`CLINICAL STUDY REPORT
`
`FULL
`
`FINAL
`
`Study Number: 109MS301
`
`Study Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Comparison
`Study to Determine the Efficacy and Safety of BG00012 in Subjects with Relapsing-Remitting
`Multiple Sclerosis
`
`Name of Study Treatment:
`
`BG00012
`
`Indication:
`
`Relapsing-Remitting Multiple Sclerosis
`
`Development Phase:
`
`3
`
`Date of First Treatment:
`
`End of Study Date:
`
`14 March 2007
`
`23 February 2011
`
`Sponsor:
`
`
`
`
`
`Biogen Idec Inc.
`14 Cambridge Center
`Cambridge, MA 02142
`United States
`
`
`Biogen Idec Ltd.
`Innovation House
`70 Norden Road
`Maidenhead Berkshire SL6 4AY
`United Kingdom
`
`Name of Sponsor Signatory:
`
`
`
`Sponsor’s Study Medical Director:
`
`
`
`Gilmore N. O’Neill, MB, MRCPI, MMSc
`Vice President, Clinical Development, MS
`
`Katherine T. Dawson, MD
`Senior Director, Clinical Development, MS
`
`Report Date:
`
`14 January 2012
`
`This study was conducted in accordance with the ethical principles of Good Clinical Practice,
`according to the ICH Harmonized Tripartite Guideline.
`
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`6.
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE
`STRUCTURE
`
`6.1.
`
`Investigators
`
`Investigator meetings were held for the purpose of training the Investigators, examining and
`treating neurologists, study coordinators, and other team members on the procedures, tests, and
`evaluations to be used in the study. The meetings occurred in Dublin, Ireland (February and
`April 2007); Boston, Massachusetts, US (June 2007); Cancun, Mexico (January 2008);
`Budapest, Hungary (January 2008); and Istanbul, Turkey (November 2008). Additionally, a live
`meeting webcast for Investigators in the US was held (December 2007). Training was also
`provided at site initiation visits that occurred before the start of the study. Subjects were not
`enrolled at a given investigational site until after the study staff training had occurred. See
`Section 9.6 for additional information on training.
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`6.3.
`
`Laboratories
`
`The central laboratories contracted to acquire and evaluate MRI scans, analyze clinical
`laboratory samples, and evaluate electrocardiograms (ECGs) collected in this study are listed in
`Table 6-1.
`
`Table 6-1: Central Laboratories Used in Study 109MS301
`
`Central Laboratory
`
`Responsibilities
`
`Analysis of clinical samples and sample
`management. The laboratory manual,
`documentation of accreditation, and reference
`ranges are provided in Appendix 16.1.10.
`
`
`
`Evaluation of ECGs collected for this study.
`
`The ECG Procedures Manual is provided in
`Appendix 16.1.10.
`
`Acquisition and evaluation of MRI scans with and
`,
`without Gd, under the direction of
`MD. The Imaging Review Charter is provided in
`Appendix 16.1.10. MRI assessments are described
`in Section 9.5.2.2.
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`6.4.
`
`Contractors and/or Vendors
`
`Contract research organizations and vendors that performed services in this study are listed in
`Table 6-2 with their respective responsibilities.
`
`Table 6-2: Contract Research Organizations and Vendors Used in Study 109MS301
`
`Contract Research Organization/Vendor
`
`Responsibilities
`
`Provided interactive voice response system
`services.
`
`Coordinated communication between
`investigational sites and INEC (see Sections 6.2.3
`and 9.5.2.1 for more information).
`
`Served as the data coordinating center for this
`study.
`
`Patient recruitment company that provided
`advertising services and an investigator web site for
`the study.
`
`Performed clinical research management for
`Bosnia and Herzegovina, France, India, Israel, and
`FYR Macedonia.
`
`Provided translations of the VAS. Printed case
`CRFs and VAS, SF-36, and EQ-5D questionnaires.
`
`Performed site management in India, providing
`5 sites with study coordinators.
`
`
`
`Prepared the submissions to regulatory authorities
`and ECs in Moldova.
`
`Performed clinical research management for
`Australia, Austria, Belgium, Canada, Croatia,
`Czech Republic, Germany, Greece, Guatemala,
`Italy, Mexico, Moldova, Netherlands, New
`Zealand, Poland, Romania, Serbia, Slovakia, South
`Africa, Switzerland, UK, Ukraine, and US. Also
`managed AE/SAE reporting for all countries (see
`Section 9.5.4.3).
`
`Licensed the subject-rated SF-36® Health Survey
`Questionnaire (SF-36) and EQ-5D Questionnaires.
`(Note: The SF-36 and EQ-5D were not available in
`all languages).
`
`Performed Expanded Disability Status Scale
`(EDSS) training and certification (Section 9.6).
`
`
`
`
`
`
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`6.5.
`
`Clinical Study Supply Management
`
`The manufacturing, packaging, labeling, and distribution of the BG00012 and placebo drug
`product were performed by the vendors listed in Table 6-3.
`
`Table 6-3: Clinical Supply Management
`
`Supplier
`
`Responsibilities
`
`Packaging, labeling, and distribution of the IMP
`(BG00012 and placebo)
`
`IMP release
`
`Packaging, labeling, and distribution of the IMP
`
`Prepared blister packs and wallets containing IMP
`
`IMP manufacturer
`
`IMP = investigational medicinal product
`
`6.6.
`
`Authors of Study Report
`
`Sponsor:
`
`
`
`Biogen Idec
`
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`9.
`
`INVESTIGATIONAL PLAN
`
`This study was conducted in accordance with Biogen Idec Protocol 109MS301, ―A Randomized,
`Multicenter, Double-Blind, Placebo-Controlled, Dose-Comparison Study to Determine the
`Efficacy and Safety of BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis.‖
`Enrollment into Study 109MS301 began under Version 1, dated 21 September 2006. The
`protocol was subsequently amended 5 times: on 24 October 2006, 20 March 2007,
`22 May 2007, 07 January 2008, and 26 May 2010.
`
`9.1.
`
`Overall Study Design and Plan
`
`This was a Phase 3, randomized, multicenter, double-blind, placebo-controlled, dose-comparison
`study designed to determine the efficacy and safety of BG00012 in subjects with RRMS.
`
`A study population of 1011 randomized subjects, at approximately 160 sites, was planned. A
`total of 1237 subjects, at 198 sites in 28 countries worldwide, were actually enrolled
`(Section 9.8.1).
`
`Following the screening visit and a pre-treatment period lasting up to 6 weeks, subjects who met
`the study entry criteria were randomly assigned to 1 of 3 groups in a 1:1:1 ratio. Randomization
`was stratified by site.
`
` Group 1: BG00012 240 mg twice daily (BID) (2 capsules [120 mg each] BID and
`2 placebo capsules QD); subsequently referred to as BG00012 BID in this report
`
` Group 2: BG00012 240 mg TID (2 capsules [120 mg each] TID); subsequently
`referred to as BG00012 TID in this report
`
` Group 3: Placebo (2 capsules TID)
`
`The duration of blinded study treatment administration was to be 96 weeks. Clinic visits
`occurred every 4 weeks, with the end-of-study visit occurring at Week 100. An overview of the
`study design is shown in Figure 9-1.
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`10.
`
`STUDY SUBJECTS
`
`10.1.
`
`Disposition of Subjects
`
`The first subject was treated on 14 March 2007, and the last subject received his or her last dose
`on 10 February 2011. The last subject completed the study on 23 February 2011.
`
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`13.
`
`DISCUSSION AND OVERALL CONCLUSIONS
`
`Despite the approval of a number of MS therapies over the past 2 decades, there remains a need
`for therapies that combine both strong efficacy and a good safety and tolerability profile with
`ease of administration. BG00012 is an oral fumarate that is being developed as a treatment for
`MS. Preclinical data suggest BG00012 may provide both anti-inflammatory and neuroprotective
`effects through its activation of the Nrf2 pathway, which plays a central role in the protection of
`cells and tissues against oxidative, metabolic, and inflammatory stress.
`
`The primary objective of Study 109MS301 was to evaluate whether BG00012, administered
`orally as 240 mg BID or 240 mg TID, reduced the proportion of subjects who relapsed at 2 years
`compared with placebo. Secondary objectives were to evaluate whether BG00012 is effective in
`reducing the development of new or newly enlarging T2 hyperintense lesions and Gd-enhancing
`lesions, reducing the rate of clinical relapses, and slowing the progression of disability at 2 years.
`Additional objectives were to determine the safety and tolerability of BG00012, and to assess its
`effects on other measures of disease activity on brain MRI, on disability as measured by the
`MSFC, cognitive dysfunction (PASAT 3), visual function, and patient-reported outcomes.
`
`The goal of enrolling a study population representative of patients with RRMS across the
`spectrum of the disease was achieved [Giovannoni 2010; Kappos 2010]. Within the overall
`study population, the 3 treatment groups were well balanced with respect to baseline
`characteristics. Likewise, within the MRI cohort, which included approximately 95% of all
`subjects enrolled at investigational sites with validated MRI capability, baseline MRI parameters
`and other baseline characteristics were well balanced across treatment groups. Baseline
`characteristics in the MRI cohort and non-MRI cohort were generally comparable, supporting the
`validity of extrapolating the MRI efficacy results to both the non-MRI cohort and the overall
`study population.
`
`The efficacy results of this study clearly demonstrated that BG00012, whether administered as
`240 mg BID or TID, had a clinically meaningful and statistically significant effect on the
`primary efficacy endpoint, all secondary endpoints, and nearly all other measures of disease
`activity assessed in the study, in comparison with placebo.
`
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