CLINICAL STUDY REPORT
`
`FINAL
`Study Number: C-1900
`
`Double-Blind, Placebo-Controlled, Dose-Ranging Study to Determine the Efficacy and
`Safety of BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis
`
`Name ofDmg:
`
`BG00012
`
`Indication:
`
`Multiple Sclerosis
`
`Dmg Development Phase:
`
`2
`
`Sponsor:
`
`Biogen Idee Inc.
`14 Cambridge Center
`Cambridge, MA 02142
`
`Study Dates:
`
`02 November 2004 through 31 March 2006
`
`Coordinating Investigator:
`
`Name of Sponsor Signatmy:
`
`Study Medical Director:
`
`Kate Dawson, MD
`(617) 914-6377; FAX (617) 679-3518
`
`Study Medical Director:
`
`Gilmore O'Neill, MB, MRCPI, MMedSc
`(617) 914-4725; FAX (617) 679-3518
`
`Study Statistician:
`
`Minhua Yang
`(617) 679-4302; FAX (617) 679-3280
`
`Study Phannacokineticist:
`
`Repott Date:
`
`12 May 2008
`
`To the best of the sponsor' s knowledge, this study was conducted in compliance with the requirements of the
`Intemational Conference on Hannonisation (ICH) Good C linical Practice (GCP), United States 21 Code of
`Federal Regulations (CFR) Parts 50, 54, and 56, and other applicable standards for the protection of human
`subjects and integrity of clinical data. It has been monitored by the sponsor or by the sponsor 's representative.
`There were no deviations from the above-referenced standards that, in the view of the sponsor, were likely to
`have compromised the integrity or quality of the study, the intetpretation of the results, subject safety, or ethical
`standat·ds. Essential documents, as described in ICH E6, have been at·chived in Central Clinical Files atid in atl
`electronic study file.
`
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`Biogen Exhibit 2092
`Coalition v. Biogen
`IPR2015-01993
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`

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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`6
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
`
`6.1
`
`Investigators
`
`An investigator meeting was held on 14 and 15 September 2004 (in Versailles). The pmpose
`of this meeting was to train Investigators, Study Coordinators, and other team members on
`the procedmes, tests, and evaluations to be used, conducted, or assessed in this study. This
`meeting was held prior to the first patient being enrolled into the study.
`
`6.2
`
`Study Committees
`
`6.2.1 Advisory Committee
`
`An Advismy Committee (AC) was formed to provide scientific and medical direction for the
`study and to oversee the administmtive progress of the study. The AC was to conduct
`quarterly reviews of the study to monitor patient accmal and to monitor compliance with the
`protocol at individual investigational sites. The AC was blinded to patient treatment
`assignments. The AC was to detennine whether the study should be stopped or amended for
`either efficacy or safety reasons.
`
`The AC was comprised of the Medical Director, Clinical Trial Manager, and Project
`Statistician from Biogen Idee (and/or their designees), and pa1ticipating Inv~ as well
`~ts who were not paiticipating as investigators in this study. -
`- -' a participating Investigator who was designated as the Coordinating
`Investigator by Biogen Idee, also chaired the AC. Cmrent curriculUlll vitae for AC members
`who were not fi:om Biogen Idee are provided in Appendix 16.1 .4.
`
`6.2.2 Clinical Safety Committee
`
`An independent Clinical Safety Committee reviewed all adverse events (AEs), clinical
`observations, vital signs, and laboratmy tests for all patients. The Clinical Safety Committee
`was comprised of 3 members who were all independent of Biogen Idee. A set of guidelines
`was established between Biogen Idee and the Clinical Safety Committee to outline the
`Clinical Safety Committee's responsibilities and procedmes. This document is included in
`Appendix 16.1.13. The first meeting was conducted prior to study onset on 02 November
`2004. Members were blinded to patient treatment assignments. Findings and conclusions
`were to be repmted to the Chaim1an of the AC and Biogen Idee Medical Director.
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`Investigational sites were to be notified of any relevant safety findings that may have
`jeopardized patient safety. The Clinical Safety Committee met after 25% of the patients had
`3 months exposme to the investigational chug. Subsequent meetings occUlTed eve1y
`3 months throughout the study dmation.
`
`6.3 Laboratories
`
`a t -
`
`Magnetic Resonance Imaging Reading Center
`
`. Pnor to patient
`investigational site's scanning
`technique by evaluating a test scan fi:om an MS patient. Original MRI films, as well as tapes
`or optical disk media, were to be sent by courier to the MRI center for review. MRis were
`evaluated by physicians/technicians who are blinded to the patients' treatment assignments.
`Additional MRI procedures and instmctions are provided in Appendix 16 .1.1 0.
`
`6.4 Vendors
`
`6.4.1 Contract Research Organization
`
`acted as the Data Coordinating Center
`for countries in the
`Russia only.
`
`The DCC was responsible for achninistrative aspects of the study including, but not limited
`to, study initiation, monitoring, management of AE repo11s, and data management. Prior to
`emollment of the first patient at each investigational site, the DCC was to review study
`responsibilities with the Investigators and other investigational site personnel, as appropriate.
`
`6.4.2 Centralized Randomization
`
`was responsible
`patient
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`screening or emollment, the investigational site was provided with appropriate training and a
`user manual.
`
`6.5 Clinical Study Supply Management
`
`manufactured the
`this study.
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`OVERALL STUDY DESIGN AND PLAN
`9.1
`This study was a Phase 2, double-blind, multicenter, randomized, placebo-controlled,
`parallel-group, dose-ranging study to determine the efficacy of 3 different BG00012 dose
`levels on brain lesion activity as measmed by MRI in patients with RRMS. Following
`screening, patients entered a 24-week 1Teatment phase (Pali 1) in which they were randomly
`assigned to receive placebo or one of three dosing regimens of BGOOO 12 (Table 9.1-1 ). TI1is
`was followed by a 24-week double-blind, safety extension phase (Pmi 2). Approximately
`260 patients at 42 sites were to be randomized in equal numbers to the 4 treatment groups.
`
`Table 9.1-1: Treatment Groups for Part 1 of Study C-1900
`
`Treatment Group
`
`BGOOO 12 Dosing Regimen
`
`BG00012 Total Daily Dose
`
`1
`
`2
`
`3
`
`4
`
`120mg QD
`
`120 mg TID
`
`240mg TID
`
`Placebo
`
`120mg
`
`360mg
`
`720mg
`
`Placebo
`
`Eligible patients were to take 2 oral capsules of study drug (BG00012 or placebo, depending
`on treatment group and the phase of the study) 3 times a day (TID) for up to 48 weeks.
`
`Dming the placebo-controlled phase, study drug tolerability was evaluated in all patients
`after the first week of dosing. Patients randomized to receive the highest dose, 240 mg TID,
`were initially dosed at 120 mg TID for the fust week to detennine tolerance to flushing
`episodes and GI distmbances. If 120 mg TID was tolerated in the first week, the dose was
`increased to 240 mg TID.
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study of BG00012 In MS
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`
`
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`
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`In the 24-week, double-blind, safety extension phase (Part 2) all patients who received
`BG00012 in Part 1 continued on the same dosing regimen. Patients who were randomized to
`receive placebo in the placebo-controlled phase received 120 mg TID BG00012 for 1 week
`in the safety extension, and then if tolerated well, the dose of BG00012 was increased to
`240 mg TID (referred to in this report as the “placebo/240 mg TID group”).
`
`
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`9.4.6.2 Site Personnel
`
`In order to maintain the blinding of study drug (BGOOO 12 or placebo), all study site
`personnel were to be blinded to treatment assignment. Physicians, nmses, pharmacists,
`patients, and any study personnel who performed patient assessments were NOT to be
`infotmed of the patient's treatment assignment except in the event of a medical emergency
`(Section 9.4.6.4).
`
`In addition, separate study personnel were designated to conduct efficacy assessments and to
`treat patients in order to protect against perceived lmblinding of heatment assignment.
`
`For each patient, the Principal Investigator of each site was to designate the following study
`site personnel:
`
`• A primary and backup 1Teating nemologist
`
`• A primaty and backup treating nmse (or study coordinator)
`
`• A primary and backup examining nemologist
`
`• An MRI technician
`
`• A phannacist (or authorized designee)
`
`Both the examining and treating nem ologists were required to have a minimlml of 2 years of
`nemology specialty training and be able to make at least a 1-year commitment to the study.
`
`Where specified, evaluations described in this section were to be perfotmed only by the
`personnel indicated.
`
`The primary heating nemologist was responsible for:
`
`• Management of the routine nemological care of the patient.
`
`• Assessment (including assignment of causality) and h eatment of AEs and MS relapses.
`
`• Review of selected hematology and blood chemisby results from the centrallaboratoty to
`assess whether the patient's study dmg should be temporar·ily withheld or petmanently
`discontinued as per the criteria detailed in Section 9.4.5.
`
`The b·eating nemologist was allowed to designate other medical personnel (i.e., the backup
`treating nem ologist or the b·eating nmse) at the study site to perform some of the tests and
`evaluations listed under "Treating Nemologist." If there was more than 1 heating
`nemologist available at a given site such that each one was assigned to particular patients,
`then those treating nem ologists were allowed to act as backup for each other. The same was
`ttue for the treating nmses.
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`Hematology and blood chemisby data were to be sent to the study sites to aid in management
`of the patient. As with other laboratmy and clinical infonnation, this data was NOT to be
`reviewed by the examining neurologist or the back-up examining neurologist.
`
`The primaty tt·eating nmse (or study coordinator) was responsible for assisting the tt·eating
`nemologist in patient management, including the heatment of AEs, the treahnent and
`assessment of disease relapses, and the recording of AEs and concomitant medications.
`
`The examining neurologist was responsible for:
`
`• Obtaining an EDSS score based on a detailed nemological examination at the scheduled
`timepoints required in the protocol.
`
`• Obtaining an EDSS score at evety Unscheduled Relapse Assessment Visit if refened by
`the treating nemologist when there is the possibility of a relapse.
`
`The examining neurologist was not allowed to be involved with any other aspect of patient
`care and management. Fmther, the examining neurologist was not to serve as tt·eating
`nemologist for any patients at a given study site. To ensure consistency across sites,
`examining neurologists were required to undergo a standardized haining session on EDSS
`scoring prior to emollment of patients at their site. The back-up examining neurologist was
`to conduct patient evaluations ONLY if the primruy examining nemologist was unavailable
`due to illness, vacation, or tt·avel. All sites were required to attempt to maintain the same
`examining neurologist throughout the study. If an examining neurologist had to be replaced,
`the new examining neurologist was required to undergo a training session. The
`commtmication of new fmdings on the nemologic examination from the examining
`nemologist to the treating neurologist was permitted (because findings on the nemologic
`examination may have been impmtant in the routine care of the patient, e.g., medical
`management of relapses). The roles of tt·eating and exrunining nemologist (prima1y and
`backup) were NOT interchangeable even for different patients. The examining neurologist
`was required to remain blinded to AEs, concomitant medications, laboratmy data, MRI data,
`and any other data that have the potential of revealing the treahnent assignment.
`
`The MRI technician was responsible for perfonning a brain MRI at all protocol-required
`timepoints. Study-specific MRI procedures and protocols, which were to be provided prior
`to study strut, were required to be followed.
`
`The phrumacist (or authorized designee) was responsible for distributing study dmg.
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`Unblinding Plan for Evaluation of Efficacy After Week 24
`
`There was a planned evaluation of efficacy after all patients completed Week 24 of the study.
`This analysis contained the complete efficacy and safety data from the Prut 1 treatment phase
`and also SAEs from the Prut 2 extension phase.
`
`Only 6 individuals at Biogen Idee (2 statisticians, 3 programmers, and 1 medical director
`who was not involved in the study) were lmblinded to the individual results of this analysis.
`
`data was transfen ed and stored in a sepru·ate folder on the
`
`As the unblinded statisticians presented only grouped safety and efficacy data to the Study
`Medical Director, he was able to continue with the study because he was not unblinded to
`individual results. Since there was no efficacy analysis in the on-going extension phase of
`the study and no placebo group, the Study Medical Director was able to present the grouped
`data from tl1e treatment phase to key Biogen Idee staff without intw ducing any bias in tl1e
`ongoing extension phase.
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`C-1900: A Phase 2, Blinded, Placebo-Controlled, Dose-Ranging Study ofBG00012 In MS
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`Table 9.5-1: Part 1: Placebo-Controlled Treatment Phase
`c=J Tests that are shaded were to be perfonued only by the examining neurologist.
`
`Tt>st/Evaluation
`
`Randomization
`Medical/Disease Hx
`Physical Exam
`Vital Sil!llS
`12-LcadECG
`Hematology
`Blood Chemistry
`HCV Ab, HBsAg
`Urinalysis
`Neopterin/Nitric Oxide'
`Serum pregnancy test'
`Urine pregnancy test~'
`mRNA analysis
`BrainMRI
`EDSS
`Tolerability Assessment
`Monitor for Relapse
`Relapse Assessment
`Dispense Drug
`AEs/Concom Meds
`
`Screening
`Within6
`Weeks Prior
`to Baseline
`
`WeekO
`(Day 1)
`Baseline
`X
`
`Treatmt>n t Phase
`Week 1 (Day 8) Week4 WeekS Week 12 Week 16 Week20 Week24
`(Day 57)
`(Day 113)
`(Day 141)
`(Day 169)
`Dose
`(Day 29)
`(Day 85)
`Escalation5
`±2d
`±2d
`±2d
`±2d
`±2d
`±2d
`
`Final
`Follow-
`up7
`
`Unscheduled
`Visit9
`
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`X
`
`X
`X
`X "
`X
`X "
`
`X
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`X
`
`X
`X
`Monitor and record throughout the study as per protocol
`
`X
`X
`X
`X
`X "
`
`X
`X
`
`X
`X
`X
`X'
`
`X
`X
`X
`X
`X"
`
`X
`X
`
`X
`X
`X
`X
`
`X
`
`X"
`
`X
`X
`
`X
`
`4.
`
`I. mRNA analysis and urine neopterin and nitric oxide metabolite levels were optional
`and only performed at selected sites. Only patients who consented at the screerting
`visit in Part I were allowed to participate. A separate consent was signed for these
`analyses. Added by the 14 October 2004 protocol amendment
`For females of childbearing potential.
`2.
`3. All urine pregnancy testing was to be perfonned at the site. Tests were to be
`perfonned and results known prior to study drug distribution. Clarified by the
`14 October 2004 protocol amendment
`If the baseline MRI was required to determine patient eligibility (as per
`Section 9.3.1, criterion #5), then the baseline MRl could be performed within
`72 hours prior to Day L
`This visit was to assess tolerability prior to dose escalation.
`5.
`6. Dispense study drug (I week supply) to patients who were continuing on to
`extension phase.
`Final Follow-up Visit was to be perfonned for any patient who prematurely
`withdrew from study before Week 24 or who completed dosing up to Week 24. but
`did not continue on to Part 2 of the study. Patients who prematurely discontinued
`study drug during Part I of the study, but continued evaluations through Week 24
`were!!!!! to undergo the Final Follow-up Visit. Tests and evaluations were to be
`performed 30 days± 2 days after patient's last dose.
`8. Was to be performed only for patients who prematurely withdraw from the study
`before Week 24.
`
`7.
`
`9. Unschednled visit was to be carried out following suspected relapse.
`10. Patients who were treated for relapse \vith IVMP were required to have an MRI
`before IVMP treatment was started.
`I L ECG at Week 12 was added by the I April2005 protocol amendment
`12. Blood cholesterol and triglyceride levels were also to be measured at this visit
`Added by the I April 2005 protocol amendment
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`Table 9.5-2: Part 2: Blinded Safety Extension Phase
`
`c=J Tests that are shaded were to be perfonned only by the examining neumlogist.
`
`Test/Evaluation
`
`Physical Exam
`Vital Signs
`12-LeadECG
`Hematology
`Blood Chemistly
`Urinalysis
`Neopterin!Nitric
`Oxide levels 1
`Senun pregnancy test'
`Urine pregnancy
`3
`test2
`•
`EDSS
`Tolerability
`Assessment
`Monitor for Relapse
`Relapse Assessment
`Dispense Dme
`AEs/Concom Meds
`
`Week 25
`(Day 176)
`Dose
`Escalation 4
`
`X
`
`X
`
`X
`
`X
`
`W eek 28
`(Day 197)
`±2d
`
`Week 32
`(Day 225)
`±2d
`
`Week 36
`(Day253)
`±2d
`
`Extension Phase
`Week40
`Week44
`(Day 281)
`(Day 309)
`±2d
`±2d
`
`Week48
`(Day 337)
`±2d
`
`Final Follow-up )
`
`Unscheduled
`Visit7
`
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`X
`x•
`X
`X'
`X
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`X
`X
`X
`
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`X
`X
`X
`X'
`X
`X
`
`X
`
`X
`
`X
`
`X
`Monitor and record tlu·oughout the study as per protocol
`
`X
`X
`X
`X
`X'
`X
`X
`
`X
`
`X'
`
`X
`
`X
`
`1. Urine neopterin and nitric oxide metabolite levels were optional and only performed at selected sites. Only patients who consented at the screening visit in Part 1 were allowed to
`participate. A separate consent was signed for these analyses. Added by the 14 October 2004 protocol amendment.
`2. For females of childbearing potential.
`3. All urine pregnancy testing was to be perfonned at the site. Tests were to be performed and results known prior to study drug distribution. Clarified by the 14 October 2004
`protocol amendment
`4. This visit was to assess tolerability for patient; that were to have their dose escalated.
`5. Final Follow-up Visit was to be performed for any patient who prematurely withdrew from study before Week 48 or who completed dosing up to Week 48. Patients who
`prematurely discontinued study drug during Part 2 of the study but continued evaluations through Week 48 were not to undergo the Final Follow-up Visit. Tests and evaluations
`were to be performed 30 days ±2 days after patient's last dose.
`6. Was to be performed only for patients who prematurely withdrew from the study before Week 48.
`7. Unscheduled visit was to be carried out following suspected relapse.
`8. ECG at Week 36 was added by the 1 April2005 protocol amendment
`9. Blood cholesterol and triglyceride levels were also to be measured at this visit (added by the 1 April 2005 protocol amendment).
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`biogen idee
`-1---~------' ™
`
`C-1900
`
`DIRECTIONS FOR HANDLING AND ADMINISTRATION
`
`BG00012 120 mg/Capsule or Placebo
`
`For Oral Administration
`
`Double-Blind, Placebo-Controlled, Dose-Ranging Study to
`Determine the Efficacy and Safety of BG00012 in Subjects
`with Relapsing-Remitting Multiple Sclerosis
`
`1 0-September-2004
`
`Version# 1
`
`Prepared
`
`Approved By:
`
`Date
`& Technology
`
`C-1900 PST Program Representative
`
`(l{h c.---: ~~
`
`Cara Lansden, Cl~elopment
`BG00012, Manager, Clinical Development
`
`Date
`
`DHA Chair
`
`Approved By:
`
`CONFIDENTIAL
`
`Page 1 of3
`
`~~
`Date ...::62.5::;....=-"""'=:T-"-ffo..-~__,-
`Science & T echnology
`
`1794
`
`1 0-September-2004
`C-1900 DHAv1.0
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