Clinical trial NCT03992196
Conditions: Restless Legs Syndrome
Keywords: RLS Neupro Rotigotine
Sponsor: UCB Biopharma SRL
Start date: 2019-12-03; Completion date: 2022-09-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the long-term safety, tolerability and the long-term efficacy of rotigotine treatment in adolescents with idiopathic Restless Legs Syndrome (RLS).

Detailed description:

Arms: arm 1: Subjects will be initiated on 1 mg/24 h rotigotine and up-titrated to a maximum of 3 mg/24 h rotigotine, with the aim of achieving the individually optimized dosage. Dose adjustment of rotigotine is allowed at any time during the following Maintenance Period up to a maximum dose of 3 mg/24 h. At the end of the Maintenance Period, subjects will be down-titrated.
Interventions: intervention 1: Rotigotine 1 mg/24 h intervention 2: Rotigotine 2 mg/24 h intervention 3: Rotigotine 3 mg/24 h
Intervention descriptions: intervention 1: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: Application of rotigotine transdermal patch with 1 mg/24 h (5 cm\^2 patch size). intervention 2: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: Application of rotigotine transdermal patch with 2 mg/24 h (10 cm\^2 patch size). intervention 3: Pharmaceutical Form: transdermal patch Route of administration: transdermal use Concentration: Application of rotigotine transdermal patch with 3 mg/24 h (15 cm\^2 patch size).

Protocol documents:
Prot_000.pdf: 
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PROTOCOL RL0007 
PROTOCOL RL0007 AMENDMENT 2 
A REMOTE, OPEN-LABEL, LONG-TERM FOLLOW-UP STUDY 
TO DETERMINE THE SAFETY, TOLERABILITY, AND 
EFFICACY OF ROTIGOTINE TRANSDERMAL SYSTEM AS 
MONOTHERAPY IN ADOLESCENTS WITH RESTLESS LEGS 
SYNDROME 
PHASE 3 
IND Number: 063902 
NCT Number: NCT03992196 
 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
 
 
1070 Brussels 
BELGIUM 
 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
04 Apr 2018 
Not applicable 
Protocol Amendment 1 
10 Feb 2021 
Nonsubstantial 
Protocol Amendment 2 
29 Apr 2021 
Nonsubstantial 
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: +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 .................................................................................................... 9 
1 
SUMMARY ..................................................................................................................... 11 
2 
INTRODUCTION ........................................................................................................... 11 
3 
STUDY OBJECTIVES .................................................................................................... 12 
4 
STUDY VARIABLES ..................................................................................................... 13 
4.1 
Safety variables ............................................................................................................ 13 
4.1.1 
Primary safety variables ...................................................................................... 13 
4.1.2 
Other safety variables .......................................................................................... 13 
4.2 
Efficacy variables......................................................................................................... 13 
4.2.1 
Secondary efficacy variables ............................................................................... 13 
4.2.2 
Other efficacy variables ....................................................................................... 13 
4.3 
Other variables ............................................................................................................. 13 
5 
STUDY DESIGN ............................................................................................................. 14 
5.1 
Study description ......................................................................................................... 14 
5.1.1 
Study duration per subject ................................................................................... 14 
5.1.2 
Planned number of subjects and site .................................................................... 14 
5.1.3 
Anticipated regions and countries ....................................................................... 14 
5.2 
Schedule of study assessments..................................................................................... 14 
5.3 
Rationale for study design and selection of dose ......................................................... 18 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 18 
6.1 
Inclusion criteria .......................................................................................................... 18 
6.2 
Exclusion criteria ......................................................................................................... 19 
6.3 
Withdrawal criteria ...................................................................................................... 19 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 20 
7 
STUDY TREATMENT ................................................................................................... 20 
7.1 
Description of investigational medicinal product ........................................................ 20 
7.2 
Treatments to be administered ..................................................................................... 21 
7.2.1 
Titration Period .................................................................................................... 21 
7.2.2 
Maintenance Period ............................................................................................. 21 
7.2.3 
Taper Period ......................................................................................................... 22 
7.2.4 
Application instructions ....................................................................................... 22 
7.2.5 
Removal instructions ........................................................................................... 23 
7.2.6 
General instructions ............................................................................................. 23 
7.3 
Packaging ..................................................................................................................... 23 
7.4 
Labeling ....................................................................................................................... 24 
7.5 
Handling and storage requirements ............................................................................. 24 
7.6 
Drug accountability ...................................................................................................... 24 
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7.7 
Procedures for monitoring subject compliance ............................................................ 25 
7.8 
Concomitant medications/treatments ........................................................................... 25 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 25 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 25 
7.8.3 
Rescue medication ............................................................................................... 25 
7.9 
Blinding........................................................................................................................ 25 
7.10 
Randomization and numbering of subjects .................................................................. 25 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 26 
8.1 
Visit 1 (Screening/Day -4) ........................................................................................... 26 
8.2 
Titration Period ............................................................................................................ 26 
8.2.1 
Visit 2 (Day 1) ..................................................................................................... 26 
8.2.2 
Visit 3 and Visit 4 (Day 8 and Day 15) ............................................................... 27 
8.2.3 
Visit 5 (Day 22) ................................................................................................... 27 
8.3 
Maintenance Period ..................................................................................................... 28 
8.3.1 
Visit 6 (Month 3) ................................................................................................. 28 
8.3.2 
Visit 7 (Month 6) ................................................................................................. 29 
8.3.3 
Visit 8 (Month 9) ................................................................................................. 30 
8.3.4 
Visit 9/ End of Maintenance Visit (Month 12) .................................................... 31 
8.4 
Taper Period ................................................................................................................. 32 
8.5 
Safety Follow-up Visit ................................................................................................. 32 
8.6 
Withdrawal Visit .......................................................................................................... 33 
8.7 
Unscheduled Visit ........................................................................................................ 33 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 34 
9.1 
International Restless Legs Rating Scale ..................................................................... 34 
9.2 
Clinical Global Impressions ......................................................................................... 35 
9.3 
RLS-6 ........................................................................................................................... 36 
9.4 
Subject Quality of Life Questionnaire ......................................................................... 36 
10 ASSESSMENT OF PHARMACOKINETIC VARIABLES ........................................... 36 
10.1 
Blood sampling for the determination of rotigotine plasma concentrations ................ 36 
10.2 
Shipment procedures .................................................................................................... 37 
10.3 
Bioanalytical method ................................................................................................... 37 
11 ASSESSMENT OF SAFETY .......................................................................................... 37 
11.1 
Adverse events ............................................................................................................. 37 
11.1.1 
Definitions ........................................................................................................... 37 
11.1.1.1 
Adverse event ............................................................................................ 37 
11.1.1.2 
Serious adverse event ................................................................................ 38 
11.1.1.3 
Adverse events of special interest ............................................................. 39 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 39 
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11.1.2.1 
Description of adverse events .................................................................... 39 
11.1.2.2 
Rule for repetition of an adverse event...................................................... 39 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 40 
11.1.3 
Follow up of adverse events ................................................................................ 40 
11.2 
Pregnancy ..................................................................................................................... 41 
11.3 
Suspected transmission of an infectious agent............................................................. 42 
11.4 
Overdose of investigational medicinal product ........................................................... 42 
11.5 
Safety signal detection ................................................................................................. 42 
11.6 
Laboratory measurements ............................................................................................ 42 
11.6.1 
Evaluation of PDILI ............................................................................................ 43 
11.6.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 47 
11.6.1.2 
Immediate action: determination of IMP discontinuation ......................... 47 
11.6.1.3 
Testing: identification/exclusion of alternative etiology ........................... 47 
11.6.1.4 
Follow-up evaluation ................................................................................. 49 
11.7 
Other safety measurements .......................................................................................... 49 
11.7.1 
12-lead electrocardiogram values ........................................................................ 49 
11.7.2 
Vital signs ............................................................................................................ 49 
11.7.3 
Physical and neurological examinations .............................................................. 49 
11.7.4 
Hormone status .................................................................................................... 50 
11.7.5 
Modified Minnesota Impulsive Disorders Interview ........................................... 50 
11.7.6 
Menstrual function ............................................................................................... 50 
11.7.7 
Assessment of suicidal ideation and behavior ..................................................... 50 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 51 
12.1 
Adherence to protocol .................................................................................................. 51 
12.2 
Monitoring ................................................................................................................... 51 
12.2.1 
Definition of source data ..................................................................................... 51 
12.2.2 
Source data verification ....................................................................................... 52 
12.3 
Data handling ............................................................................................................... 52 
12.3.1 
Case Report form completion .............................................................................. 52 
12.3.2 
Database entry and reconciliation ........................................................................ 52 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 52 
12.4 
Termination of the study .............................................................................................. 53 
12.5 
Archiving and data retention ........................................................................................ 53 
12.6 
Audit and inspection .................................................................................................... 53 
12.7 
Good Clinical Practice ................................................................................................. 54 
13 STATISTICS ................................................................................................................... 54 
13.1 
Definition of analysis sets ............................................................................................ 54 
13.2 
General considerations ................................................................................................. 54 
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13.3 
Planned efficacy analyses ............................................................................................ 54 
13.3.1 
Analysis of the efficacy variables ........................................................................ 54 
13.4 
Planned safety and other analyses................................................................................ 54 
13.4.1 
Safety analyses ..................................................................................................... 54 
13.4.2 
Other analyses ...................................................................................................... 55 
13.5 
Handling of protocol deviations................................................................................... 55 
13.6 
Handling of dropouts or missing data .......................................................................... 55 
13.7 
Planned interim analysis and data monitoring ............................................................. 55 
13.8 
Determination of sample size ....................................................................................... 55 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 56 
14.1 
Informed consent ......................................................................................................... 56 
14.2 
Subject identification cards .......................................................................................... 56 
14.3 
Institutional Review Boards ......................................................................................... 57 
14.4 
Subject privacy............................................................................................................. 57 
14.5 
Protocol amendments ................................................................................................... 58 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 58 
16 REFERENCES ................................................................................................................ 58 
17 APPENDICES ................................................................................................................. 60 
17.1 
Protocol Amendment 1 ................................................................................................ 60 
17.2 
Protocol Amendment 2 ................................................................................................ 76 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 82 
19 SPONSOR DECLARATION .......................................................................................... 83 
 
LIST OF TABLES 
Table 5-1: 
Schedule of study assessments......................................................................... 15 
Table 7‒1: 
Investigational medicinal product .................................................................... 21 
Table 7‒2: 
Dose titration schedule until optimal dose is reached ...................................... 21 
Table 7‒3: 
Taper de-escalation schedule ........................................................................... 22 
Table 11‒1: 
Anticipated serious adverse events for the RLS population ............................ 39 
Table 11‒2: 
Laboratory measurements ................................................................................ 43 
Table 11‒3: 
Required investigations and follow up for PDILI............................................ 45 
Table 11‒4: 
PDILI laboratory measurements ...................................................................... 47 
Table 11‒5: 
PDILI information to be collected ................................................................... 48 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
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  
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 
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 
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 
LTFU 
long-term follow-up 
MAO 
monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMIDI 
Modified Minnesota Impulsive Disorder Interview 
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PD 
pharmacodynamic 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic 
PLATFORM 
Science 37 Platform 
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 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SFU 
Safety Follow-Up 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
ULN 
upper limit of normal 
 
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1 
SUMMARY 
This is a Phase 3, remote, open-label, long-term follow-up (LTFU) study of monotherapy 
administration of rotigotine transdermal patch in adolescent subjects with idiopathic Restless 
Legs Syndrome (RLS). 
The total study duration per subject will be approximately 14 months after study entry or until 
the investigational product development is stopped by the Sponsor. The study will include a 
Titration Period of up to 3 weeks (at maximum), a Maintenance Period of up to 1 year, a Taper 
Period up to a maximum of 4 days (de-escalation of study medication), and a 30-day Safety 
Follow-Up (SFU) Period. 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose (with a maximum dose of 3mg/24h) prior to completing the scheduled 
assessments for that visit. Subjects who have reached their optimal dose will maintain that dose 
and complete the Titration Period without titrating to the next higher dose.  
Up to 138 subjects are planned to be treated during the study, assuming that all subjects had 
tolerated the first dose level of rotigotine in the previous study in adolescent subjects with 
idiopathic RLS (eg, SP1006) and choose to rollover into the present study (RL0007). A single 
remote site in the USA is planned to be included in the study. The remote study model to be used 
in this study 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 assess the long-term safety and tolerability of rotigotine 
treatment in adolescents with idiopathic RLS. The secondary objective of this study is to assess 
the long-term efficacy of rotigotine treatment in adolescents with idiopathic RLS. 
Primary safety variables include adverse events (AEs) and withdrawals due to AEs. Other safety 
variables include changes from Baseline in the following: 12-lead electrocardiograms (ECGs), 
vital signs, hormone status, laboratory tests (hematology, clinical chemistry, and urinalysis), 
menstrual function, modified Minnesota Impulsive Disorders Interview (mMIDI), body weight, 
height, and body mass index (BMI).  
Efficacy variables include changes from Baseline in the following: International Restless Legs 
Rating Scale (IRLS) sum score, Clinical Global Impressions (CGI) Item 1 score; and RLS-6 
Rating Scales. All statistical analyses of the efficacy variables will be considered exploratory. 
Other variables include the Subject Quality of Life and plasma concentrations of rotigotine. 
Baseline values from SP1006 will serve as Baseline in RL0007. 
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 
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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 
(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 safety, tolerability, and efficacy 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 (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 assess the long-term safety and tolerability of rotigotine 
treatment in adolescents with idiopathic RLS. 
The secondary objective of this study is to assess the long-term efficacy of rotigotine treatment 
in adolescents with idiopathic RLS. 
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4 
STUDY VARIABLES 
Baseline values from SP1006 will serve as Baseline in RL0007. Baseline values for the other 
safety variables were collected at Visit 1 of SP1006. 
4.1 
Safety variables 
4.1.1 
Primary safety variables 
• Occurrence of treatment-emergent adverse events (TEAEs) 
• Treatment-emergent adverse events leading to permanent withdrawal of study medication 
4.1.2 
Other safety variables 
• Changes from Baseline (Visit 1, SP1006) in 12-lead ECGs  
• Changes from Baseline (Visit 1, SP1006) in vital signs (including assessment of orthostasis)  
• Changes from Baseline (Visit 1, SP1006) in hormone status  
• Changes from Baseline (Visit 1, SP1006) in laboratory data (hematology, clinical chemistry, 
and urinalysis) 
• Changes from Baseline in menstrual function for all female subjects 
• Changes in mMIDI  
• Changes from Baseline (Visit 1, SP1006) in body weight, height, and BMI 
4.2 
Efficacy variables 
4.2.1 
Secondary efficacy variables 
• Changes from Baseline in IRLS sum score at Visit 9 
• Changes from Baseline in CGI Item 1 at Visit 9 
• Changes from Baseline in RLS-6 at Visit 9 
There are no primary efficacy variables. 
4.2.2 
Other efficacy variables 
• Changes from Baseline in IRLS sum score at all visits except Visit 9 
• Changes from Baseline in CGI Item 1 at all visits except Visit 9 
• Changes from Baseline in RLS-6 at all visits except Visit 9 
4.3 
Other variables 
• Plasma concentrations of rotigotine 
• Subject Quality of Life Questionnaire 
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5 
STUDY DESIGN 
5.1 
Study description 
This is a Phase 3, remote, open-label, LTFU study of monotherapy administration of the 
rotigotine transdermal system. Subjects entering this study from the previous rotigotine study in 
adolescents (SP1006) must have tolerated the first dose level of rotigotine in that study without 
meeting the withdrawal criteria. 
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). Subjects are allowed to be up-titrated and down-
titrated at the discretion of the investigator during the Maintenance Period. 
The study will begin with a Titration Period of 3 weeks with the aim of achieving the 
individually optimized dosage. During the Titration Period, investigators should determine at 
each visit whether the subject has reached his or her optimal dose prior to completing the 
scheduled assessments. Once subjects have reached their optimal dose, they will maintain that 
dose and complete the Titration Period without titrating to the next higher dose. 
Titration will be followed by a Maintenance Period of up to 1 year. Dose adjustment of 
rotigotine is allowed at any time during the Maintenance Period, based on clinical judgment up 
to a maximum dose of 3mg/24h. At the End of Maintenance (EoM), subjects will enter a 4-day 
Taper Period followed by a 30-day SFU. 
Visits will be scheduled every week during the Titration Period, every 3 months for the 
Maintenance Period, and at the end of the SFU. 
5.1.1 
Study duration per subject 
The total study duration per subject will be approximately 14 months after study entry or until 
the investigational product development is stopped by the Sponsor. The study will include a 
Titration Period of up to 3 weeks (at maximum), a Maintenance Period of up to 1 year, a Taper 
Period up to a maximum of 4 days (de-escalation of study medication), and a 30-day SFU 
Period. 
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 site 
Up to 138 subjects are planned to be treated during the study, assuming that all subjects had 
tolerated the first dose level of rotigotine in the previous study in adolescent subjects with 
idiopathic RLS (eg, SP1006) and choose to rollover into the present study (RL0007). A remote 
clinical study model in the USA is planned to be utilized in the study. 
5.1.3 
Anticipated regions and countries 
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 study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
 
V5 
 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22 
D90 
(M3) 
D180 
(M6) 
D270 
(M9) 
D360 
(M12) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
Withdrawal criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Reproductive potential and 
birth control 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Brief physical examination 
 
 
 
 
 
 
 
 
X 
 
X 
Neurological examination 
 
 
 
 
 
 
 
 
X 
 
 
Telemedicine neurological 
examination 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Vital signs  
 
 
 
 
X 
Xf 
X 
Xf 
X 
 
Xg 
Body weight, height, and 
BMI 
 
 
 
 
X 
 
X 
 
X 
 
 
12-lead ECG 
 
 
 
 
X 
 
 
 
X 
 
Xg 
Safety labs 
 
 
 
 
X 
 
X 
 
X 
 
Xg 
Urine drug screen  
 
 
 
 
X 
 
X 
 
X 
 
 
Urine pregnancy test 
(females) (hCG) 
 
 
 
 
X 
Xf 
X 
Xf 
X 
X 
X 
Hormone status 
 
 
 
 
X 
 
 
 
X 
 
X 
PK sampling (blood) 
 
 
 
 
X 
 
 
 
X 
 
 
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29 Apr 2021 
Clinical Study Protocol Amendment 2 
Rotigotine 
RL0007 
 
 
 
Confidential 
Page 16 of 83 
Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
 
V5 
 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22 
D90 
(M3) 
D180 
(M6) 
D270 
(M9) 
D360 
(M12) 
 
 
IRLS 
 
 
 
 
X 
X 
X 
X 
X 
 
 
CGI 
 
 
 
 
X 
X 
X 
X 
X 
 
 
RLS-6 Rating Scales 
 
 
 
 
X 
X 
X 
X 
X 
 
 
mMIDI 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Menstrual function 
 
 
 
 
X 
 
X 
 
X 
 
 
Subject Quality of Life 
Questionnaire 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Recording of medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
AE assessment  
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication  
 
Xi 
 
 
Xi 
Xi 
Xi 
Xi 
 
 
Xg 
Return unused study 
medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
AE=adverse event; BMI=Body Mass Index; CGI=Clinical Global Impressions; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; 
ECG=electrocardiogram; EoM=End of Maintenance; EoT=End of Taper; hCG=human chorionic gonadotropin; IMP=investigational medicinal product; 
IRLS=International Restless Legs Rating Scale; IRT=interactive response technology; lab=laboratory; M=Month; mMIDI=modified Minnesota Impulsive 
Disorder Interview; PK=pharmacokinetic; RLS=Restless Legs Syndrome; SC=Screening; SFU=Safety Follow-Up; SoM=Start of Maintenance; V=Visit; 
WD=withdrawal 
Note: It is preferred that a subject directly continue from SP1006 into RL0007; however, if a subject cannot directly continue into RL0007, the subject has until the 
SFU Visit of SP1006 to enroll in RL0007.  
Note: Visit 1 should occur 4 days prior to Visit 2/Day 1 to allow for direct-to-subject shipment of study medication. Visit 2/Day 1 is the first day of study 
medication exposure. All subsequent visits are calculated based on Visit 2/Day 1. 
Note: Visit 5 is the end of the Titration Period and start of the Maintenance Period. Visit 9 is the end of the Maintenance Period and the start of the Taper Period. 
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Clinical Study Protocol Amendment 2 
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RL0007 
 
 
 
Confidential 
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Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
 
V5 
 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22 
D90 
(M3) 
D180 
(M6) 
D270 
(M9) 
D360 
(M12) 
 
 
Note: The visit window for Screening is ±3 days relative to Day -4. The visit window for Titration Visits is ±3 days relative to Visit 2/Day 1 (day of first dose). 
The visit window for visits during the Maintenance Period, including the End of Maintenance Visit, is ±14 days relative to Visit 5. The Taper Period, which will 
last up to a maximum of 4 days, will start after the End of Maintenance Visit (Visit 9). 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.  
a Subjects who are down-titrated during the Titration Period will automatically enter the Maintenance Period. Subjects are allowed to be up-titrated and 
down-titrated at the discretion of the investigator during the Maintenance Period. 
b All subjects are required to complete the SFU Visit 30 days ±5 days after the final patch removal (end of the Taper Period). 
c Assessments for Visit 1 of RL0007 should be performed on the same day as the evaluation in the previous rotigotine study (Visit 9 of SP1006).  
d Taper Period de-escalation study medication will be part of the IMP that will be shipped with Visit 8. 
e Required if an AE is the reason for the Unscheduled Visit. 
f May be performed at the subject’s/legal representative’s home, excluding temperature and respiration rate, by the subject/legal representative if mobile study 
personnel are not able to be physically present at the home. 
g Assessments to be performed are at the investigator’s discretion. 
h From Visit 10 of SP1006, if available. If not available from Visit 10 of SP1006, should be collected within 2 weeks of that visit in SP1006. 
i Study medication to be shipped to subject’s home to be available no later than this date. 
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Clinical Study Protocol Amendment 2 
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5.3 
Rationale for study design and selection of dose 
This study will gather data on the long-term safety, tolerability, and efficacy of rotigotine 
transdermal system in adolescents with idiopathic RLS, allowing subjects from a prior study of 
rotigotine in adolescents with RLS (SP1006) to continue to receive rotigotine for approximately 
13 months. The safety and efficacy data collected in this study are expected to provide valuable 
information on rotigotine treatment of adolescents with RLS and support fulfillment of the 
Pediatric Research Equity Act requirements associated with development of rotigotine in the 
RLS indication. 
Restless Legs Syndrome has a prevalence of about 2% in the pediatric population, with 25% of 
affected children and 50% of affected teenagers reporting moderate to severe symptoms 
(Pichietti et al, 2007). The etiology of RLS in children is currently poorly understood and 
diagnosis in young children (<13 years old) may be especially challenging due to their relative 
inability to describe typical RLS symptoms or because symptoms may not be manifest at young 
ages (Simakajornboon et al, 2009). Dopaminergic agents are the first choice treatment for RLS in 
adults; however, to date, no treatment for RLS has been approved for children. Although there is 
limited information on dopaminergic medications in children, small published reports suggest the 
effectiveness of dopamine agonists in the management of RLS in children (Simakajornboon et al, 
2009). Rotigotine, a D3/D2/D1 receptor agonist, has been approved for the treatment of RLS 
symptoms in adults in the EU and in the US. Adolescents with RLS may benefit from treatment 
with rotigotine and administration as a patch formulation may increase the acceptance of 
medication in this group of subjects. 
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: 
1. An Institutional Review Board (IRB)-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 all questionnaires and diaries), visit schedule, or 
medication intake according to the judgment of the investigator. 
3. Subject weighs ≥40kg. 
4. Subject has completed at least one dose step in SP1006, a previous study of rotigotine in 
adolescents with RLS, without meeting withdrawal criteria. 
5. 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 drug. 
6. Subject is expected to benefit from participation, in the opinion of the investigator. 
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6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject is experiencing an ongoing serious AE (SAE) that is assessed to be related to 
rotigotine by the investigator or Sponsor. 
2a.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 Columbia-Suicide Severity 
Rating Scale (C-SSRS) at the final evaluation visit of the previous rotigotine study (ie, 
Visit 9 of SP1006). 
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 an illness 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. Subject takes prohibited concomitant medications as defined in this protocol. 
4. Subject or parent(s)/legal representative withdraws his/her consent. 
5. The investigator feels that it is in the subject’s best interest to be withdrawn. 
6. Subject is unwilling to manage the application and removal of patches at any time during the 
study. 
7. The subject develops clinically relevant symptomatic orthostatic hypotension. 
8. 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. 
9. The subject has a QTc interval ≥500ms or a QTc interval which has increased by ≥60ms as 
compared to the QTc interval taken at Baseline of SP1006 (Visit 2/Day 0) of the subject’s 
previous study. Bazett’s method must be used for correction of QT intervals. 
10. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
11. The Sponsor or a regulatory agency requests withdrawal of the subject. 
12. 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 staff should attempt to obtain information on subjects in the case of 
withdrawal or discontinuation. For subjects considered lost to follow up, the 
investigator/designated 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 
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Clinical Study Protocol Amendment 2 
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evaluations and observations, together with a narrative description of the reason(s) for removing 
the subject, must be recorded in the source documents. The electronic Case Report form (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%). 
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. 
7 
STUDY TREATMENT 
7.1 
Description of investigational medicinal product 
Table 7‒1 provides summary information regarding the products that will be used in this study. 
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Clinical Study Protocol Amendment 2 
Rotigotine 
RL0007 
 
 
 
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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 
3 
15 
Supplier 
UCB Clinical Trial Supply Group 
 
7.2 
Treatments to be administered 
7.2.1 
Titration Period 
The study will begin with a Titration Period of up to 3 weeks (at maximum) with the aim of 
achieving the individually optimized dosage (with a maximum dose of 3mg/24h). 
Subjects will be treated at Visit 1 using the following dose titration schedule until their optimal 
dose is reached (Table 7‒2). 
Table 7‒2: 
Dose titration schedule until optimal dose is reached 
Visit/Day 
Dose 
Visit 2/Day 1 
1mg/24h  
Visit 3/Day 8 
2mg/24h 
Visit 4/Day 15 
3mg/24h 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose prior to completing the scheduled assessments for that visit. Subjects who 
have reached their optimal dose should continue at that dose and remain in the Titration Period 
until they have reached Visit 5 and enter the Maintenance Period. Subjects are allowed to be up-
titrated and down-titrated at the discretion of the investigator during the Maintenance Period.  
The optimal dose for each subject will be defined as absence of or maximal reduction in RLS 
symptoms without intolerable side effects. If the investigator judges that the subject is likely to 
benefit from a dose increase, then dose titration should continue. If the investigator judges that 
the subject is unlikely to benefit from a dose increase, then the dose is defined as optimal. 
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 down-titrated to 
their previous dose level and continue at that dose until they reach Visit 5 and enter the 
Maintenance Period.  
7.2.2 
Maintenance Period 
Titration will be followed by a Maintenance Period of up to 1 year. Dose adjustment of 
rotigotine is allowed at any time during the Maintenance Period, based on clinical judgment, up 
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Clinical Study Protocol Amendment 2 
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to a maximum dose of 3mg/24h. 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 SFU Period. 
7.2.3 
Taper Period 
After the EoM/Withdrawal Visit, subjects will enter a Taper Period up to a maximum of 4 days. 
Based on the final maintenance dose, subjects will begin dose de-escalation by 1 dose level every 
2 days (Table 7‒3). 
Table 7‒3: 
Taper de-escalation schedule 
Final maintenance dose 
Day 1/Day 2 
Day 3/Day 4 
3mg/24h 
2mg/24h 
1mg/24h 
2mg/24h 
1mg/24h 
0 
1mg/24h 
0 
0 
7.2.4 
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/legal representative) as 
needed, should apply the patch at approximately the same time each day. 
• The patch should be worn continuously for 24 hours. After 24 hours, the patch should be 
removed and a new one applied immediately. 
• 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. 
• 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/legal representatives) should wash their hands 
with soap and water immediately after handling the patch. 
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7.2.5 
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/legal representative should tell their investigator. 
7.2.6 
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, 
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. 
• 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. 
• The parent/legal representative 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. 
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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. 
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 parent/legal representative 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), 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. 
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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. 
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 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 parent/legal representative 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) 
No concomitant medications are prohibited during the study. 
7.8.3 
Rescue medication 
Not applicable.  
7.9 
Blinding 
This is an open-label study. 
7.10 
Randomization and numbering of subjects 
To enroll a subject at Visit 1, the investigator (or designee) will call the IRT and provide brief 
details about the subject to be enrolled. Each subject will maintain their 5-digit subject number 
assigned at Visit 1 of their previous RLS study (SP1006). The subject number will be required in 
all communication between the investigator (or designee) and the IRT regarding a particular 
subject. The investigator (or designee) will be given the kit number to be dispensed to the 
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subject. The IRT will allocate kit numbers based on subject number during the course of the 
study. Subject numbers and kit numbers will be tracked via the IRT throughout the study.  
8 
STUDY PROCEDURES BY VISIT  
8.1 
Visit 1 (Screening/Day -4)  
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 and which complies with regulatory 
requirements. 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 and parent/legal representative will be given the opportunity to ask the investigator any 
questions regarding potential risks and benefits of participation in the study. 
Assessments for Visit 1 of RL0007 should be performed on the same day as the final evaluation 
visit of the previous rotigotine study (Visit 9 of SP1006). 
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. 
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:  
• Reproductive potential and birth control 
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 study medication kit numbers for the Titration Period.  
8.2 
Titration Period 
The visit window for the Titration Period is ±3 days relative to Visit 2 (day of first dose). The 
Titration Period starts at Visit 2/Day 1 and ends at Visit 5/Day 22. 
8.2.1 
Visit 2 (Day 1) 
Subjects will be contacted via telemedicine call. The following assessments will be performed: 
• Demographics 
• Eligibility criteria 
• Withdrawal criteria 
• C-SSRS (Since Last Visit version) 
Additional assessments and procedures are listed below. 
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• Recording of medication and procedures: See Section 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Dispense study medication. Study medication for the Titration Period will be shipped to the 
subject’s/legal representative’s home/preferred address to be available for the first dose of 
study medication in RL0007 at Visit 2/Day 1. See Section 7.5 for the description of the 
direct-to-subject shipment process for the remote study model. 
8.2.2 
Visit 3 and Visit 4 (Day 8 and Day 15) 
Subjects will be contacted via telemedicine call. The following assessments will be performed: 
• Withdrawal criteria 
• C-SSRS (Since Last Visit version) 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures: See Section 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Return 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. 
8.2.3 
Visit 5 (Day 22) 
The Titration Period ends at Visit 5.  
Information and procedures listed below will be collected/completed by the investigator and/or 
study staff, as appropriate, via a telephone/telemedicine call with the subject/legal representative. 
• Withdrawal criteria 
• Reproductive potential and birth control 
• Menstrual function for all female subjects 
• Telemedicine neurological examination 
The assessments listed below will be completed by the subject/subject’s legal representative’s 
local health provider or mobile study personnel will be sent to the subject’s/legal representative’s 
home. Records of the procedures will be obtained, with information noted as part of the subject’s 
study record. 
• 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 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 drug screen 
• 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 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted to obtain study medication kit numbers for the 
Maintenance Period. 
• Dispense study medication. Study medication for Visit 5 will be shipped to the 
subject’s/legal representative’s home/preferred address to be available for that visit. See 
Section 7.5 for the description of the direct-to-subject shipment process for the remote study 
model. 
• Return unused study medication. See Section 8.2.2. 
8.3 
Maintenance Period  
The Maintenance Period starts at Visit 5 and ends at Visit 9. 
8.3.1 
Visit 6 (Month 3) 
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 
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• Reproductive potential and birth control 
• Telemedicine neurological examination 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
• Vital signs  
• Urine pregnancy test for all female subjects  
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 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Dispense study medication. Study medication for Visit 6 will be shipped to the 
subject’s/legal representative’s home/preferred address to be available for that visit. See 
Section 7.5 for the description of the direct-to-subject shipment process for the remote study 
model. 
• Return unused study medication. See Section 8.2.2. 
8.3.2 
Visit 7 (Month 6) 
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 
• Reproductive potential and birth control 
• Menstrual function for all female subjects 
• Telemedicine neurological examination 
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. 
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• Vital signs 
• Body weight, height, and BMI 
• Safety laboratory tests 
• Urine drug screen 
• Urine pregnancy test for all female subjects 
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 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Dispense study medication. Study medication for Visit 7 will be shipped to the 
subject’s/legal representative’s home/preferred address to be available for that visit. See 
Section 7.5 for the description of the direct-to-subject shipment process for the remote study 
model. 
• Return unused study medication. See Section 8.2.2.  
8.3.3 
Visit 8 (Month 9) 
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 
• Reproductive potential and birth control 
• Telemedicine neurological examination 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
• Vital signs  
• Urine pregnancy test for all female subjects  
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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 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Dispense study medication. Study medication for Visit 8 will be shipped to the 
subject’s/legal representative’s home/preferred address to be available for that visit. See 
Section 7.5 for the description of the direct-to-subject shipment process for the remote study 
model. 
• Return unused study medication. See Section 8.2.2. 
8.3.4 
Visit 9/ End of Maintenance Visit (Month 12) 
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 
• Reproductive potential and birth control 
• Menstrual function for all female subjects 
The assessments listed below will be completed by the subject/subject’s/legal representative’s 
local healthcare provider or mobile study personnel will be sent to the subject’s/legal 
representative’s home. Records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination 
• Body weight, height, and BMI 
• Vital signs 
• Neurological examination 
• 12-lead ECG 
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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 
• 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 8.1.  
• AE assessment: See Section 8.1.  
• Contact IRT: The IRT will be contacted. 
• Dispense study medication. Study medication for the Taper Period will be shipped to the 
subject’s/legal representative’s home/preferred address to be available by Visit 9. 
See Section 7.5 for the description of the direct-to-subject shipment process for the remote 
study model.  
• Return unused study medication. See Section 8.2.2. 
8.4 
Taper Period 
The Taper Period, which will last up to a maximum of 4 days, will start after the subject has 
completed the EoM Visit (Visit 9). Taper Period de-escalation study medication will be part of 
the IMP that will be shipped with Visit 8. 
8.5 
Safety Follow-up Visit  
The visit window for SFU Period is 30 days ±5 days relative to the end of the Taper Period. 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
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• Urine pregnancy test for all female subjects 
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. 
• Telemedicine neurological examination 
• C-SSRS (Since Last Visit version) 
Additional assessments and procedures are listed below. 
• Recording of medication and procedures. See Section 8.1.  
• AE assessment. See Section 8.1.  
• Contact IRT. The IRT is contacted to process the subject’s completion of the study. 
• Return unused study medication. See Section 8.2.2. 
8.6 
Withdrawal Visit 
Procedures for a withdrawal visit are the same as for the EoM Visit (Visit 9/Month 12). 
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.  
• Withdrawal criteria 
• Menstrual function for female subjects 
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 
• Telemedicine neurological examination 
• 12-lead ECG 
For lab collections listed below, mobile study personnel may 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 pregnancy test for female subjects 
• Hormone status 
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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 8.1. 
• AE assessment. See Section 8.1. 
• 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 8.2.2. 
9 
ASSESSMENT OF EFFICACY 
Refer to Table 5-1 for timings of all efficacy assessments. 
9.1 
International Restless Legs Rating Scale 
The IRLS will be performed at Visit 6 and subsequent visits through 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) 
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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.  
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: 
• IRLS responder: A relative reduction in IRLS total score in percentage points at the EoM 
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 Visit 6 and subsequent visits 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. 
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. 
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9.3 
RLS-6 
The RLS-6 will be performed at Visit 6 and subsequent visits 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. 
Post-baseline missing values will not be imputed. 
9.4 
Subject Quality of Life Questionnaire 
The RLS-QoL will be performed at Visit 8 and subsequent visits through 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 through Visit 9 (refer to Table 5-1 for timing of PK assessments). The sampling time 
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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 
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, 
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. Adverse events present at Visit 9 for 
SP1006 will have to be recorded for RL0007 since this is Visit 1 and the start of this study. 
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. 
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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 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria 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, important medical event]. 
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. 
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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. 
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 
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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. 
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 Investigator 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 
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. 
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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: 
• The subject should return for an early discontinuation visit. 
• The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the early discontinuation visit.  
• A SFU 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 
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 and should be 
available in the Investigator Site File. In case of questions about the consent process, the 
investigator may contact the UCB/contract research organization (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 a serious adverse event (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. 
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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 will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the 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 following laboratory parameters 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 
 
Prolactin 
Ketones 
 
Testosteronec 
Urine pregnancy testa 
 
T3 
 
 
T4FR 
 
 
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; T4FR=free thyroxine; TSH=thyroid-stimulating 
hormone 
a Females only 
b With differential 
c Males only 
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 
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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 11‒4 (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 
 
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  
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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) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
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Table 11‒5: PDILI information to be collected 
New or updated information 
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 body systems may be performed when mobile study personnel 
are present. 
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The neurological examination may be performed when mobile study personnel are present and 
may include assessment of mental status, cranial nerves, plantar reflexes, deep tendon reflexes, 
muscle strength, gait, coordination/balance, involuntary movements, and sensory perception. 
The telemedicine neurological examination may include assessment of mental status, gait, and 
coordination/balance. 
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], free thyroxine [T4FR], 
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 
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occur during the study. The C-SSRS will be completed according to the tabular schedule of study 
assessments (see Table 5-1). 
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, 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 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. 
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 (ink, typing, printing, 
optical disc). Photocopies and/or printouts of eCRFs are not considered acceptable source 
documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Source documents that are computer generated and stored electronically must be 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 
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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 files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the CRF 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 in 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 in the subject’s medical 
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 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 (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 
Trial Master File. 
12.6 
Audit and inspection 
The investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic 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/investigational device have been processed and reported in compliance with the planned 
arrangements, the protocol, investigational site, and IRB 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. 
13.1 
Definition of analysis sets 
• Safety Set (SS): all subjects who have at least 1 patch (rotigotine) applied. This analysis set 
will be used for all analyses. 
13.2 
General 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 efficacy variables 
Summary statistics will be provided for the efficacy variables by final dose or if applicable, the 
dose most frequently administrated to the subject. 
The number of subjects (n), arithmetic mean, standard deviation, median, minimum, and 
maximum will be provided for all visits for IRLS and RLS-6. Baseline for IRLS and RLS-6 is 
defined as the last assessment before first dosing in the previous RLS study of rotigotine 
(SP1006). 
Frequency tables will be provided for the CGI Item 1 by visit. Additionally, the changes from 
Baseline will be tabulated for CGI Item 1 by dose. No imputation rules will be applied.  
Baseline for CGI Item 1 is defined as last assessment before first dosing in the previous RLS 
study of rotigotine (SP1006). 
In order to evaluate the impact of total duration of exposure, results for efficacy variables will 
also be presented by categories of total duration of exposure, including exposure from SP1006. 
13.4 
Planned safety and other analyses 
13.4.1 
Safety analyses 
All safety data will be analyzed for the SS. In general, Baseline is defined as the last assessment 
before first dosing in the previous study of rotigotine, SP1006.  
Safety variables will be analyzed in a descriptive way. Results will be presented overall.  
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Individual listings of AEs (age, body height, body weight, race, gender, system organ class 
[SOC]), and preferred term according to the Medical Dictionary for Regulatory Activities 
[MedDRA®], AE as reported, start and end with relative days to study medication administration, 
duration, intensity, seriousness, and relationship to study medication, action taken and final 
outcome) will be provided. The start and stop of each AE will be given as absolute and relative 
to the time of patch application. In addition, listings for subjects with SAEs, AEs leading to 
discontinuation, and other significant AEs will be provided. 
The incidence of treatment-emergent AEs will be summarized in frequency tables by actual dose 
at the start of the event, modal dose, and intensity, ordered by primary SOC, high level term, and 
PTs. The incidence of drug-related AEs will be described in the same way. Frequency tables for 
withdrawals due to AEs by last dose and by modal dose will be provided. 
13.4.2 
Other analyses 
Summary statistics will be provided for the laboratory data, menstrual function, mMIDI, vital 
signs, body weight, height, BMI, ECG, and neurological examination findings. 
Plasma concentration of unconjugated rotigotine will be summarized by dose levels and visit. In 
addition, these concentrations may be used for population PK-PD analyses. 
In order to evaluate the impact of total duration of exposure, results for safety variables will also 
be presented by categories of total duration of exposure. Appropriate categories for duration of 
exposure are data driven and will be defined during data analysis. 
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 key safety 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. 
13.6 
Handling of dropouts or missing data 
In general, data will be analyzed as observed, however for subjects who prematurely withdraw 
for any reason, data collected during the Withdrawal Visit will be used to impute measurements 
at the next planned visit. 
13.7 
Planned interim analysis and data monitoring 
Due to the single-arm, open-label design of this study, no formal interim analysis is planned. 
However, interim database locks may be performed to allow safety and efficacy analyses in 
support of submission activities or to allow optimization of the development program. 
13.8 
Determination of sample size 
No formal sample size calculation was performed for this study. Initially, a maximum of 
138 subjects from a prior study (SP1006) are expected to participate in the current study, based 
on the assumption that all planned subjects from SP1006 will roll-over into the present study. 
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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. 
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 legal representative). 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 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 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. 
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14.3 
Institutional Review Boards  
The study will be conducted under the auspices of an IRB, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The investigator/UCB will ensure that an appropriately constituted IRB 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 for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB for the protocol. 
The investigator will also promptly report to the IRB 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 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 as allowed. 
As part of the IRB requirements for continuing review of approved studies, the investigator will 
be responsible for submitting periodic progress reports to the IRB (based on IRB 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 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 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 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 in previous study SP1006. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB, 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, 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. 
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.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. 
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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 amendment was to remove visits by the subjects/legal representatives 
to their local healthcare provider or to national Patient Service Centers for various lab collections 
and designated study procedures.  
Other changes included in this amendment are as follows: 
• Sponsor contact information has been updated. 
• Clarified primary safety variables and other safety variables.  
• Changed the heading Key efficacy variables to Secondary efficacy variables, and clarified 
that there are no primary efficacy variables. 
• Clarified the definition of neurological examination.  
• Clarified Titration Period dose titration schedule and entry into Maintenance Period. 
• Typographic errors and changes of an editorial nature were made. 
 
Modifications and changes 
Global changes 
The following change was made throughout the protocol: 
• Changed eC-SSRS to C-SSRS 
Specific changes 
Change #1 
Study contact information 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH  
Alfred-Nobel-Strasse 10, 40789 Monheim, Germany 
Phone: 
 
Email: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES Inc. 
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8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
Email: 
 
Clinical Trial Biostatistician 
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 Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
Email: 
 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
Email: 
 
 
Clinical Trial Biostatistician 
Name: 
 
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Address: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
 
Change #2 
Section 1, Summary 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose (with a maximum dose of 3mg/24h) prior to completing the scheduled 
assessments for that visit. Subjects who have reached their optimal dose should proceed to the 
Maintenance Period (Visit 5) and complete those assessments. 
Has been changed to: 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose (with a maximum dose of 3mg/24h) prior to completing the scheduled 
assessments for that visit. Subjects who have reached their optimal dose will maintain that dose 
and complete the Titration Period without titrating to the next higher dose. 
 
Change #3 
Section 2, Introduction 
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 Network Oriented Research Assistant (NORA®), which is the 
backbone of the studies conducted via this model. NORA 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, 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: 
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 Network Oriented Research Assistant (NORA®), which is the 
backbone of the studies conducted via this model. NORA is the software interface that connects 
subjects/legal representatives to their investigators/study teams through a study-issued 
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smartphone. This technology will be used in combination with visits from mobile study 
personnel to subjects’/legal representatives’ homes. 
 
Change #4 
Section 4, Study variables 
The following text was added: Baseline values from SP1006 will serve as Baseline in RL0007. 
 
Change #5 
Section 4.1.1, Primary safety variables 
• AEs 
• Withdrawals due to AEs 
Has been changed to: 
• Occurrence of treatment-emergent adverse events (TEAEs) 
• Treatment-emergent adverse events leading to permanent withdrawal of study medication 
 
Change #6 
Section 4.1.2, Other safety variables 
• Changes from Baseline in body weight, height, and BMI 
Has been changed to: 
• Changes from Screening in body weight, height, and BMI 
 
Change #7 
Section 4.1.2, Key efficacy variables 
4.1.2, Key efficacy variables 
• Changes from Baseline in IRLS sum score at Visit 9 
• Changes from Baseline in CGI Item 1 at Visit 9 
• Changes from Baseline in RLS-6 at Visit 9 
Has been changed to: 
4.1.2, Secondary efficacy variables 
• Changes from Baseline in IRLS sum score at Visit 9 
• Changes from Baseline in CGI Item 1 at Visit 9 
• Changes from Baseline in RLS-6 at Visit 9 
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There are no primary efficacy variables. 
 
Change #8 
Section 5.1, Study design 
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. Subjects 
who are back-titrated during the Titration Period will automatically enter the Maintenance 
Period. Subjects are allowed to be up-titrated and down-titrated at the discretion of the 
investigator during the Maintenance Period. 
The study will begin with a Titration Period of up to 3 weeks (at maximum) with the aim of 
achieving the individually optimized dosage. During the Titration Period, investigators should 
determine at each visit whether the subject has reached his or her optimal dose prior to 
completing the scheduled assessments. Once subjects have reached their optimal dose, they 
should proceed to Maintenance Period (Visit 5) and complete those assessments. 
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 will visit subjects’/legal 
representatives’ homes to complete certain study procedures (eg, neurological exams, physical 
exams, ECGs, lab collections, and vital signs). Subjects are allowed to be up-titrated and 
down-titrated at the discretion of the investigator during the Maintenance Period. 
The study will begin with a Titration Period of 3 weeks with the aim of achieving the 
individually optimized dosage. During the Titration Period, investigators should determine at 
each visit whether the subject has reached his or her optimal dose prior to completing the 
scheduled assessments. Once subjects have reached their optimal dose, they will maintain that 
dose and complete the Titration Period without titrating to the next higher dose. 
  
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Change #9 
Section 5.2, Schedule of study activities 
Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22  
M3 
M6 
M9 
M12 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Return unused study 
medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
AE=adverse event; BMI=Body Mass Index; CGI=Clinical Global Impressions; D=Day; ECG=electrocardiogram; eC-SSRS=electronic Columbia-Suicide Severity 
Rating Scale; EoM=End of Maintenance; EoT=End of Taper; hCG=human chorionic gonadotropin; IRLS=International Restless Legs Rating Scale; 
IRT=interactive response technology; lab=laboratory; M=Month; mMIDI=modified Minnesota Impulsive Disorder Interview; PK=pharmacokinetic; 
RLS=Restless Legs Syndrome; SC=Screening; SFU=Safety Follow-Up; SoM=Start of Maintenance; V=Visit; WD=withdrawal 
Note: 1 month=30 days. 
Note: It is preferred that a subject directly continue from SP1006 into RL0007; however, if a subject cannot directly continue into RL0007, the subject has until the 
SFU Visit of SP1006 to enroll in RL0007.  
Note: Visit 1 should occur 4 days prior to Visit 2/Day 1 to allow for direct-to-subject shipment of study medication. Visit 2/Day 1 is the first day of study 
medication exposure. All subsequent visits are calculated based on Visit 2/Day 1. 
Note: Visit 5 is the end of the Titration Period and start of the Maintenance Period. Visit 9 is the end of the Maintenance Period and the start of the Taper Period. 
Note: The visit window for Screening is ±3 days relative to Day -4. The visit window for Titration Visits is ±3 days relative to Visit 2/Day 1 (day of first dose). 
The visit window for visits during the Maintenance Period, including the End of Maintenance Visit, is ±14 days relative to Visit 5. The Taper Period, which will 
last up to a maximum of 4 days, will start after the End of Maintenance Visit (Visit 9). 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.  
a Subjects who are back-titrated during the Titration Period will automatically enter the Maintenance Period. Subjects are allowed to be up-titrated and 
down-titrated at the discretion of the investigator during the Maintenance Period. 
b All subjects are required to complete the SFU Visit 30 days ±5 days after the final patch removal (end of the Taper Period). 
c Assessments for Visit 1 of RL0007 should be performed on the same day as the evaluation in the previous rotigotine study (Visit 9 of SP1006).  
d Taper Period de-escalation study medication will be shipped to the subject’s/legal respresentative’s home/preferred address to be available by this visit. 
e Required if an AE is the reason for the Unscheduled Visit. 
f May be performed at the subject’s/legal representative’s home. 
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Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22  
M3 
M6 
M9 
M12 
 
 
g Assessments to be performed are at the investigator’s discretion. 
h From Visit 10 of SP1006, if available. If not available from Visit 10 of SP1006, should be collected within 2 weeks of that visit in SP1006. 
i Study medication to be shipped to subject’s home to be available no later than this date. 
Has been changed to: 
Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22  
D90 
(M3) 
D180 
(M6) 
D270 
(M9) 
D360 
(M12 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Return unused study 
medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
AE=adverse event; BMI=Body Mass Index; CGI=Clinical Global Impressions; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; 
ECG=electrocardiogram; EoM=End of Maintenance; EoT=End of Taper; hCG=human chorionic gonadotropin; IMP=investigational medicinal product; 
IRLS=International Restless Legs Rating Scale; IRT=interactive response technology; lab=laboratory; M=Month; mMIDI=modified Minnesota Impulsive 
Disorder Interview; PK=pharmacokinetic; RLS=Restless Legs Syndrome; SC=Screening; SFU=Safety Follow-Up; SoM=Start of Maintenance; V=Visit; 
WD=withdrawal 
Note: It is preferred that a subject directly continue from SP1006 into RL0007; however, if a subject cannot directly continue into RL0007, the subject has until the 
SFU Visit of SP1006 to enroll in RL0007.  
Note: Visit 1 should occur 4 days prior to Visit 2/Day 1 to allow for direct-to-subject shipment of study medication. Visit 2/Day 1 is the first day of study 
medication exposure. All subsequent visits are calculated based on Visit 2/Day 1. 
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Table 5-1: 
Schedule of study assessments 
 
SC 
(±3 days) 
 
Titration Perioda 
 
 
Maintenance Period 
Year 1a 
 
SFUb 
(30±5 days) 
Unscheduled 
Visit 
Visit 
V1c 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9d 
 
Day/Month 
D-4 
D1 
D8 
D15 
D22  
D90 
(M3) 
D180 
(M6) 
D270 
(M9) 
D360 
(M12 
 
 
Note: Visit 5 is the end of the Titration Period and start of the Maintenance Period. Visit 9 is the end of the Maintenance Period and the start of the Taper Period. 
Note: The visit window for Screening is ±3 days relative to Day -4. The visit window for Titration Visits is ±3 days relative to Visit 2/Day 1 (day of first dose). 
The visit window for visits during the Maintenance Period, including the End of Maintenance Visit, is ±14 days relative to Visit 5. The Taper Period, which will 
last up to a maximum of 4 days, will start after the End of Maintenance Visit (Visit 9). 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.  
a Subjects who are down-titrated during the Titration Period will automatically enter the Maintenance Period. Subjects are allowed to be up-titrated and 
down-titrated at the discretion of the investigator during the Maintenance Period. 
b All subjects are required to complete the SFU Visit 30 days ±5 days after the final patch removal (end of the Taper Period). 
c Assessments for Visit 1 of RL0007 should be performed on the same day as the evaluation in the previous rotigotine study (Visit 9 of SP1006).  
d Taper Period de-escalation study medication will be part of the IMP that will be shipped with Visit 8. 
e Required if an AE is the reason for the Unscheduled Visit. 
f May be performed at the subject’s/legal representative’s home, excluding temperature and respiration rate, by the subject if mobile study personnel are not able to 
be physically present at the home. 
g Assessments to be performed are at the investigator’s discretion. 
h From Visit 10 of SP1006, if available. If not available from Visit 10 of SP1006, should be collected within 2 weeks of that visit in SP1006. 
i Study medication to be shipped to subject’s home to be available no later than this date. 
 
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Change #10 
Section 6.2, Exclusion criterion #2 
2. 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 electronic Columbia 
Suicide Severity Rating Scale (eC-SSRS) at the final evaluation visit of the previous 
rotigotine study (ie, Visit 10 of SP1006). 
Has been changed to: 
2a. 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 Columbia-Suicide Severity 
Rating Scale (C-SSRS) at the final evaluation visit of the previous rotigotine study (ie, 
Visit 9 of SP1006). 
 
Change #11 
Section 7.2.1, Titration Period 
Table 7-2: 
Dose titration schedule until optimal dose is reached 
Visit/Day 
Dose 
Visit 1/Day 1 
1mg/24h  
Visit 2/Day 8 
2mg/24h 
Visit 3/Day 15 
3mg/24h 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose prior to completing the scheduled assessments for that visit. Subjects who 
have reached their optimal dose should proceed to the Maintenance Period (Visit 5) and 
complete those assessments. Subjects who are back-titrated during the Titration Period will 
automatically enter the Maintenance Period. Subjects are allowed to be up-titrated and 
down-titrated at the discretion of the investigator during the Maintenance Period.  
The optimal dose for each subject will be defined as absence of or maximal reduction in RLS 
symptoms without intolerable side effects. If the investigator judges that the subject is likely to 
benefit from a dose increase, then dose titration should continue. If the investigator judges that 
the subject is unlikely to benefit from a dose increase, then the dose is defined as optimal, and 
the subject enters 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. 
Has been changed to: 
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Table 7-2: 
Dose titration schedule until optimal dose is reached 
Visit/Day 
Dose 
Visit 2/Day 1 
1mg/24h  
Visit 3/Day 8 
2mg/24h 
Visit 4/Day 15 
3mg/24h 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her optimal dose prior to completing the scheduled assessments for that visit. Subjects who 
have reached their optimal dose should continue at that dose and remain in the Titration Period 
until they have reached Visit 5 and enter the Maintenance Period. Subjects are allowed to be 
up-titrated and down-titrated at the discretion of the investigator during the Maintenance Period.  
The optimal dose for each subject will be defined as absence of or maximal reduction in RLS 
symptoms without intolerable side effects. If the investigator judges that the subject is likely to 
benefit from a dose increase, then dose titration should continue. If the investigator judges that 
the subject is unlikely to benefit from a dose increase, then the dose is defined as optimal. 
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 down-titrated to 
their previous dose level and continue at that dose until they reach Visit 5 and enter the 
Maintenance Period. 
 
Change #12 
Section 8.2, Titration Period 
The visit window for the Titration Period is ±3 days relative to Visit 2 (day of first dose). The 
Titration Period starts at Visit 2/Day 1 and ends at Visit 5/Day 22 or when the subject reaches 
his/her optimal dose. 
Has been changed to: 
The visit window for the Titration Period is ±3 days relative to Visit 2 (day of first dose). The 
Titration Period starts at Visit 2/Day 1 and ends at Visit 5/Day 22. 
 
Change #13 
Section 8.2.3, Visit 5 (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. 
Has been changed to: 
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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. 
 
Change #14 
Section 8.3, Maintenance Period 
The Maintenance Period starts at Visit 6 and ends at Visit 9. 
Has been changed to: 
The Maintenance Period starts at Visit 5 and ends at Visit 9. 
 
Change #15 
Section 8.3.1, Visit 6 (Month 3) 
For lab collections listed below, subjects/legal representatives will either visit their local Patient 
Service Center or healthcare practitioner, 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. 
• Vital signs (may be performed at the subject’s/legal representative’s home) 
• Urine pregnancy test for all female subjects (may be performed at the subject’s/legal 
representative’s home) 
Has been changed to: 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
• Vital signs  
• Urine pregnancy test for all female subjects  
 
Change #16 
Section 8.3.2, Visit 7 (Month 6) 
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. 
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. 
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Change #17 
Section 8.3.3, Visit 8 (Month 9) 
Lab collections listed below, subjects/legal representatives will either visit their local Patient 
Service Center or healthcare practitioner, 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. 
• Vital signs (may be performed at the subject’s/legal representative’s home) 
• Urine pregnancy test for all female subjects (may be performed at the subject’s/legal 
representative’s home) 
Has been changed to: 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
• Vital signs  
• Urine pregnancy test for all female subjects  
 
Change #18 
Section 8.3.4, Visit 9/End of Maintenance (Month 12) 
The assessments listed below will be completed by the subject/subject’s/legal representative’s 
local healthcare provider or mobile study personnel will be sent to the subject’s/legal 
representative’s home. Records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination 
• Body weight, height, and BMI 
• 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. 
Has been changed to: 
The assessments listed below will be completed by the subject/subject’s/legal representative’s 
local healthcare provider or mobile study personnel will be sent to the subject’s/legal 
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representative’s home. Records of the procedures will be obtained, with information noted as 
part of the subject’s study record. 
• Brief physical examination 
• Body weight, height, and BMI 
• Vital signs 
• Telemedicine 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. 
 
Change #19 
Section 8.4, Taper Period 
The Taper Period, which will last up to a maximum of 4 days, will start after the subject has 
completed the EoM Visit (Visit 9). The de-escalation study medication to be taken during the 
Taper Period will be shipped for receipt at the subject’s/legal representative’s home/preferred 
address by Visit 9. 
Has been changed to: 
The Taper Period, which will last up to a maximum of 4 days, will start after the subject has 
completed the EoM Visit (Visit 9). Taper Period de-escalation study medication will be part of 
the IMP that will be shipped with Visit 8.  
 
Change #20 
Section 8.5, Safety Follow-Up Visit 
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. 
Has been changed to: 
For lab collections listed below, samples will be collected at home by the subject/legal 
representative, and results will be provided to the study site. 
 
Change #21 
Section 8.7, Safety Follow-Up Visit 
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 
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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. 
Has been changed to: 
For lab collections and procedures listed below, mobile study personnel may 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. 
 
Change #22 
Sectoin 9.1, International Restless Legs Rating Scale 
The fifth paragraph:  
A minimum score of 15 points (moderate) is typically required for inclusion in a study at 
Baseline.  
Has been changed: 
A minimum score of 15 points (moderate) is typically required for inclusion in a study.  
 
Change #23 
Sectoin 9.2, Clinical Global Impression 
The fourth paragraph has been removed:  
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. 
 
Change #24 
Section 11.7.3, Physical and neurological examination 
A brief physical examination of body systems will be performed. 
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. 
Has been changed to: 
A brief physical examination of body systems may be performed when mobile study personnel 
are present. 
The neurological examination may be performed when mobile study personnel are present and 
may include assessment of mental status, cranial nerves, plantar reflexes, deep tendon reflexes, 
muscle strength, gait, coordination/balance, involuntary movements, and sensory perception. 
 
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Change #25 
Section 11.6, Laboratory measurements (Table 11-2) and Section 11.7.4, Hormone status 
Thyroxine [T4] 
Has been changed to: 
Free thyroxine [T4FR] 
 
Change #26 
Section 11.7.7, Assessment of suicidal ideation and behavior 
Suicidal ideation and behavior will be assessed by trained study personnel using the eC-SSRS. 
This scale will be used for screening as well as to assess suicidal ideation and behavior that may 
occur during the study. The eC-SSRS will be completed according to the tabular schedule of 
study assessments (see Table 5-1). 
Has been changed to: 
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). 
 
Change #27 
Section 13.3.1, Analysis of the efficacy variables 
The first and fifth paragraphs: 
Summary statistics will be provided for the efficacy variables by dose. 
In order to evaluate the impact of total duration of exposure, results for efficacy variables will 
also be presented by categories of total duration of exposure. 
Have been changed to: 
Summary statistics will be provided for the efficacy variables by final dose or if applicable, the 
dose most frequently administrated to the subject. 
In order to evaluate the impact of total duration of exposure, results for efficacy variables will 
also be presented by categories of total duration of exposure, including exposure from SP1006. 
 
Change #28 
Section 13.6, Handling of dropouts or missing data 
In general, data will be analyzed as observed, however for subjects who prematurely withdraw 
for any reason, data collected during the Withdrawal Visit will be used to impute measurements 
at the next consecutive visit. 
Has been changed to: 
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In general, data will be analyzed as observed, however for subjects who prematurely withdraw 
for any reason, data collected during the Withdrawal Visit will be used to impute measurements 
at the next planned visit. 
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17.2 
Protocol Amendment 2 
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 (SP1006). 
• Typographic errors were corrected. 
 
Modifications and changes 
Global changes 
The following change was 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: 
 
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Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
Email: 
 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
Email: 
 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive  
Raleigh, NC 27617 
USA 
Phone: 
 
 
Email: 
 
 
Has been changed to: 
Sponsor 
UCB Biopharma SRL, Allée de la Recherche 60, 1070 Brussels, BELGIUM 
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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: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Biosciences Inc. 
4000 Paramount Parkway, 
  
Morrisville, NC 27560 
USA 
Phone: 
 
Email: 
 
 
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Change #2 
Section 4, Study variables 
Baseline values from SP1006 will serve as Baseline in RL0007. 
Has been changed to: 
Baseline values from SP1006 will serve as Baseline in RL0007. Baseline values for the other 
safety variables were collected at Visit 1 of SP1006. 
 
Change #3 
Section 4.1.2, Other safety variables  
• Changes from Baseline in 12-lead ECGs  
• Changes from Baseline in vital signs (including assessment of orthostasis)  
• Changes from Baseline in hormone status  
• Changes from Baseline in laboratory data (hematology, clinical chemistry, and urinalysis) 
• Changes from Baseline in menstrual function for all female subjects 
• Changes in mMIDI 
• Changes from Screening in body weight, height, and BMI 
Has been changed to: 
• Changes from Baseline (Visit 1, SP1006) in 12-lead ECGs  
• Changes from Baseline (Visit 1, SP1006) in vital signs (including assessment of orthostasis)  
• Changes from Baseline (Visit 1, SP1006) in hormone status  
• Changes from Baseline (Visit 1, SP1006) in laboratory data (hematology, clinical chemistry, 
and urinalysis) 
• Changes from Baseline in menstrual function for all female subjects 
• Changes in mMIDI  
• Changes from Baseline (Visit 1, SP1006) in body weight, height, and BMI 
 
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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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), 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), 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. 
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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 
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 2 
Rotigotine 
RL0007 
 
 
 
Confidential 
Page 82 of 83 
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 2 
Rotigotine 
RL0007 
 
 
 
Confidential 
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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:
rl0007-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000173921
Title:
RL0007 Protocol Amendment 2 - Phase 3, Open-Label
Approved Date:
03 May 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 30-Apr-2021 17:45:17 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 30-Apr-2021 19:15:43 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 03-May-2021 19:58:50 GMT+0000
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SAP_001.pdf: 
UCB 
  
25 APR 2023 
Statistical Analysis Plan 
Rotigotine 
RL0007 
 
 
 
Confidential 
Page 1 of 24 
 
  
STATISTICAL ANALYSIS PLAN  
Study: RL0007 
Product: Rotigotine 
A REMOTE, OPEN-LABEL, LONG-TERM FOLLOW-UP STUDY TO DETERMINE THE 
SAFETY, TOLERABILITY, AND EFFICACY OF ROTIGOTINE TRANSDERMAL 
SYSTEM AS MONOTHERAPY IN ADOLESCENTS WITH RESTLESS LEGS SYNDROME 
 
SAP/Amendment Number Date 
SAP 
06 Dec 2018 
SAP/1 
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 
RL0007 
 
 
 
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Page 2 of 24 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1 
INTRODUCTION ............................................................................................................. 6 
2 
PROTOCOL SUMMARY ................................................................................................. 6 
2.1 
Study objectives ............................................................................................................. 6 
2.1.1 
Efficacy variables .................................................................................................. 6 
2.1.1.1 
Secondary efficacy variables ....................................................................... 6 
2.1.1.2 
Other efficacy variables ............................................................................... 6 
2.1.2 
Safety variables ...................................................................................................... 6 
2.1.2.1 
Primary safety variables .............................................................................. 6 
2.1.2.2 
Other safety variables .................................................................................. 7 
2.1.3 
Other variables ....................................................................................................... 7 
2.2 
Study design and conduct .............................................................................................. 7 
2.3 
Determination of sample size ......................................................................................... 7 
3 
DATA ANALYSIS CONSIDERATIONS ........................................................................ 8 
3.1 
General presentation of summaries and analyses .......................................................... 8 
3.2 
General study level definitions ...................................................................................... 8 
3.2.1 
Analysis time points .............................................................................................. 8 
3.2.1.1 
Relative day ................................................................................................. 8 
3.2.1.2 
Date of last patch removal ........................................................................... 9 
3.2.2 
Study periods ......................................................................................................... 9 
3.2.3 
Visit mapping ....................................................................................................... 10 
3.3 
Definition of Baseline values ....................................................................................... 11 
3.4 
Protocol deviations....................................................................................................... 11 
3.5 
Analysis sets................................................................................................................. 11 
3.5.1 
Enrolled Set (ES) ................................................................................................. 11 
3.5.2 
Safety Set ............................................................................................................. 11 
3.5.3 
Pharmacokinetic Set ............................................................................................ 11 
3.6 
Treatment assignment and treatment groups ............................................................... 11 
3.7 
Center pooling strategy ................................................................................................ 12 
3.8 
Coding dictionaries ...................................................................................................... 12 
3.9 
Changes to protocol-defined analyses ......................................................................... 12 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 12 
4.1 
Adjustments for covariates .......................................................................................... 12 
4.2 
Handling of dropouts or missing data .......................................................................... 12 
4.2.1 
Missing efficacy data ........................................................................................... 12 
4.2.2 
Missing and Incomplete Dates for Adverse Events and Concomitant Medication12 
4.2.3 
General Imputation Rule for Incomplete Dates ................................................... 14 
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RL0007 
 
 
 
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5 
STUDY POPULATION CHARACTERISTICS ............................................................. 14 
5.1 
Subject disposition ....................................................................................................... 14 
5.2 
Protocol deviations....................................................................................................... 14 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 15 
6.1 
Demographics .............................................................................................................. 15 
6.2 
Other Baseline characteristics ...................................................................................... 15 
6.3 
Family medical history ................................................................................................ 15 
6.4 
Prior and concomitant medications .............................................................................. 15 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 16 
8 
EFFICACY ANALYSES ................................................................................................ 16 
8.1 
Statistical analysis of key efficacy variables ............................................................... 16 
8.1.1 
Derivations of key efficacy variables .................................................................. 16 
8.1.2 
Analysis of the key efficacy variables ................................................................. 16 
9 
PHARMACOKINETICS ................................................................................................. 16 
9.1 
Plasma concentration ................................................................................................... 16 
9.2 
Population Pharmacokinetics ....................................................................................... 17 
10 SAFETY ANALYSES ..................................................................................................... 17 
10.1 
Extent of exposure ....................................................................................................... 17 
10.2 
Adverse events ............................................................................................................. 17 
10.3 
Clinical laboratory evaluations .................................................................................... 18 
10.3.1 
Elevated liver function tests ................................................................................. 19 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 19 
10.4.1 
Vital signs ............................................................................................................ 19 
10.4.2 
Electrocardiograms .............................................................................................. 20 
10.4.3 
Modified Minnesota Impulsive Disorders Interview ........................................... 20 
10.4.4 
Physical and neurological examinations .............................................................. 20 
10.4.5 
Suicide ideation and behavior .............................................................................. 20 
11 OTHER ANALYSES ...................................................................................................... 20 
11.1 
Subject Quality of Life Questionnaire. ........................................................................ 20 
12 REFERENCES ................................................................................................................ 22 
13 APPENDICES ................................................................................................................. 23 
13.1 
Amendment 1 ............................................................................................................... 23 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 24 
 
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Statistical Analysis Plan 
Rotigotine 
RL0007 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ARDL 
actual Rotigotine dose level  
BMI 
body mass index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CGI 
Clinical Global Impressions 
eCRF 
electronic Case Report form 
ECG 
12-lead electrocardiograms 
EoM 
end of the Maintenance Period 
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 
PD 
pharmacodynamic 
PDILI 
potential drug induced liver injury 
PK 
pharmacokinetic 
PKS 
Pharmacokinetic Set 
PRD 
planned Rotigotine dose 
PRDL 
planned Rotigotine dose level 
PT 
preferred term 
RLS 
Restless Legs Syndrome 
RLS-6 
Restless Legs Syndrome - 6 Rating Scales 
RLS-QoL 
restless legs syndrome quality of life 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
SoM 
Start of Maintenance Period 
SS 
Safety Set 
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Rotigotine 
RL0007 
 
 
 
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T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Rotigotine 
RL0007 
 
 
 
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1 
INTRODUCTION 
This document contains details for the statistical analyses of study RL0007 supporting the 
clinical study report 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 SAP describes the statistical principles that are applied for the analyses as well as tables and 
listings that are foreseen for this study. Changes in the statistical methodology result in a 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 
The primary objective of this study is to assess the long-term safety and tolerability of rotigotine 
treatment in adolescents with idiopathic Restless Legs Syndrome (RLS). 
The secondary objective of this study is to assess the long-term efficacy of rotigotine treatment 
in adolescents with idiopathic RLS. 
2.1.1 
Efficacy variables 
2.1.1.1 
Secondary efficacy variables 
The key efficacy variables are change from Baseline at Visit 9 in International Restless Legs 
Rating Scale (IRLS) sum score, Clinical Global Impressions (CGI) Item 1 and Restless Legs-6 
Rating Scales (RLS-6): 
• Changes from Baseline in IRLS sum score at Visit 9 
• Changes from Baseline in CGI Item 1 at Visit 9 
• Changes from Baseline in RLS-6 at Visit 9 
2.1.1.2 
Other efficacy variables 
Other efficacy variables are: 
• Changes from Baseline in IRLS sum score at all visits except Visit 9 
• Changes from Baseline in CGI Item 1 at all visits except Visit 9 
• Changes from Baseline in RLS-6 at all visits except Visit 9 
2.1.2 
Safety variables 
2.1.2.1 
Primary safety variables 
The primary safety variables are: 
• Occurrence of treatment-emergent adverse events (TEAEs) 
• TEAEs leading to permanent withdrawal of study medication 
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Rotigotine 
RL0007 
 
 
 
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2.1.2.2 
Other safety variables 
Other safety variables are: 
• Changes from Baseline in 12-lead electrocardiograms (ECGs) 
• Changes from Baseline in vital signs (including orthostatic assessment)  
• Changes from Baseline in hormone status 
• Changes from Baseline in laboratory data (hematology, blood chemistry, and urinalysis) 
• Changes in menstrual function for all female subjects 
• Changes from Baseline in Modified Minnesota Impulsive Disorder Interview (mMIDI) 
• Changes from Baseline in body weight, height, and calculated body mass index (BMI)  
2.1.3 
Other variables 
Other variables are: 
• Plasma concentrations of unconjugated rotigotine 
• Subject Quality of Life Questionnaire 
2.2 
Study design and conduct 
This is a Phase 3, remote, open-label, LTFU study of monotherapy administration of the 
rotigotine transdermal system. Subjects entering this study from the previous rotigotine study in 
adolescents (SP1006) must have tolerated the first dose level of rotigotine in that study without 
meeting the withdrawal criteria. 
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. 
The study will begin with a Titration Period of up to 3 weeks (at maximum) with the aim of 
achieving the individually optimized dosage. During the Titration Period, investigators should 
determine at each visit whether the subject has reached his or her optimal dose prior to 
completing the scheduled assessments. Once subjects have reached their optimal dose, they 
should proceed to Maintenance Period (Visit 5) and complete those assessments.  
Titration will be followed by a Maintenance Period of up to 1 year. Dose adjustment of 
rotigotine is allowed at any time during the Maintenance Period, based on clinical judgment up 
to a maximum dose of 3mg/24h. At the End of Maintenance (EoM), subjects will enter a 4-day 
Taper Period followed by a 30-day Safety Follow-Up. 
Visits will be scheduled every week during the Titration Period, every 3 months for the 
Maintenance Period, and at the end of the Safety Follow-Up. 
2.3 
Determination of sample size 
No statistical sample size calculation was performed for this study. Initially, a maximum of 138 
subjects from a prior study (SP1006) are expected to participate in the current study, based on 
the assumption that all planned subjects from SP1006 will roll-over into the present study. 
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RL0007 
 
 
 
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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 
(eg, changes from Baseline) will be generated.  
Unless otherwise noted, all summaries will be displayed by the final dose group (rotigotine 
1mg/24h, rotigotine 2mg/24h and rotigotine 3mg/24h). The ‘final dose’ is the final titrated or 
back-titrated dose level administered at the start of the Maintenance Period. The ‘final dose’ for 
subjects who withdrew before the Maintenance Period is defined as the last dose taken. A 
summary with all dose groups combined (i.e., total column) will be presented for the 
demographic and Baseline characteristics, and for the prior and concomitant medications. 
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 optimal dose, 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: 
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RL0007 
 
 
 
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• 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. 
• 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, with less patches returned than dispensed, 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.  
• Titration Period:  
The Titration Period starts at the day of the first patch application and ends the day before the 
date of Visit 5. In case of a premature withdrawal before Visit 5, 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 is before the Withdrawal Visit, the Titration Period ends at the day of last 
patch removal. 
• Maintenance Period:  
The Maintenance Period starts at Visit 5 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, no Taper Period is defined for 
this subject. 
• Treatment Period:  
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RL0007 
 
 
 
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The Treatment Period comprises the Titration Period, the Maintenance Period, 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 last study assessment. However, AEs starting within 30 days following the 
date of last patch removal will be included for analysis, even if the start date is after the date 
of last study assessment. 
3.2.3 
Visit mapping 
The visits are planned for the follow days: 
Visit 
Day 
Visit Window 
Visit 1 (Screening) Day -4 to Day -1 
 
Visit 2, Day 1 
Day 1 
 
Visit 3, Day 8 
Day 8 
± 3 Days 
Visit 4, Day 15 
Day 15 
± 3 Days 
Visit 5 (SoM) 
Day 22 (or after reaching optimal 
dose) 
± 3 Days 
Visit 6 (Month 3) 
90 Day after SoM  
± 14 Days 
Visit 7(Month 6) 
180 Day after SoM 
± 14 Days 
Visit 8 (Month 9) 
270 Day after SoM 
± 14 Days 
Visit 9 (EoM) 
360 Day after SoM 
± 14 Days 
 
 
 
Safety Follow-Up 
30 Days after End of Taper Period 
± 5 Days 
During the Titration Period, the investigator should determine whether the subject has reached 
his/her final titrated dose level prior to completing the scheduled assessments for that visit. 
Subjects who have reached their final dose level should proceed to the Maintenance Period (Visit 
5) and complete those assessments. Subjects who are back-titrated during the Titration Period 
will automatically enter the Maintenance 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.  
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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 falls within the SAP defined visit windows shown above 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 as an unscheduled visit. 
3.3 
Definition of Baseline values 
Unless otherwise noted, baseline is defined as the last assessment before first dosing in the 
previous RLS study of rotigotine (SP1006). 
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 database lock. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set (ES) 
The ES will consist of all subjects with a signed informed consent form. 
3.5.2 
Safety Set 
The Safety Set (SS) will consist of all subjects who have at least one patch (rotigotine) applied. 
This analysis set will be used for all analyses except for the pharmacokinetic data. 
3.5.3 
Pharmacokinetic Set 
The Pharmacokinetic Set (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. 
3.6 
Treatment assignment and treatment groups 
Generally, all summaries/analyses will be performed using the final dose group, i.e., the starting 
dose of the maintenance period. In addition, some summaries/analyses will be present for longest 
dose or actual dose. 
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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 be not calculated. Missing 
IRLS baseline value will be regarded as an important protocol deviation. 
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 
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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.  
• Completely missing stop date: 
Adverse events with a completely missing stop date will be considered ongoing. 
Medications with a start date before the first patch application will be considered as prior and 
concomitant medications. Medications with a start date during the Treatment Period will be 
considered as concomitant medication. 
• Imputed stop date prior to imputed start date: 
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. 
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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. 
5 
STUDY POPULATION CHARACTERISTICS 
Study population characteristics will be summarized for the SS and by final dose group and all 
subjects combined. 
5.1 
Subject disposition 
Subject disposition will be presented 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 
• started the Maintenance Period (attended Visit 5) and either completed or withdrew 
(including reasons) during the Maintenance Period 
• started and completed the Taper Period, with reasons if applicable 
• and completed the Safety Follow-up Period or withdrew (including reasons) prior to the 
Safety Follow-up visit 
Subjects will be counted as completed study and maintenance period, if they don’t withdraw 
before EoM, and as completed titration, taper, and safety follow-up periods, if they don’t 
withdraw before the end of the respective period. 
Summaries will also be provided for discontinuations due to AEs and disposition of analysis sets. 
Reasons for screen failure will be listed. 
5.2 
Protocol deviations 
All important protocol deviations will be listed. 
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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: 
• 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) 
• 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). 
Baseline characteristics will be listed only. 
6.3 
Family medical history 
 Family medical history will be listed for cases where a potential drug-induced liver injury 
(PDILI) is reported. 
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 (in RL0007). 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. Medications starting prior to first patch application and continuing 
into the Treatment Period will be considered both prior and concomitant medication. 
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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 therapeutic 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 
All efficacy analyses will be performed for the SS and summarized by final dose group and all 
subjects combined. 
8.1 
Statistical analysis of key efficacy variables 
The key efficacy variables are the changes from Baseline at EoM (Visit 9) in IRLS sum score, 
CGI Item 1 and RLS-6, but will be presented and analyzed together with all other visits.  No 
imputation will be applied. 
8.1.1 
Derivations of key efficacy variables 
The IRLS consists of 10 questions, each using a 5-point scale ranging from 0=not present to 
4=severe. The IRLS sum score will be calculated by summing up the single scores of all 
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. 
The RLS-6 Rating Scales (Kohnen, 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) to 10 (completely dissatisfied). No sum score will be calculated. 
8.1.2 
Analysis of the key efficacy variables 
Summary statistics for observed values as well as changes from Baseline by visit will be 
provided for IRLS sum score, each subscale of the RLS-6 rating scales and CGI item 1. 
9 
PHARMACOKINETICS  
9.1 
Plasma concentration 
Plasma samples will be collected at Visit 5 and Visit 9.  The results of plasma concentrations of 
unconjugated rotigotine will be presented in a listing. 
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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. 
 
10 
SAFETY ANALYSES 
All safety analyses will be conducted for the SS and results will be presented by final dose group 
and for all subjects combined. 
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). 
The final dose level (‘final dose’) is defined as the dose administered at the start of the 
Maintenance Period (i.e., at Visit 5) 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 5, 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). 
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. 
A listing will be presented for the following variables: 
• Duration of exposure (days) 
• Final dose level (mg/24h) at the start of Maintenance (1mg/24h, 2mg/24h and 3mg/24h) 
• Dose of longest duration (1mg/24h, 2mg/24h and 3mg/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” 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) 
within HLTs. If there is more than one PT with the same frequency 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 (HCT), Hemoglobin (HGB), Platelets (PLAT), Red 
Blood Cells (RBC), White Blood Cells (WBC), 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 (Total 
CO2), Blood Urea Nitrogen (BUN), Calcium, Chloride (CL) Creatinine, Ferritin, Gamma-
glutamyl transferase (GGT), Glucose, Iron Binding Capacity Total (IBCT), Iron Binding 
Capacity Unsaturated (IBCU), Lactate Dehydrogenase (LDH), 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) 
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 and final dose 
group 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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A listing of results for vital signs, and body weight, BMI, temperature, respiratory rate, height 
and height percentile (based on CDC growth charts at http://www.cdc.gov/growthcharts) 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, QTcB interval, and QTcF interval) 
will be presented by visit. 
ECG results and findings 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) (Kohnen, 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 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 height percentile; cited CDC growth chart 
reference. 
• Section 12 “References”: Added reference to CDC growth charts, RLS-6 and RLS-QoL; 
removed two statistical references. 
• 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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