Protocol Amendment 2, dated 05 Apr 2005, provided for the following changes: • Change of the clinical research organization (CRO) for Data Monitoring, Drug Safety Officer, and Pharmacokineticist • Increase in the number of expected subjects and duration of the study • Clarification on the use of narcotic analgesics • Addition of Section 4.8. “Allowance for entering SPM 927 Trial SP757” • Change of Visit 10 to Week 78 (6 weeks later) and revision of telephone contacts to occur at Weeks 72, 76, 82, 86, 90, and 94 • Deletion of Visit 11 at Week 84; Visit 11 was to occur at Week 96 (previously Visit 12), Visit 12 was to occur at Week 120 (previously Visit 13), and Visit 13 was to occur at Week 144 (previously Visit 14) • Addition of visit at Week 168 (new Visit 14) and telephone contacts at Weeks 148, 152, 156, 160, 164, 172, 176, 180, 184, and 188 • Correction to the error in the heading for Section 5.5, which inadvertently omitted reference to the Termination Visit • Removal of PK assessments at Visits 12, 13, and 14, at Unscheduled Visits after Year 2, at Early Termination after Year 2 (unless the subject dropped out due to an adverse Event [AE]), and at the Final Clinic Visit • Addition of information regarding surgery as an AE and definition of life-threatening to the AE section • Provide clarification for recording AEs that increase in intensity • Addition of “worsening” as an AE outcome • Remove drop-outs due to AEs from the list of immediately reportable adverse Events (IRAEs) and specification of 1 exception to this rule • Slight modification to the cardiac conduction abnormality IRAE • Addition of Section 7.1.3.8. “Pregnancy during trial participation” • Addition of kit number to bottle label • Change in the dictionary used for coding of AEs from World Health Organization- Adverse Reaction Terms to Medical Dictionary for Regulatory Activities (MedDRA®) • Minor administrative changes

Protocol Amendment 3, dated 19 May 2006, provided for the following changes: • The physical address for SCHWARZ BIOSCIENCES, GmbH was changed in the address for study personnel • Contact information for the Clinical Program Director was changed • Contact information for the Clinical Trial Statistician was changed • Contact information for the Clinical Program Medical Scientist was changed • The title and contact information for the Drug Safety Officer was changed • Additional specifications concerning withdrawal criteria regarding cardiac function were included • The title and contact information for the Safety Monitor were changed

Protocol Amendment 4, dated 17 Mar 2008, provided for the following changes: • Contact information for the Associate Medical Director (Medical Therapeutics) and Associate Medical Director (Drug Safety) were added to Section 7.1.3.5, Re-exposure • Section 7.2, Laboratory measurements. In the urinalysis column in the table, albumin was changed to protein, and acetone was changed to ketones to be consistent with terminology in the clinical database • The information in Section 7.4.2, Sample labeling, was changed from “must” be filled in on all labels to “may” be filled in on all labels • Kit number in Section 8.1, Manufacturing, packaging, and labeling, was changed to Kit number (ie, bottle number) • Reference to the Per-Protocol Set in Section 11, Statistics, was removed • In Section 11.1.2, text was revised to accurately state that 1 of the safety variables was changes in 12-lead ECG instead of changes in vital sign measurements. Vital sign measurements are still listed as a safety variable • The CRF numbers were added as a way to identify data in Section 12.5, Subject privacy • The Schedule of Trial Procedures was updated to reflect the removal of the requirement to perform LCM plasma sampling after Year 2 if a subject discontinued due to an AE • The footnote in the Schedule of Trial Procedures describing the Early Termination Visit was updated • The Schedule of Trial Procedures was updated to include the additional visits associated with the additional year of the study • The individuals in Section 16.1, Declarations and signatures of persons responsible for the study, were updated

Protocol Amendment 4, dated 17 Mar 2008, provided for the following changes: • The name of the study management and monitoring CRO and the vendor for central ECG services was updated • The title and contact information for the Clinical Project Manager was changed. In addition, the title of the Clinical Program Medical Scientist changed, and clarification was added to the title of the Associate Medical Director. Updates to job titles within SCHWARZ were made throughout the document. Finally, the email addresses of all SCHWARZ contacts were changed • The name of the vendor providing Central ECG Services was updated • The list of abbreviations was updated to no longer include Per-Protocol Set (PPS) • Throughout the protocol, the maximum duration of a subject’s study participation was changed from 4 years to approximately 5 years, or until LCM is otherwise (eg, commercially) available, whichever is earlier • Section 2, Background information, a reference to the most recent Investigator’s Brochure was added • Language was added to clarify that blood sampling for LCM plasma concentrations only needed to be performed through Year 2. Language stating that plasma sampling was necessary after Year 2, if a subject discontinued due to an AE, was deleted • The description of study medication was clarified to note that the tablets were provided in strengths rather than doses of 50 mg and 100 mg • Language was added to Section 4.6, Concomitant medications/treatments, to clarify that in general, it is no longer necessary to discontinue LCM for subjects undergoing surgery, although, it is still essential that each case be discussed on a case-by-case basis with the SCHWARZ Associate Medical Director • Treatment procedures for the new visits added by extending the duration of the study to 5 years were added to Section 5, Treatment procedures by visit • Clarification was added to the definition of a serious adverse event

Protocol Amendment 5 dated 08 Jan 2009, provided for the following changes: • Contact information for the data management CRO was changed • The title and contact information for the Medical Director (Medical Therapeutics) was changed • Additional detail was added regarding bioanalytics, including a new vendor • The vendor and contact information for central ECG services was changed • The duration of the study was modified to include “or until the sponsor closes the trial” as an option for conclusion of the study. In addition, information regarding procedures that will be followed if LCM is not commercially available in a subject’s country at the time the sponsor closes the trial was added • Information was added regarding procedures to follow for subjects completing the study who continue on LCM • Instructions for taper of study medication (if a subject withdraws during the trial) were placed in a new section (Section 4.4.2, Taper of trial medication) • A new section was added (Section 4.4.3, Trial completion) describing the procedures to follow for subjects who choose to continue on LCM and for subjects who choose not to continue on LCM • Section 5.5, Early Termination/Termination Visit was changed to Early Termination Visit and a new section, Section 5.6, Termination Visit, was added. Assessments to be conducted or the Early Termination Visit did not change. Assessments to be conducted at the Termination Visit were added • Contact information for the SCHWARZ Safety Scientist was changed • The classification of protocol deviations was revised to be consistent with ICH E3 • Table 1, Table 2, and Table 3 were updated to reflect the changes to the protocol