Clinical Study Report
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`CLINICAL STUDY REPORT
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`FULL
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`FINAL
`Study Number: 109MS302
`Study Title: A Randomized, Multicenter, Placebo-Controlled and Active Reference (Glatiramer
`Acetate) Comparison Study to Evaluate the Efficacy and Safety of BG00012 in Subjects With
`Relapsing-Remitting Multiple Sclerosis
`
`BG00012 (dimethyl fumarate)
`Relapsing-Remitting Multiple Sclerosis
`3
`28 July 2007
`24 August 2011
`Biogen Idec Inc.
`Biogen Idec Ltd.
`14 Cambridge Center
`Innovation House
`Cambridge, MA 02142
`70 Norden Road
`United States
`Maidenhead Berkshire SL6 4AY
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`United Kingdom
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`Name of Study Treatment:
`Indication:
`Development Phase:
`Date of First Treatment:
`End of Study Date:
`Sponsor:
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`Name of Sponsor Signatory:
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`Sponsor’s Study Medical Director:
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`Gilmore O’Neill, MB, MRCPI, MMSc
`Vice President, Clinical Research
`Phone (617) 914-4725; Fax (617) 679-3518
`Katherine T. Dawson, MD
`Senior Director, Clinical Development, MS
`Phone (617) 914-6377; Fax (617) 679-3518
`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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`Clinical Study Report
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`6.
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`INVESTIGATORS AND STUDY ADMINISTRATIVE
`STRUCTURE
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`6.1.
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`Investigators
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`Investigator meetings and/or site initiation visits 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. Investigator 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). Training for site personnel who did not attend an Investigator meeting was
`also provided at site initiation visits that occurred before the start of the study. Additionally, a
`live meeting webcast for Investigators in the US was held (December 2007), and additional mid-
`study meetings were held to provide ongoing training to site personnel. 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 1.
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`Table 1:
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`Central Laboratories Used in Study 109MS302
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`Central Laboratory
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`Responsibilities
`Analysis of clinical samples and sample
`management. The laboratory manual,
`documentation of accreditation, and reference
`ranges are provided in Appendix 16.1.10.
`
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`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 gadolinium, was performed under the
`direction of
`. The Imaging
`Review Charter and site acquisition guidelines are
`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 2 with their respective responsibilities.
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`Table 2:
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`Contract Research Organizations and Vendors Used in Study 109MS302
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`Contract Research Organization/Vendor
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`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, Bulgaria, India, Israel,
`Mexico, and FYR Macedonia.
`Performed site management in India, providing
`7 sites with study coordinators.
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`Prepared the submissions to regulatory authorities
`and ECs in Moldova and Belarus.
`Performed clinical research management for
`Belarus, Belgium, Canada, Costa Rica, Croatia,
`Czech Republic, Estonia, France, Germany,
`Greece, Ireland, Latvia, Moldova, New Zealand,
`Poland, Puerto Rico, Romania, Serbia, Slovakia,
`Spain, 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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`Clinical Study Supply Management
`6.5.
`The manufactm-ing, packaging, labeling, and distribution of the BG00012 and placebo dmg
`listed in Table 3. Glatiramer acetate (GA) was
`product were performed
`the
`manufactured by
`and was provided to the
`sites by Biogen
`regarding study
`treatment supply and n .L.\. i V U lJ
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`Table 3:
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`Clinical Supply Management
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`Responsibilities
`Packaging, labeling, and disttibution of the IMP
`(BG00012, placebo, and GA) to the clinical sites in
`the US and Canada. Distribution of A VONEX®
`(alternative MS medication) to clinical sites.
`IMP release
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`Packaging, labeling, and distribution of the IMP to
`all other investigational sites outside the US and
`Canada
`Prepared blister packs and wallets containing IMP
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`IMP manufacttu·er
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`6.6.
`Sponsor:
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`Authors of Study Report
`Biogen Idee Inc.
`
`Medical Director:
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`9.
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`INVESTIGATIONAL PLAN
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`This study was conducted in accordance with Biogen Idec Protocol 109MS302, ―A Randomized,
`Multicenter, Placebo-Controlled and Active Reference (Glatiramer Acetate) Comparison Study
`to Evaluate the Efficacy and Safety of BG00012 in Subjects With Relapsing-Remitting Multiple
`Sclerosis.‖ Enrollment into Study 109MS302 began under Version 1, dated 16 October 2006.
`The protocol was subsequently amended 3 times: on 23 March 2007, 22 May 2007, and
`09 January 2008. A summary of the changes from each amendment is provided in Section 9.8.1.
`The original protocol (Version 1, under which subject enrollment began), the final protocol
`(Version 4, dated 09 January 2008), and Amendment Summary documents describing changes
`incorporated into Versions 2, 3, and 4 are provided in Appendix 16.1.1. The sample case report
`forms (CRFs) current at the time of database lock are provided in Appendix 16.1.2.
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`9.1.
`Overall Study Design and Plan
`This was a Phase 3, randomized, multicenter, parallel-group, placebo-controlled and reference
`comparator, double-blind (only for BG00012/placebo), rater-blind study.
`A study population of approximately 1230 randomized subjects, at approximately 175 sites, was
`planned. A total of 1430 subjects were actually enrolled at 200 sites in 28 countries worldwide
`(Section 10.1).
`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 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 4 groups in a 1:1:1:1 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)
` Group 4: GA (20 mg subcutaneous [SC] injection, QD)
`Subjects in Groups 1, 2, and 3 were to take 2 capsules of blinded study treatment orally TID,
`except during the first week, when they were to take 1 capsule orally TID. Subjects in Group 4
`were to receive GA as noted above (there was no GA placebo in this study). Study treatment
`was to be taken with food (Sections 9.4.1 and 9.4.5). Subjects who discontinued the study
`treatment prematurely for any reason were to remain in the study and continue with an
`abbreviated visit schedule (Section 9.3.3.1). Subjects who chose to switch to alternative MS
`treatment and remain in the study were given the option to receive alternative MS treatment with
`open-label AVONEX®. Subjects who opted to receive AVONEX were provided with a 4-week
`supply at each study visit.
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`10.
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`STUDY SUBJECTS
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`10.1.
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`Disposition of Subjects
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`The first subject was treated on 28 July 2007, and the last subject received the last dose on
`04 Aug 2011. The last subject completed the study on 24 August 2011.
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