will be sent to the subject’s/legal 
representative’s home. Samples will be prepared and sent to a central laboratory for processing 
and analysis, and results will be provided to the study site. 
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• Vital signs 
• Body weight, height, and BMI 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Has been changed to: 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Vital signs 
• Body weight, height, and BMI 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Change #21 
Section 8.3.2, Visit 7 (Day 50) ad Visit 8 (Day 78) 
The following bullets were added to the list of additional assessments and procedures: 
• Contact IRT. The IRT will be contacted to obtain study medication kit assignments. 
• Dispense study medication. Study medication for the Maintenance Period will be distributed. 
See Section 7.5 for a description of the direct-to-subject shipment process for the remote 
study model. 
Change #22 
Section 8.3.3, Visit 9 (Day 106)/End of Maintenance 
Assessments listed below will be completed by the subject/subject’s/legal representative’s local 
healthcare provider and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, subjects/legal representatives will either visit 
their local Patient Service Center or mobile study personnel will be sent to the subject’s/legal 
representative’s home. Samples will be prepared and sent to a central laboratory for processing 
and analysis, and results will be provided to the study site. 
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• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• eC-SSRS (Since Last Visit version) 
• IRLS 
• CGI 
• RLS-6  
• mMIDI 
• Subject Quality of Life Questionnaire 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures: See Section 8.2.1.  
• AE assessment: See Section 8.2.1.  
• Contact IRT: The IRT will be contacted to obtain study medication kit numbers for the Taper 
Period. 
• Dispense study medication (Taper Period de-escalation study medication will be dispensed at 
this visit). Study medication for the Taper Period will be distributed. See Section 7.5 for the 
description of the direct-to-subject shipment process for the remote study model. 
• Return any unused study medication 
Has been changed to: 
Assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
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• Hormone status 
• PK sampling–record sampling time, time of application of study medication, and application 
site of study medication in eCRF 
Assessments listed below will be completed either by the subject or investigator/trained study 
staff, as required. Assessments that require interviews will be completed via a telephone or 
telemedicine call. 
• C-SSRS (Since Last Visit version) 
• IRLS 
• CGI 
• RLS-6  
• mMIDI 
• Subject Quality of Life Questionnaire 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures: See Section 8.2.1.  
• AE assessment: See Section 8.2.1.  
• Contact IRT: The IRT will be contacted to obtain study medication kit numbers for the Taper 
Period. 
• Dispense study medication for the Taper Period. See Section 7.5 for the description of the 
direct-to-subject shipment process for the remote study model. 
• Return any unused study medication.  
Change #23 
Section 8.5, Safety Follow-Up Visit (if applicable) 
The assessments listed below will be completed by the subject/subject’s/legal representative’s 
local healthcare provider and records of the procedures will be obtained, with information noted 
as part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, subjects/legal representatives will either visit 
their local Patient Service Center or mobile study personnel will be sent to the subject’s/legal 
representative’s home. Samples will be prepared and sent to a central laboratory for processing 
and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
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Has been changed to: 
The assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
Change #24 
Section 8.7, Unscheduled Visit 
The assessments listed below will be completed by the subject/subject’s/legal representative’s 
local healthcare provider and records of the procedures will be obtained, with information noted 
as part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
• 12-lead ECG 
For lab collections listed below, subjects/legal representatives will either visit their local Patient 
Service Center or mobile study personnel will be sent to the subject’s/legal representative’s 
home. Samples will be prepared and sent to a central laboratory for processing and analysis, and 
results will be provided to the study site. 
• Vital signs 
• Safety laboratory tests 
• Urine pregnancy test for all female subjects 
• Hormone status 
Has been changed to: 
The assessments listed below will be completed by mobile study personnel at the subject’s/legal 
representative’s home and records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination, including body weight, height, BMI, and vital signs 
• Neurological examination 
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• 12-lead ECG 
For lab collections and procedures listed below, mobile study personnel will be sent to the 
subject’s/legal representative’s home. Samples will be prepared and sent to a central laboratory 
for processing and analysis, and results will be provided to the study site. 
• Vital signs 
• Safety laboratory tests 
• Urine drug screen 
• Urine pregnancy test for all female subjects 
• Hormone status 
Change #25 
Section 9.1, International Restless Legs Rating Scale (IRLS) 
The IRLS will be performed at Screening, Baseline (Visit 2), and subsequent visits through 
Visit 8. The IRLS should also be performed in the event that a subject is prematurely withdrawn 
from the study (Withdrawal Visit). 
Has been changed to: 
The IRLS will be performed at Screening, Baseline (Visit 2), Visit 6, Visit 7, Visit 8, and Visit 9. 
The IRLS should also be performed in the event that a subject is prematurely withdrawn from the 
study (Withdrawal Visit). 
Change #26 
Section 11.6, Laboratory measurements 
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Table 11-2: Laboratory measurements 
Hematology 
Endocrine 
Urinalysis 
Red blood cell count 
Estradiola 
Color 
Hematocrit 
FSH 
Appearance 
Hemoglobin 
IGF-1 
Glucose 
Platelet count 
LH 
Protein 
White blood cell countb 
Progesteronea 
Blood 
 
Prolactin 
Ketones 
 
Testosteronec 
Urine pregnancy testa 
 
T3 
 
 
T4 
 
 
TSH 
 
Chemistry 
 
ALT 
Glucose 
 
AST 
Phosphorus 
 
Albumin 
LDH 
 
Alkaline phosphatase 
Potassium 
 
Bicarbonate 
Serum iron 
 
BUN 
Sodium 
 
Calcium 
Total cholesterol 
 
Chloride 
Total bilirubin 
 
Creatinine 
Total protein 
 
Ferritin 
Transferrin 
 
GGT 
Uric acid 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; GGT=gamma-glutamyl transferase; IGF-1=insulin-like growth factor-1; LDH=lactate 
dehydrogenase; LH=luteinizing hormone; T3= triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone 
a Females only 
b With differential 
c Males only 
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Has been changed to: 
Table 11-2: Laboratory measurements 
Hematology 
Endocrine 
Urinalysis 
Red blood cell count 
Estradiola 
Color 
Hematocrit 
FSH 
Appearance 
Hemoglobin 
IGF-1 
Glucose 
Platelet count 
LH 
Protein 
White blood cell countb  
Progesteronea 
Blood 
RBC indices 
MCH 
MCV 
MCHC 
RDW 
Prolactin 
Ketones 
Testosteronec 
Pregnancy testa 
T3 
 
T4 
 
TSH 
 
Chemistry 
 
ALT 
Glucose 
 
AST 
Phosphorus 
 
Albumin 
LDH 
 
Alkaline phosphatase 
Potassium 
 
Bicarbonate 
Serum iron 
 
BUN 
Sodium 
 
Calcium 
Total cholesterol 
 
Chloride 
Total bilirubin 
 
Creatinine 
Total protein 
 
Ferritin 
Transferrin 
 
GGT 
Uric acid 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; GGT=gamma-glutamyl transferase; IGF-1=insulin-like growth factor-1; LDH=lactate 
dehydrogenase; LH=luteinizing hormone; MCH=mean corpuscular hemoglobin; MCHC= mean corpuscular 
hemoglobin concentration; MCV=mean cell volume; RBC=red blood cell; RDW=red cell distribution width; T3= 
triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone 
a Females only. Serum pregnancy test at Screening and urine pregnancy test at all other visits. A positive urine 
pregnancy test must be confirmed by a serum pregnancy test. 
b With differential. 
c Males only. 
 
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17.2 
Protocol Amendment 2 
Rationale for the amendment 
The protocol has been amended for the following reasons: 
• Change the sponsor company name from “UCB Biopharma SPRL” to “UCB Biopharma 
SRL” since the name of the legal form of the entity UCB Biopharma has changed into 
“société à responsabilité limitée” abbreviated “SRL”. 
 
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17.3 
Protocol Amendment 3 
Rationale for the amendment 
The main purpose of this amendment was to change the shipment of study medication and all 
required supplies from the study site to the study site’s depot/pharmacy. 
Other changes included in this amendment are as follows: 
• Principal Investigator and Sponsor contact information has been updated. 
• Changed Network Oriented Research Assistant (NORA®) to Science 37 Platform 
(PLATFORM). 
• Clarified that the Baseline for the other safety variables is Visit 1. 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
• Changed Network Oriented Research Assistant (NORA®) to Science 37 Platform 
(PLATFORM) throughout the protocol. 
Specific changes 
Change #1 
STUDY CONTACT INFORMATION: 
Sponsor 
UCB BIOSCIENCES Inc., 8010 Arco Corporate Drive, Raleigh, NC 27617, UNITED STATES 
Principal/Coordinating Investigator 
Name: 
David Kudrow, 
 
Affiliation: 
Science 37 
Address: 
12121 Bluff Creek Drive, 
 
Los Angeles, CA 90094 
USA 
Phone: 
 
 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH  
Alfred-Nobel-Strasse 10, 40789 Monheim, Germany 
Phone: 
 
Email: 
 
 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
Confidential 
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Clinical Project Manager 
Name: 
 
Address: 
UCB Biosciences Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
Email: 
 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Celltech 
216 Bath Road, Slough SL1 3WE, UK 
Phone: 
 
Email: 
 
 
Has been changed to: 
Sponsor 
UCB Biopharma SRL, Allée de la Recherche 60, 1070, Brussels, BELGIUM 
Principal/Coordinating Investigator 
Name: 
David Kudrow, 
 
Affiliation: 
Science 37 
Address: 
600 Corporate Pointe, 
 
Culver City, CA 90230-7600 
USA 
Phone: 
 
 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
Confidential 
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Sponsor Study Physician 
Name: 
 
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
 
 
Change #2 
Section 4.2.2, Other safety variables 
• Changes from Baseline in 12-lead ECGs  
• Changes from Baseline in vital signs (including assessment of orthostasis)  
• Changes from Baseline in laboratory data (hematology, blood chemistry, and urinalysis)  
• Changes from Baseline in hormone status  
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
Confidential 
Page 95 of 99 
• Changes from Screening in body weight, height, and BMI  
• Changes from Baseline in mMIDI 
• Changes in menstrual function for all female subjects 
Has been changed to: 
• Changes from Baseline (Visit 1) in 12-lead ECGs  
• Changes from Baseline (Visit 1) in vital signs (including assessment of orthostasis)  
• Changes from Baseline (Visit 1) in laboratory data (hematology, blood chemistry, and 
urinalysis)  
• Changes from Baseline (Visit 1) in hormone status  
• Changes from Baseline (Visit 1) in body weight, height, and BMI  
• Changes in mMIDI 
• Changes in menstrual function for all female subjects 
Change #3 
Section 5.1, Study description 
Fourth paragraph 
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists must discontinue the therapy at least 14 days 
prior to Visit 2/Baseline. Subjects taking L-dopa must discontinue the therapy at least 7 days 
prior to Visit 2/Baseline. Discontinuation of therapy must be driven by the subject’s medical 
need and not undertaken for the purpose of making a potential subject eligible for the study. 
Has been changed to: 
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists or taking L-dopa must discontinue the 
therapy at least 7 days prior to Visit 2/Baseline. Discontinuation of therapy must be driven by the 
subject’s medical need and not undertaken for the purpose of making a potential subject eligible 
for the study. 
Change #4 
Section 7.5, Handling and storage requirements 
First and fourth paragraphs 
Rotigotine transdermal patches should be stored in the original pouch. Rotigotine should be 
stored according to the labeling on the clinical trial supply packaging. The investigator (or 
designee) is responsible for the safe and proper storage of rotigotine at the site. Rotigotine stored 
by the investigator is to be kept in a secured area with limited access according to the storage 
conditions mentioned on the label. 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
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As part of the remote study model, the study site will provide study medication and all required 
supplies via direct-to-subject shipments. Once eligibility is confirmed, the study site will contact 
the interactive response technology (IRT) for randomization assignment, and shipments will be 
prepared and sent out for delivery to the subject’s/legal representative’s home/preferred address. 
Shipments will be confirmed as delivered by the study staff, with appropriate documentation in 
the subject’s study records. The study medication will be confirmed as received in good 
condition and within the acceptable temperature range (ie, fit for use). A telemedicine call will 
be completed to instruct the subject/legal representative on the correct storage and administration 
of the study medication, which will also be documented as part of subject’s study record. 
Has been changed to: 
Rotigotine transdermal patches should be stored in the original pouch. Rotigotine should be 
stored according to the labeling on the clinical trial supply packaging. The investigator (or 
designee) is responsible for the safe and proper storage of rotigotine at the site. Rotigotine stored 
by the investigator (or designee) is to be kept in a secured area with limited access according to 
the storage conditions mentioned on the label. 
As part of the remote study model, the study site’s depot/pharmacy will provide study 
medication and all required supplies via direct-to-subject shipments. Once eligibility is 
confirmed, the study site will contact the interactive response technology (IRT) for 
randomization assignment, and shipments will be prepared and sent out for delivery to the 
subject’s/legal representative’s home/preferred address. Shipments will be confirmed as 
delivered by the study staff, with appropriate documentation in the subject’s study records. The 
study medication will be confirmed as received in good condition and within the acceptable 
temperature range (ie, fit for use). A telemedicine call will be completed to instruct the 
subject/legal representative on the correct storage and administration of the study medication, 
which will also be documented as part of subject’s study record.  
Change #5 
Section 7.6, Drug accountability 
First and third paragraphs 
At the designated timepoints during the study, subjects/legal representatives will return to the 
study site the unused study medication patches remaining as part of the medication kits, along 
with the kit itself, via the return shipment materials provided. A Drug Accountability form will 
be used to record IMP dispensing and return information on a by subject basis and will serve as 
source documentation during the course of the study. Details of any IMP lost, damaged (due to 
breakage or wastage), not used, disposed of at the study site, or returned to the sponsor or 
designee must also be recorded on the appropriate forms. All supplies and drug accountability 
documentation must be made available throughout the study for UCB (or designee) to review. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate designee. 
Has been changed to: 
At the designated timepoints during the study, subjects/legal representatives will return to the 
study site’s depot/pharmacy the unused study medication patches remaining as part of the 
medication kits, along with the kit itself, via the return shipment materials provided. A Drug 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
Confidential 
Page 97 of 99 
Accountability form will be used to record IMP dispensing and return information on a by 
subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, disposed of at the study site’s 
depot/pharmacy, or returned to the sponsor or designee must also be recorded on the appropriate 
forms. All supplies and drug accountability documentation must be made available throughout 
the study for UCB (or designee) to review. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site’s depot/pharmacy to an appropriate designee.  
Change #6 
Section 7.7, Procedures for monitoring subject compliance 
First paragraph 
At the designated visits (see Table 5‒1), subjects/legal representatives will return all unused IMP 
and empty IMP containers, using the return shipment supplies provided to them by the study 
staff. Upon receipt of the returned medication at the study site, the designated study staff will 
review drug accountability with the subject/legal representative via a telephone or a telemedicine 
call in order to obtain explanations regarding any discrepancies in compliance with the dosing 
regimen. 
Has been changed to: 
At the designated visits (see Table 5‒1), subjects/legal representatives will return all unused IMP 
and empty IMP containers, using the return shipment supplies provided to them by the study 
staff. Upon receipt of the returned medication at the study site’s depot/pharmacy, the designated 
study staff will review drug accountability with the subject/legal representative via a telephone 
or a telemedicine call in order to obtain explanations regarding any discrepancies in compliance 
with the dosing regimen. 
 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
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18 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract. 
Investigator: 
 
 
 
 
Printed name  
 
Date/Signature 
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Clinical Study Protocol Amendment 3 
Rotigotine 
SP1006 
 
 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
sp1006-protocol-amend-3
Version:
1. 0
Document Number:
CLIN-000173862
Title:
SP1006 Protocol Amendment 3 - Phase 3 Placebo-Controlled Double-Blind
Approved Date:
03 May 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 30-Apr-2021 17:43:07 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 30-Apr-2021 19:17:59 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 03-May-2021 19:58:16 GMT+0000
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SAP_001.pdf: 
UCB 
  
25 APR 2023 
Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
Confidential 
Page 1 of 28 
  
STATISTICAL ANALYSIS PLAN  
Study: SP1006 
Product: Rotigotine 
A REMOTE, DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED STUDY OF 
ROTIGOTINE TRANSDERMAL SYSTEM IN ADOLESCENT SUBJECTS WITH 
IDIOPATHIC RESTLESS LEGS SYNDROME 
 
SAP/Amendment Number Date 
SAP/1 
27 Aug 2020 
SAP/2 
25 Apr 2023 
  
 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
Confidential 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study objectives ............................................................................................................. 7 
2.1.1 
Primary objective ................................................................................................... 7 
2.1.2 
Secondary objectives ............................................................................................. 7 
2.2 
Study variables ............................................................................................................... 7 
2.2.1 
Efficacy variables .................................................................................................. 7 
2.2.1.1 
Primary efficacy variable ............................................................................ 7 
2.2.1.2 
Secondary efficacy variables ....................................................................... 7 
2.2.1.3 
Other efficacy variables ............................................................................... 7 
2.2.2 
Safety variables ...................................................................................................... 7 
2.2.3 
Other variables ....................................................................................................... 8 
2.3 
Study design and conduct .............................................................................................. 8 
2.4 
Adaptations due to interim analysis decision................................................................. 9 
2.5 
Determination of sample size ......................................................................................... 9 
3 
DATA ANALYSIS CONSIDERATIONS ........................................................................ 9 
3.1 
General presentation of summaries and analyses .......................................................... 9 
3.2 
General study level definitions .................................................................................... 10 
3.2.1 
Analysis time points ............................................................................................ 10 
3.2.1.1 
Relative day ............................................................................................... 10 
3.2.1.2 
Date of last patch removal ......................................................................... 11 
3.2.2 
Study periods ....................................................................................................... 11 
3.2.3 
Visit mapping ....................................................................................................... 12 
3.3 
Definition of Baseline values ....................................................................................... 13 
3.4 
Protocol deviations....................................................................................................... 13 
3.5 
Analysis sets................................................................................................................. 13 
3.5.1 
Enrolled Set (ES) ................................................................................................. 13 
3.5.2 
Randomized Set (RS) .......................................................................................... 13 
3.5.3 
Safety Set (SS) ..................................................................................................... 13 
3.5.4 
Full Analysis Set (FAS) ....................................................................................... 13 
3.5.5 
Per Protocol Set (PPS) ......................................................................................... 13 
3.5.6 
Pharmacokinetic Set (PKS) ................................................................................. 13 
3.6 
Treatment assignment and treatment groups ............................................................... 14 
3.7 
Center pooling strategy ................................................................................................ 14 
3.8 
Coding dictionaries ...................................................................................................... 14 
3.9 
Changes to protocol-defined analyses ......................................................................... 14 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
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4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 14 
4.1 
Adjustments for covariates .......................................................................................... 14 
4.2 
Handling of dropouts or missing data .......................................................................... 14 
4.2.1 
Missing efficacy data ........................................................................................... 14 
4.2.2 
Missing and Incomplete Dates for Adverse Events and Concomitant Medication15 
4.2.3 
General Imputation Rule for Incomplete Dates ................................................... 16 
4.3 
Interim analyses and data monitoring .......................................................................... 16 
4.4 
Multicenter studies ....................................................................................................... 16 
4.5 
Multiple comparisons/multiplicity ............................................................................... 16 
4.6 
Use of an efficacy subset of subjects ........................................................................... 16 
4.7 
Examination of subgroups ........................................................................................... 16 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 16 
5.1 
Subject disposition ....................................................................................................... 16 
5.2 
Protocol deviations....................................................................................................... 17 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 17 
6.1 
Demographics .............................................................................................................. 17 
6.2 
Other Baseline characteristics ...................................................................................... 18 
6.3 
Medical history and concomitant diseases ................................................................... 18 
6.4 
Prior and concomitant medications .............................................................................. 18 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 18 
8 
EFFICACY ANALYSES ................................................................................................ 18 
8.1 
Statistical analysis of the primary efficacy variables ................................................... 18 
8.1.1 
Derivations of primary efficacy variables ........................................................... 18 
8.1.2 
Primary analysis of the primary efficacy variables ............................................. 19 
8.1.3 
Secondary analyses of the primary efficacy variable .......................................... 19 
8.1.4 
Supportive and sensitivity analyses of the primary efficacy variable ................. 19 
8.2 
Statistical analysis of the secondary efficacy variables ............................................... 19 
8.2.1 
Restless Legs Syndrome-6 Rating Scales ............................................................ 19 
9 
PHARMACOKINETICS ................................................................................................. 19 
9.1 
Plasma concentration ................................................................................................... 19 
9.2 
Population Pharmacokinetics ....................................................................................... 19 
10 SAFETY ANALYSES ..................................................................................................... 20 
10.1 
Extent of exposure ....................................................................................................... 20 
10.2 
Adverse events ............................................................................................................. 20 
10.3 
Clinical laboratory evaluations .................................................................................... 21 
10.3.1 
Elevated liver function tests ................................................................................. 22 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 22 
10.4.1 
Vital signs ............................................................................................................ 22 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
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10.4.2 
Electrocardiograms .............................................................................................. 23 
10.4.3 
Modified Minnesota Impulsive Disorders Interview ........................................... 23 
10.4.4 
Physical and neurological examinations .............................................................. 23 
10.4.5 
Suicide ideation and behavior .............................................................................. 23 
11 OTHER ANALYSES ...................................................................................................... 23 
11.1 
Subject Quality of Life Questionnaire ......................................................................... 23 
12 REFERENCES ................................................................................................................ 25 
13 APPENDICES ................................................................................................................. 26 
13.1 
Amendment 1 ............................................................................................................... 26 
13.2 
Amendment 2 ............................................................................................................... 27 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 28 
 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
Confidential 
Page 5 of 28 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate transaminase 
BMI 
body mass index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CGI 
Clinical Global Impressions 
DEM 
Data Evaluation Meeting 
eCRF 
electronic Case Report form 
ECG 
12-lead electrocardiograms 
EoM 
end of the Maintenance Period 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
HLT 
High Level Term 
ICH 
International Council for Harmonization 
IGF-1 
insulin-like growth factor 1 
IRLS 
International Restless Legs Syndrome Study Group 
Rating Scale 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMIDI 
Modified Minnesota Impulsive Disorder Interview 
nR 
ratio of hepatocellular to cholestatic values 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PKS 
Pharmacokinetic Set 
PPS 
Per Protocol Set 
PT 
preferred term 
RLS 
Restless Legs Syndrome 
RLS-6 
Restless Legs Syndrome - 6 Syndrome Rating Scales 
RLS-QoL 
restless legs syndrome quality of life 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
Confidential 
Page 6 of 28 
RS 
Randomized Set 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
SS 
Safety Set 
T3 
triiodothyronine 
T4FR 
thyroxine free 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
Confidential 
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1 
INTRODUCTION 
This document contains details for the statistical analyses of study SP1006 which has been 
written in consideration of the International Council for Harmonization (ICH)/Food and Drug 
Administration (FDA) E9 Guidance documents (Phillips et al, 2003). The reader is referred to 
the study protocol and the electronic Case Report form (eCRF) for details of study conduct and 
data collection. 
The Statistical Analysis Plan (SAP) describes the statistical principles that will be applied for the 
analyses as well as tables and listings that are foreseen for this study. Changes in the statistical 
methodology will result in an SAP amendment. Amendments to this document will be finalized 
prior to database lock.  
This study was terminated early, and therefore the analysis described in this analysis plan is 
much more limited than that described in the protocol.  
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
To demonstrate the efficacy of rotigotine against placebo in adolescent subjects with idiopathic 
Restless Legs Syndrome (RLS) over a 12-week Maintenance Period.  
2.1.2 
Secondary objectives 
To investigate the safety and tolerability of rotigotine in adolescent subjects with idiopathic RLS. 
2.2 
Study variables 
2.2.1 
Efficacy variables 
2.2.1.1 
Primary efficacy variable 
• Change from Baseline in International Restless Legs Rating Scale (IRLS) sum score at end of 
the Maintenance Period (EoM) 
• Change from Baseline in Clinical Global Impressions (CGI) Item 1 at EoM  
2.2.1.2 
Secondary efficacy variables 
• Change from Baseline in Restless Legs-6 Rating Scales (RLS-6) at EoM 
2.2.1.3 
Other efficacy variables 
• Change from Baseline in CGI Item 1 by visit*  
• Change from Baseline in RLS-6 Rating Scales by visit* 
• Change from Baseline in IRLS sum score by visit* 
* For the IRLS, CGI, and RLS-6 the EoM visit is already covered under primary and secondary 
variables. 
2.2.2 
Safety variables 
• Occurrence of treatment emergent adverse events (TEAEs) 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
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• TEAEs leading to withdrawal 
• Changes from Baseline in 12-lead electrocardiograms (ECGs) 
• Changes from Baseline in vital signs (including orthostatic assessment)  
• Changes from Baseline in laboratory data (hematology, blood chemistry, and urinalysis) 
• Changes from Baseline in hormone status 
• Changes from Screening in body weight, height, and calculated body mass index (BMI)  
• Changes from Baseline in Modified Minnesota Impulsive Disorder Interview (mMIDI) 
• Changes in menstrual function for all female subjects 
2.2.3 
Other variables 
• Plasma concentrations of unconjugated rotigotine 
• Subject Quality of Life Questionnaire 
2.3 
Study design and conduct 
This is a Phase 3, remote, double-blind, randomized, adaptive placebo-controlled study of fixed 
dose administration of the rotigotine transdermal system. The study will be conducted in 
adolescent subjects, 13 to17 years of age, with idiopathic RLS. Subjects will be randomized to 1 
of 3 treatment groups: placebo, 2mg/24h rotigotine, or 3mg/24h rotigotine. 
The study will be conducted using the remote study model, which uses telemedicine technology 
(i.e., Science 37 PLATFORM) for interactions between the investigator/study staff and study 
subjects/legal representatives.  Mobile study personnel will visit subjects’/legal representatives’ 
homes to complete certain study procedures (e.g., neurological exams, physical exams, ECGs, 
lab collections, and vital signs).    
The study will begin with a Screening Period of at least 7 days (maximum of 28 days) prior to 
Visit 2/Baseline to ensure homogeneous baseline conditions can be established for all subjects. 
Subjects with prior intake of any dopamine agonists must discontinue therapy at least 14 days 
prior to Visit 2/Baseline. Subjects taking L-dopa must discontinue therapy at least 7 days prior to 
Visit 2/Baseline. 
The Screening Period will be followed by the Titration Period. Subjects will receive their first 
dose of study medication at Visit 3/Day 1. Subjects will be initiated either on placebo or 
1mg/24h rotigotine. The dose of rotigotine taken by subjects randomized to rotigotine will then 
be up-titrated on a weekly basis by 1mg/24h at a time to 2mg/24h or 3mg/24h, depending on the 
subject’s assigned dose level. 
Subjects will be allowed to back-titrate one dose level during the Titration Period. Subjects are to 
complete the Titration Period at the back-titrated dose level and remain at this dose level for the 
duration of the Maintenance Period. Subjects who do not tolerate the assigned dose in the first 
week (placebo or 1mg/24h) will be withdrawn from the study. If subjects withdraw due to lack 
of efficacy, they are eligible to roll-over to the open-label study, RL0007, after the 3 weeks of 
the Titration Period are completed. 
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
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The Titration Period will be followed by a 12-week Maintenance Period. Subjects will remain at 
the assigned (or back-titrated) dose level throughout the Maintenance Period. At the end of the 
Maintenance Period, subjects will enter a Taper Period lasting up to a maximum of 4 days 
(de-escalation of study medication), followed by a 30-day Safety Follow-Up Period. 
Visits will be scheduled every week during the Titration Period. During the Maintenance Period, 
visits will be scheduled every 4 weeks. There is a 4-day interval until the end of the Taper 
period, followed by a 30-day interval (±5 days) until the Safety Follow-Up Visit.  
2.4 
Adaptations due to interim analysis decision 
Due to early stopping of the study, this section is no longer applicable. 
2.5 
Determination of sample size 
The sample size estimate is based on the efficacy results observed in the adult RLS Phase 3 
confirmatory trial SP792, which was conducted in the USA. In this study, a range of rotigotine 
doses were compared to placebo. 
The sample size computation assumes that adolescent and adult patients will show a similar 
effect of rotigotine with respect to IRLS score and CGI (Item 1) changes from Baseline in 
comparison to placebo, with a similar proportion of patients not included in the primary analysis. 
In the adult study, the observed difference between the 3mg/24h rotigotine group and placebo in 
the Change from Baseline to end of 3-month Maintenance Period in IRLS sum score was 5.9. A 
difference between rotigotine and placebo of 4.0 can be considered as clinically relevant. The 
common standard deviation (SD) estimate in the adult study was 7.9. For the CGI Item 1, the 
difference between 3mg/24h rotigotine group and placebo was 0.8 with a SD of 1.2. 
With these assumptions, a total sample size of 45 evaluable patients in each group will provide a 
power of 93% for the IRLS endpoint, and a power of 87% for the CGI (Item 1) endpoint in the 
analysis of the 3mg/24h dose.  Assuming independence of the 2 endpoints will result in a power 
of 80% for the analysis of the co-primary variables.  Since it is known that the 2 endpoints will 
have a relatively high correlation (approximately 0.7), the calculated 80% is a conservative 
estimator for the power. 
Assuming similar effects for the 2mg/24h dose group, the conditional power for the 2mg/24h 
dose group is also 80% with an overall power for the study >60%. To obtain 135 evaluable 
patients (i.e., FAS), 138 patients must be randomized (assuming approximately 2% of the 
randomized patients cannot be utilized). 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS Version 9.3 or higher. All tables and listings will use Courier New 
font size 9. 
A complete set of raw data listings containing both all documented data and all calculated data 
(e.g., changes from Baseline) will be generated.  
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Statistical Analysis Plan 
Rotigotine 
SP1006 
 
 
 
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Unless otherwise noted, all summaries will be displayed by randomized treatment group 
(placebo, rotigotine 2mg/24h and rotigotine 3mg/24h, respectively) regardless of the doses 
individual subjects received. A summary with all treatment groups combined (i.e., total column) 
will be presented for the demographic and Baseline characteristics, for the prior medications, as 
well as for the medical history. 
In general, summary statistics for quantitative variables will include n (number of available 
measurements), arithmetic mean, SD, median, minimum, and maximum. For categorical 
parameters, descriptive statistics will consist of the number and percentage of subjects in each 
category. Unless otherwise specified the denominator for calculating percentages will be the 
number of subjects in the respective population. 
Unless otherwise noted, all percentages with the exception of 0 and 100 will be expressed to 1 
decimal place. 100% will be presented as integer. If a category has the frequency 0 the 
percentage value will be omitted. Mean and median changes from baseline lower than the 
minimal displayable change will be displayed without sign (e.g., -0.00 will be displayed as 0.00). 
For descriptive statistics, the following rules regarding decimal places will apply: 
• n will be an integer. 
• Mean, SD, and median will use 1 additional decimal place compared to the original data. 
• Minimum and maximum will have the same number of decimal places as the original value. 
Unless otherwise noted, listings will be sorted by randomized treatment, site-subject number, 
parameter (if applicable) and time point (if applicable). All listings will include assessments on 
scheduled and unscheduled visits; data from unscheduled visits will appear in chronological 
order together with the scheduled time points – a repeated measurement will appear directly after 
the time point for which the repeat measurement was performed.  
In individual subject data listings, values are presented as documented in eCRF using the same 
number of digits. Derived data are presented with 1 digit more than the original data used in the 
derivation. Dates are presented as documented without imputing incomplete dates. 
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
Relative day 
The relative day of a visit or an event with respect to the first application of study medication 
will be presented in subject data listings. Relative days will be calculated as follows: 
• If the start (stop) date occurred prior to the first application of study medication, the relative 
day is calculated as start (stop) date minus date of first patch application. That means that in 
subject data listings, relative days based on this situation will be preceded by a ‘-‘. 
• If the start (stop) date occurred on or after the first application of study medication but prior 
to the last patch removal, the relative day is calculated as start (stop) date minus date of first 
patch application + 1. 
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• If the start (stop) date occurred after the date of last patch removal, the relative day is 
calculated as start (stop) date minus date of first patch application + 1. In subject data 
listings, relative days based on this situation will be preceded by a ‘+’. 
Relative days will not be presented for partial or missing dates. 
3.2.1.2 
Date of last patch removal 
The date of last patch application is documented on the Study Termination page of the eCRF. If 
the date of last patch application on this page is missing the last available kit start date on the 
Drug Accountability log form will be used as the date of last patch application.  Thus, the date of 
the last patch removal is defined as the date of the last patch application + 1. 
3.2.2 
Study periods 
The following time periods are defined for this study. 
• Screening Period:  
The Screening Period starts with Visit 1 and ends the day before the date of the first patch 
application.  This period includes Visit 2/Day 0 at which the subjects are randomized, and 
study medication is assigned and shipped. 
• Titration Period:  
The Titration Period starts at the day of the first patch application (Day 1) and ends on the 
day prior to Visit 6. In case of a premature withdrawal before Visit 6, the Titration Period 
ends at the day of the Withdrawal Visit. If the Withdrawal Visit is missing or the date of the 
last patch removal (or last known patch removal) is before the Withdrawal Visit, the Titration 
Period ends at the day of last patch removal. 
• Maintenance Period:  
The Maintenance Period starts at Visit 6 and ends at Visit 9. If the subject withdraws prior to 
Visit 9, the Maintenance Period ends at the day of the Withdrawal Visit date or the last patch 
removal date (or last known patch removal date), whichever is earlier.  
• Taper Period:  
The Taper Period starts at the date of last maintenance patch removal and ends at the day of 
last patch removal. If the day of last patch removal is on the date of last maintenance patch 
removal, i.e., no de-escalation was performed for any reason, then no Taper Period is defined 
for this subject. 
• Treatment Period:  
The Treatment Period comprises the Titration Period, the Maintenance Period, and the Taper 
Period, i.e., it starts with the day of first patch application and ends on the maximum end date 
of the Titration, Maintenance and Taper periods. 
• Safety Follow-Up Period:  
The Safety Follow-Up Period starts the day after the end of the Treatment Period and ends at 
the date of the Safety Follow-Up Visit. However, AEs starting within 30 days following the 
date of last patch removal will be considered for analysis, even if the start date is after the 
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date of last study assessment.  If the subject rolls over into the RL0007 study, then the Safety 
Follow-up Period dates will be missing. 
3.2.3 
Visit mapping 
The visits are planned as shown in the Protocol Table 5-1 Schedule of assessments.  These visit 
windows were revised for the purpose of identifying important protocol deviations at visits 2, 7 
and 8: 
Visit 
Day 
Visit Window 
Visit 1 (Screening) 
Day -28 to Day -1 
 
Visit 2 (Baseline) 
Day 0 
+5 Days  
Visit 3 
Day 1 
+5 Days 
Visit 4 
Day 8 
± 1 Day 
Visit 5 
Day 15 
± 1 Day 
Visit 6 (Start of Maintenance) Day 22 
± 2 Days 
Visit 7 
Day 50 
± 5 Days 
Visit 8 
Day 78 
± 5 Days 
 Visit 9 (EoM) 
Day 106 
± 2 Days 
Visit 10 
Day 110  
Visit 9 + 4 days 
Safety Follow-Up 
30 Days after End of Taper Period 
 
Analysis by visit will be done as documented in the eCRF, i.e., no visit correction will be 
conducted due to deviations from scheduled time points.  
Assessments at premature withdrawal of the study are documented in the eCRF pages of Visit 9 
(EoM/ Withdrawal). For data listings, assessments of Withdrawal Visit and of Visit 9 as 
scheduled will be presented separately as 
• Premature Withdrawal for subjects who prematurely terminated the study 
• Visit 9 (EoM) for subjects who completed the study. 
Unscheduled assessments may be recorded during the study. Information collected in the log 
forms (e.g., AEs and concomitant medications) is included in the analysis. However, assessments 
at unscheduled visits will not be considered in the by-visit analysis unless data captured at these 
visits fall within the protocol defined visit windows (Protocol Table 5-1) and there was no 
corresponding endpoint data collected at the same scheduled visit. The information collected 
during unscheduled visits will be presented in the listings labeled as the unscheduled visit. 
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3.3 
Definition of Baseline values 
Unless otherwise noted, baseline is defined as the last available value on or before the day of the 
first patch application. 
3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy, key safety, or PK outcomes for 
an individual subject. The criteria for identifying important protocol deviations will be defined 
within the appropriate protocol-specific document. Important protocol deviations will be 
reviewed as part of the ongoing data cleaning process and data evaluation. All important 
deviations will be identified and documented prior to unblinding. 
3.5 
Analysis sets 
Six analysis sets will be defined for this study. 
3.5.1 
Enrolled Set (ES) 
The ES will consist of all subjects with a signed informed consent form and any demographic 
data. 
3.5.2 
Randomized Set (RS) 
The RS will consist of all subjects from the ES who have been randomized. 
3.5.3 
Safety Set (SS) 
The SS will consist of all subjects from the RS who have at least one patch (rotigotine or 
placebo) applied.  This population will be used for safety analysis. 
3.5.4 
Full Analysis Set (FAS) 
The FAS will consist of all subjects from the SS who have a valid IRLS score with a valid post-
Baseline IRLS score or a valid CGI Item 1 score at Baseline paired with a valid post-Baseline 
CGI Item 1 score. This population is the primary population for efficacy analysis. 
A valid IRLS or CGI Item 1 score at Baseline is defined as a completely answered questionnaire 
on or before the date of first study medication. A valid post-Baseline IRLS or CGI Item 1 score 
is defined as a completely answered questionnaire during the Treatment Period, i.e., measured 
after Baseline and on or before one day after the last patch removal. 
3.5.5 
Per Protocol Set (PPS) 
Due to early termination of the study, the analyses planned using the PPS will no longer be 
performed. 
3.5.6 
Pharmacokinetic Set (PKS) 
The PKS will consist of all subjects from the SS who provided at least 1 valid post-dose plasma 
concentration of unconjugated rotigotine. 
Due to early stopping of the study, the analyses planned using the PKS will no longer be 
performed. 
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3.6 
Treatment assignment and treatment groups 
The treatment comparisons of primary interest will be each rotigotine group versus placebo. All 
summaries/analyses will generally be performed using the randomized treatment, i.e., placebo, 
rotigotine 2mg/24h and rotigotine 3mg/24h independent from the dose of administration.  
3.7 
Center pooling strategy 
Not applicable. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the most recent version of Medical 
Dictionary for Regulatory Activities (MedDRA 25.1). Prior or concomitant medication will be 
coded using the most recent version of the World Health Organization Drug Dictionary (WHO 
DD MAR/2022). 
3.9 
Changes to protocol-defined analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical outputs 
will be performed using SAS Version 9.3 or higher. None of the planned analyses require SAS 
Version 9.4 and can all be performed on SAS Version 9.3. 
Analyses will not be performed as defined in the study protocol due to early study termination.  
All data will be listed and key summary tables will be produced. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
Subjects who prematurely discontinue the study will be evaluated based on the data collected at 
each visit attended.  If the premature discontinuation occurs at a scheduled visit, data collected at 
that visit will be summarized at the scheduled visit time point.  Otherwise, the data will be 
attributed to the next scheduled visit for the purpose of by-visit endpoint summaries. 
With respect to AEs, events with missing intensity will be assumed to be severe. Events with 
missing relationship to study medication per the investigator will be assumed to be related. 
Events with a missing answer to the question “Serious Adverse Event?” will be considered 
serious. 
4.2.1 
Missing efficacy data 
For subjects who prematurely withdraw for any reason before EoM, values for planned efficacy 
assessments scheduled at subsequent visits will not be imputed.  Efficacy assessments must be 
performed no later than 1 day after the last patch removal to be utilized for analysis (valid 
measurements). 
For IRLS analysis, if any item is missing, the IRLS sum score will not be calculated. Missing 
IRLS baseline items and therefore the total score will be regarded as an important protocol 
deviation. 
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4.2.2 
Missing and Incomplete Dates for Adverse Events and Concomitant 
Medication 
For analyses of AEs and concomitant medication usage, a complete date must be established in 
order to correctly identify the AE or medication as occurring during treatment in the study or not. 
For the purposes of imputing missing date or missing components of partially-reported start and 
stop dates for AEs and for medication use, the algorithms listed below will be followed. Start and 
stop dates of AEs or concomitant medication will be displayed as reported in the subject data 
listings (i.e., no imputed values will be displayed in data listings). 
• Missing start day, but month and year present: 
If the first patch application occurred in the same month and year as the occurrence of the 
AE/medication, the start day of the event/medication will be assigned to the day of first patch 
application. 
Otherwise the start day will be set to the 1st day of the month. 
• Missing start day and month, but year present: 
If the first patch application occurred in the same year as the occurrence of the 
AE/medication, the start day and month will be assigned to the date of first patch application. 
Otherwise the start day and month will be set to January 1st. 
• Missing end day, but month and year present: 
The end day will be set to the last day of the month. 
• Missing end day and month, but year present: 
The end day and month will be set to the date of study termination or the date equivalent to 
30 days after last patch removal, whatever occurs later. 
However, if the study termination year and year for the date which is 30 days after the last 
patch removal are greater than the event/concomitant medication year, the day and month are 
to be set to December 31st. 
• Completely missing start date: 
An AE will be considered as occurring during treatment. 
Medications with an unknown stop date or a stop date after the date of the first patch 
application will be considered as concomitant medication but not as prior medication. 
Medications with a stop date prior to first patch application will be considered as prior 
medication but not as concomitant medication.  For these cases, impute the day and month to 
January 1st of the year of the first patch application. 
• Completely missing stop date: 
Adverse events with a completely missing stop date will be considered ongoing. 
• Imputed stop date prior to imputed start date: 
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If the year of start date is the same as the year of first patch application and the stop date is 
after the date of first patch application, then set the start date to the date of first patch 
application. 
Otherwise, set the start day and month to January 1st of the start year. 
In the event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication was concomitant, or an adverse event was treatment emergent, the medication will be 
considered as concomitant or the adverse event will be considered treatment emergent. 
 
4.2.3 
General Imputation Rule for Incomplete Dates 
Where necessary for the calculation of derived variables (e.g., age), partial dates will be imputed 
using the earliest calendar date based on the partial date provided. This rule is valid for all partial 
dates with the exception of the following: 
• Start and stop dates of AEs 
• Start and stop dates of prior and concomitant medication 
• Stop dates of past and concomitant diseases 
• Patch application dates 
Completely missing dates will not be replaced, and the corresponding derived variables will be 
set to missing. 
4.3 
Interim analyses and data monitoring 
Due to early stopping of the study, the interim analyses will no longer be performed. 
4.4 
Multicenter studies 
Not applicable. 
4.5 
Multiple comparisons/multiplicity 
Not applicable. 
4.6 
Use of an efficacy subset of subjects 
Not applicable. 
4.7 
Examination of subgroups 
Not applicable. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
Subject disposition will be presented for the RS in terms of the number of subjects who  
• completed or withdrew (including reasons) during the study 
• started the Titration Period (attended Visit 2 and was treated) and subsequently completed 
(attended Visit 5) or withdrew (including reasons) during the Titration Period 
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• started the Maintenance Period (attended Visit 6) and either completed or withdrew 
(including reasons) during the Maintenance Period 
• started the Taper Period and completed (attended Visit 10) or withdrew (including reasons) 
during the Taper Period. 
 
Subjects will be counted as completed study and maintenance period, if they don’t withdraw 
before EoM, and as completed titration/taper period, if they don’t withdraw before the end of the 
titration/taper period. 
Summaries will also be provided for discontinuations due to AEs and disposition of analysis sets. 
Reasons for screen failure will be listed for the ES. 
5.2 
Protocol deviations 
The subject incidence (and percentage) of important protocol deviations will be summarized both 
overall and by treatment group for the RS. These summaries will also be provided by site. 
All important protocol deviations will also be listed for the RS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
Age will be derived in years applying all rules for missing date imputation as described in 
Section 4.2.3 as integer ((Date of informed consent - date of birth) / 365.25). 
Weight recorded in pounds (lb) will be converted to kilograms (kg) as weight(lb)*0.4536kg/lb. 
Height recorded in inches (in) will be converted to height in centimeters (cm) as 
height(in)*2.54cm/in. 
The BMI will be calculated as weight (kg) / (height (m))2. 
The following demographics will be summarized for the RS: 
• Age (years) 
• Age (EudraCT age categories) 
• Age (clinicaltrials.gov age categories) 
• Gender (Male; Female) 
• Racial Group (American Indian/Alaskan Native; Asian; Black; Native Hawaiian or Other 
Pacific Islander; White; Other/Mixed) 
• Ethnicity (Hispanic or Latino; Not Hispanic or Latino) 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
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• BMI (<18.5, 18.5-<25, 25-<30, 30-<35, 35-<40, >=40, Missing) 
6.2 
Other Baseline characteristics 
Time since diagnosis of RLS will be derived in years applying all rules for missing date 
imputation as described in Section 4.2.3 as integer ((date of informed consent - date of diagnosis) 
/ 365.25). 
The following Baseline characteristics will be summarized for the SS: 
• Time since diagnosis of RLS (years) 
Other Baseline characteristics (e.g., lifestyle items) will be listed.  
6.3 
Medical history and concomitant diseases 
Previous and ongoing diseases will be derived from the medical history form of the eCRF.  
Medical history (except RLS) will be presented for the SS, summarized by MedDRA System 
Organ Class (SOC) and preferred term (PT). 
Procedure history and concomitant medical procedures will be listed.  Family medical history 
will be collected only when PDILI is reported and will be provided in a listing. 
6.4 
Prior and concomitant medications 
Medications will be considered as prior if the start date of the medication is before the date of 
first patch administration. Medications will be considered as concomitant if it was taken at least 
once in the Treatment Period starting with the first patch administration and ending the day of 
last patch removal during the study. Medications starting prior to first patch application and 
continuing into the Treatment Period will be considered both prior and concomitant medication. 
For cases of partial or missing dates the rules described in Section 4.2.2  will be applied. 
Prior and concomitant medications will be summarized for the SS. The number and percentage 
of subjects who used prior or concomitant medications, respectively, will be presented according 
to the Anatomical Therapeutic Chemical main group, the Pharmacological subgroup, and the 
preferred drug name. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Compliance will not be calculated for the early study termination scenario. Refer to Section 10.1 
for information about study medication exposure. 
8 
EFFICACY ANALYSES 
If not stated otherwise, all efficacy analyses will be performed for the FAS. 
8.1 
Statistical analysis of the primary efficacy variables 
The co-primary efficacy variables are change from Baseline to EoM in IRLS sum score and 
change from Baseline in CGI Item 1 to EoM. 
8.1.1 
Derivations of primary efficacy variables 
The IRLS consists of 10 questions, each using a 5-point scale ranging from 0=not present to 
4=very severe. The IRLS sum score will be calculated by summing up the single scores of all 
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applicable questions, i.e., the sum score will range between 0 and 40. If any answer is missing, 
the IRLS sum score will also be missing. 
The CGI item 1 (Severity of Illness) scale ranges from 0 to 7 as follows: : 0=not assessed, 
1=normal, not ill at all, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 
6=severely ill, 7=among the most extremely ill. 
8.1.2 
Primary analysis of the primary efficacy variables 
Observed results and changes from Baseline in IRLS sum score and CGI (Item 1) will be 
summarized by visit and by treatment group. 
8.1.3 
Secondary analyses of the primary efficacy variable 
 Not applicable. 
8.1.4 
Supportive and sensitivity analyses of the primary efficacy variable 
Not applicable. 
8.2 
Statistical analysis of the secondary efficacy variables 
All summaries and analyses of the secondary efficacy variables will be based on the FAS. 
8.2.1 
Restless Legs Syndrome-6 Rating Scales 
The RLS-6 Rating Scales (Kohnen et al, 2003) is designed to assess the severity of RLS and 
consists of 6 subscales. The subscales assess severity of symptoms at the following times of the 
day/evening: falling asleep, during the night, during the day at rest, and during the day when 
engaged in daytime activities. In addition, the subscales assess satisfaction with sleep and 
severity of daytime tiredness/sleepiness. Scores for each of the 6 subscales range from 0 
(completely satisfied/none /not at all) to 10 (completely dissatisfied/very severe). 
The change from baseline will be derived for each of the 6 subscales. No sum score will be 
calculated.  
Summary statistics for observed values as well as changes from Baseline by visit will be 
provided for each of the RLS-6 rating scales.  
 
9 
PHARMACOKINETICS  
9.1 
Plasma concentration 
Plasma samples will be collected at Visit 6 and Visit 9.  For subjects in the rotigotine groups, 
plasma concentrations will be listed. 
9.2 
Population Pharmacokinetics 
The plasma concentrations of unconjugated rotigotine may also be used for population PK-PD 
analyses. Details and methods of these analyses will be described in the Data Analysis Plan and 
the results will be reported in a separate modeling report. 
 
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10 
 SAFETY ANALYSES 
If not stated otherwise, all safety analyses will be conducted for the SS. 
10.1 
Extent of exposure 
The duration of exposure will be calculated as (date of last patch removal – date of first patch 
application + 1 day). 
All derivations of rotigotine doses given below are nominal doses, i.e., include placebo patches 
in the rotigotine 2mg/24h or placebo arm. 
The final dose level (‘final dose’) is defined as the dose administered at the start of the 
Maintenance Period (i.e., at Visit 6) and intended to be used during the Maintenance Period.  If 
the subject down titrates to the previous dose during the Titration Period and continues on that 
dose at Visit 6, then the back-titrated dose level is the ‘final dose’. 
The determination of the dose of longest duration is based on the entries given in the drug dosing 
log of the eCRF. The duration of a single dose will be calculated as the sum of the durations of 
each dosing interval with intake of the respective dose whereas the duration of each dosing 
interval will be calculated as (end date – start date + 1). 
Where more than one dose has the same ‘longest duration’, the highest dose will be selected. For 
subjects who dropped out during the Titration Period, the last applied dose during the Titration 
Period will be used as dose of longest duration. If the dose of longest duration is 0mg/24h, but 
the subject was exposed at least once to active drug, the minimum active dose will be utilized. 
Summary statistics will be presented for the following variables: 
• Duration of exposure (days) 
• Final dose (mg/24h) at the start of Maintenance (0 mg/24h, 1 mg/24h, 2 mg/24h and 3 
mg/24h) 
• Dose of longest duration (0 mg/24h, 1 mg/24h, 2 mg/24h and 3 mg/24h) 
A listing of patch adhesiveness findings, including date and time of detachment, location and 
side of body, percent adherence and kit number will be provided. 
 
10.2 
Adverse events 
Adverse events will be documented throughout the entire study on an ongoing basis. TEAEs are 
defined as events that started during the Treatment Period or within 30 days following the end of 
the Treatment Period (i.e., on or after the date of first patch application and within 30 days 
following the date of last patch removal) or any unresolved event already present before 
administration of treatment that worsens in intensity following exposure to the treatment. For 
AEs with a partial or missing start date, the imputation rules as described in Section 4.2.2  will 
be applied. 
Adverse events with a missing start date are defined as treatment-emergent if the end date of the 
AE is not on or before the date of first patch application. 
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An AE with action taken regarding study medication reported on the AE page of the eCRF as 
“drug permanently withdrawn” will be regarded as an AE leading to discontinuation of study 
medication. 
Adverse events which have the question “Serious Adverse Event?” answered “yes” or missing 
are considered serious. 
Treatment emergent AEs will be tabulated by MedDRA SOC, High Level Term (HLT) and PT. 
The number and percentage of subjects experiencing each event at least once will be summarized 
in addition to the number of events. In summaries of TEAEs by relationship and intensity, 
respectively, the number of events will not be presented. 
All summaries will be sorted alphabetically by SOC and HLT and by frequency of events (PT) in 
the total rotigotine group within HLTs. If there is more than one PT with the same frequency in 
the total rotigotine group these events will be sorted alphabetically. 
An overview of the incidence and frequency of all TEAEs, serious TEAEs, TEAEs leading to 
discontinuation of study medication, related TEAEs, severe TEAEs, all deaths and TEAEs 
leading to death will also be provided. 
The following tabular summaries will be presented also. 
• TEAEs 
• TEAEs by intensity 
• TEAEs by maximum intensity 
• TEAEs by relationship to study medication per the Investigator 
• Serious TEAEs 
• Serious TEAEs by Relationship to study medication per the Investigator 
• non-serious TEAEs above reporting frequency threshold of 5% 
Individual subject data listings will be presented for all AEs. 
10.3 
Clinical laboratory evaluations 
The following laboratory parameters are measured within the study: 
• Hematology parameters: Hematocrit, Hemoglobin, Platelets, Red Blood Cells, White Blood 
Cells, and differential count and percentile (Lymphocytes, Basophils, Eosinophils, 
Monocytes, Neutrophils) 
• Liver Function Tests and other Chemistry parameters: Alanine Aminotransferase (ALT), 
Aspartate Transaminase (AST), Albumin, Alkaline Phosphatase (ALP), Bicarbonate, Blood 
Urea Nitrogen, Calcium, Chloride Creatinine, Ferritin, Gamma-glutamyl transferase, 
Glucose, Iron Binding Capacity Total, Iron Binding Capacity Unsaturated, Lactate 
Dehydrogenase, Potassium, Phosphorus, Serum Iron, Sodium, Total cholesterol, Total 
bilirubin, Total protein, Transferrin, Uric acid 
• Endocrine parameters: Estradiol (females only), Follicle-stimulating Hormone (FSH), 
Insulin-like Growth Factor 1 (IGF-1), Luteinizing Hormone (LH), Progesterone (females 
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only), Prolactin, Testosterone (males only), Thyroxine Free (T4FR), Triiodothyronine (T3), 
Thyroid Stimulating Hormone (TSH) 
− Endocrine normal ranges are provided by the central lab and included in the dataset 
specifications. 
• Urinalysis: Color, Appearance, Glucose, Protein, Blood, Ketones, Urine Pregnancy Test 
Summary statistics of the observed values and their change from Baseline and the frequency of 
abnormal values based on normal ranges will be presented by visit for laboratory parameters of 
hematology, chemistry and endocrinology. 
Laboratory data outside the reference range will be highlighted with “L” for low and “H” for 
high in all laboratory subject data listings where applicable. Individual subject data listings will 
be presented for laboratory parameters of hematology, chemistry and endocrinology.  Urinalysis 
and pregnancy test results will only be listed. 
10.3.1 
Elevated liver function tests 
A listing of subjects with elevated liver function results will be provided.  This listing will 
include subjects who potentially meet Hy’s Law at least 1 time during exposure.  Potential Hy’s 
Law is defined as a subject with AST or ALT >= 3x upper limit of normal and total bilirubin >= 
2x upper limit of normal where ALP <2 at the same visit.  
For all subjects potentially meeting Hy’s Law, the ratio of hepatocellular to cholestatic values 
will be calculated using the following formula and included in the listing: 
 
nR = max(ALT /ULN, AST /ULN) / (ALP /ULN), where ULN is the upper limit of normal 
Potential cholestatic injury is defined as a ratio of hepatocellular to cholestatic values <=2, 
potential mixed hepatocellular/cholestatic injury is defined as values >2 and <5, and potential 
hepatocellular injury is defined as values >=5. 
 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
Summary statistics of the observed values and changes from Baseline for vital sign parameters 
(systolic and diastolic blood pressure, and pulse rate) will be presented by visit for supine 
measurements (after 1 and 5 minutes) as well as standing measurements (after 1 and 3 minutes). 
Observed values and change from Baseline values will also be presented for the orthostatic 
reaction after 1- and 3-minutes standing. 
Orthostatic hypotension will be assessed using the difference between supine and standing 
systolic and diastolic blood pressure at each visit.  For systolic BP, diastolic BP and pulse, the 
difference will be calculated using the 5-minute supine values with both the 1 and 3 minute 
standing values for each parameter, respectively.  A drop in systolic BP of ≥20 mmHg or a drop 
in diastolic BP of ≥10 mmHg after 1 or 3 minutes in the standing position is indicative of 
orthostatic hypotension. 
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Summary statistics of body weight, calculated BMI, temperature, and respiratory rate (including 
corresponding changes from Baseline) will be presented by visit.  Summary statistics of height 
percentile (based on CDC growth charts at http://www.cdc.gov/growthcharts) and including 
corresponding changes from Baseline will be presented by visit. 
A listing of results for vital signs, and body weight, BMI, temperature, respiratory rate, height 
and height percentile will be provided. A separate listing for orthostatic hypotension will also be 
provided. 
10.4.2 
Electrocardiograms 
Summary statistics of the observed values and changes from Baseline for ECG parameters (Heart 
rate, RR interval, PQ/PR interval, QRS duration, QT interval, and QTcB interval) will be 
presented by visit. 
ECG results and findings (normal, abnormal not clinically significant, and abnormal clinically 
significant) will be listed. 
10.4.3 
Modified Minnesota Impulsive Disorders Interview 
Assessments of mMIDI will only be listed. 
10.4.4 
Physical and neurological examinations 
Physical and neurological examination abnormalities will be listed only.  Changes in menstrual 
function will also be listed. 
10.4.5 
Suicide ideation and behavior 
Suicide ideation and behavior will be measured using the Columbia-Suicide Severity Rating 
Scale (C-SSRS). Results of the C-SSRS will only be listed. 
11 
OTHER ANALYSES  
11.1 
Subject Quality of Life Questionnaire 
The restless legs syndrome quality of life (RLS-QoL) questionnaire (Kohnen et al, 2002) will be 
used to evaluate quality of life. This disease-specific instrument consists of 12 questions with 
numeric outcome (0 – 5). The RLS-QoL total score will be calculated as the sum of all 12 items. 
Subscales will be calculated as the sum of the items within each subscale.  If an item within the 
subscale is missing, then the subtotal for that subscale will also be missing.  The exception to this 
rule is for missing answers to question 7 (
) at 
Baseline.  The answer to this question might be not applicable, which will be substituted by a 
score of 0 (not at all). 
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A listing of individual items, subscales and total score will be provided. 
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12 
REFERENCES 
CDC growth charts: http://www.cdc.gov/growthcharts. 
Kohnen R, Benes H, Heinrich B, Kurella B. Development of the disease-specific restless legs 
syndrome quality of life (RLS-QoL) questionnaire [abstract]. Mov Disord. 2002;17 Suppl 5:232. 
 
Kohnen R, Oertel WH, Stiasny-Kolster K, Benes H, Trenkwalder C. Severity rating of RLS: 
review of ten years experienced with the RLS-6 scales in clinical trials [abstract]. Sleep. 2003;26 
Abstract suppl: A342. 
 
Phillips A, Haudiquet V. ICH E9 guideline ‘Statistical principles for clinical trials’: a case study. 
Stat Med. 2003;22(1):1-11; discussion 13-7. 
 
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13 
APPENDICES 
13.1 
Amendment 1 
Rationale for the amendment: 
This amendment reflects changes for consistency with the definition of important protocol 
deviations and other minor corrections. 
• Section 2.4: Updated to describe actions resulting from the interim analysis decision 
• Section 3.1: Removes Procedures from the list of summaries. These data will be listed 
only. 
• Section 3.2.2: Clarifies study period definitions. 
• Section 3.2.3:  
o Visit mapping table updated to reflect definition of important protocol deviations. 
o Clarification was added to indicate that any visit exclusions due to the IPD 
windows applies to the PPS only. 
o Clarification was added for the case where the efficacy endpoints were collected 
after a visit at an unscheduled visit. 
• Section 3.5.5: Clarifies that only the visit that falls outside the IPD windows will be 
excluded from the PPS, not all subject efficacy data. 
• Section 4.2.2: Added clarification for imputation of partial dates. 
• Section 5.1: Removed reasons for screen failure. 
• General: Grammatical and typographic corrections were made. 
• Section 2 and Section 7: Updated wording to be in alignment with amended protocol. 
Clarification added for compliance calculation. 
• Section 8.1.4: Added sensitivity analyses to assess impact of Covid-19 pandemic. 
• Section 10.1: Replaced ‘Optimal dose’ with ‘Final back-titrated dose level’ to refer to the 
final dose level intended for the subject throughout the Maintenance Period. 
• Section 10.4.2: Removed QTcF interval from list of ECG parameters. 
• Section 10.4.4 : Added listing for changes in menstrual function. 
 
 
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13.2 
Amendment 2 
Rationale for the amendment: 
This amendment reflects changes for consistency with the SSD SAP, clarification regarding 
treatment periods and other minor corrections.  It also reflects a reduced list of displays due to 
early study termination. 
• Section 3.2.1.2: Clarification of the definition of the date of last patch removal. 
• Section 3.2.2: Clarifies study period definitions. 
• Section 4.2.1: Clarification of missing data handling for IRLS efficacy endpoint. 
• Section 4.2.2: Added instructions for AE and concomitant medication missing start dates. 
• Section 10.1: Clarification of the definition of ‘final dose’. 
• Section 10.2: Clarification of the definition of TEAEs. 
• Section 10.3: Administrative editing of list of lab parameters to include full spelling and 
abbreviations. 
• Section 10.4.1 “Vital Signs”: Updated to add descriptive statistics for height percentiles 
including change from baseline; cited CDC growth chart reference. 
• Section 12 “References”: Added references for CDC growth charts, RLS-6 Rating Scales and 
ICH E9. 
• General: Grammatical and typographic corrections were made. 
• General: Statistical analyses have been removed and the number of summary tables reduced. 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
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Approval Signatures
Name:
sp1006-sap-amend-2
Version:
1. 0
Document Number:
CLIN-000221293
Title:
sp1006-sap-amend-2
Approved Date:
24 Apr 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 24-Apr-2023 07:54:12 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 24-Apr-2023 13:17:03 GMT+0000
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