The main purpose of this substantial amendment was to include the suicidality risk assessment (Columbia-Suicide Severity Rating Scale [C-SSRS]). In accordance with the FDA draft Guidance for Industry, which went into effect on 29 Oct 2010. In addition, a list of anticipated serious adverse events (SAEs) was included in this amendment in compliance with the recent FDA guidance on safety reporting requirements for studies conducted under an open Investigational New Drug Application. The Beck Depression Inventory II and the Beck Anxiety Inventory were removed from the study assessments. Other changes included in this amendment were as follows: - Procedures for subjects wishing to enter the open-label, LTFU study (SP1005) following dose de-escalation but prior to the SFU Visit were added. - Definition of clinically relevant renal dysfunction at Visit 1/Screening Period as an exclusion criterion was increased from serum creatinine >1.0mg/dL to >1.5mg/dL since the previous serum creatinine level >1.0mg/dL was within the central laboratory’s normal range. Physical examination was removed as a safety variable. - The version number of the Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale was added. - For clarity, a dose de-escalation table (Table 3-3) was added. - Storage requirements for the rotigotine patch were updated. - Use of a topical anesthetic prior to the needle stick was permitted. - Corrections were made to the definitions of some PK parameters, as well as the preparation and handling of the blood and saliva PK samples. - Reference to patch size was removed from all sections, except Section 7.1 of the protocol, Description of investigational medicinal product (IMP). - Vital sign parameters to be measured were specified as pulse rate, SBP, DBP, and orthostatic hypertension assessments. - Sponsor Clinical Project Manager contact information was updated. - Typographic errors and changes of an editorial nature were made.

The purpose of this substantial amendment was to increase the minimum weight for enrollment in the study from 30kg to 40kg. An additional change clarifying that subjects must tolerate the first dose step to be able to transition into the open-label, LTFU study was also made.

The main purpose of this substantial amendment was to ensure consistency between the protocol and the FDA Pediatric Development Plan for the RLS indication in subjects 13 to <18 years of age. Since the subject’s dosing was no longer dependent on body weight, the dosing schedules for each study period were revised. The primary PK variables were changed to reflect those that were requested by the FDA for the revised sample size calculation. In addition, PK saliva sampling was removed from the study. Data from a recently completed PK study (RL0002) suggest that saliva concentrations of rotigotine cannot be used as a surrogate for plasma concentrations of rotigotine. Other changes included in this amendment were as follows: - Updated contact information for SAE reporting and procedures for reporting SAEs to be consistent with the current protocol template. - Updated the regulatory status of rotigotine for the treatment of RLS in adults in the US. - Removed the requirement for the PK blood samples to be centrifuged at a controlled temperature. - Corrected typographic errors and minor inconsistencies of an editorial nature.