NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`← History of this study
`
`↑ Current version of this study
`
`ClinicalTrials Identifier:
`Updated:
`
`NCT00168701
`2005_09_14
`
`Descriptive Information
`Brief title
`Official title
`
`Effacacy and Safety of BG00012 in MS
`Double-Blind, Placebo-Controlled, Dose-Ranging Study to
`Determine the Effacacy and Safety of BG00012 in Subjects
`with Relapsing-Remitting Multiple Sclerosis
`
`Brief summary
`DMF, the active ingredient in BG00012, is an immunomodulator demonstrating
`definite therapeutic efficacy in psoriasis (Carboni et al, 2004; Altmeyer et al, 1994;
`Mrowietz et al, 1999) and possible therapeutic efficacy in MS (Schimrigk et al, 2001).
` However, the target site of action and the exact mechanism of action of DMF are
`unknown.
`
`Like psoriasis, MS has been postulated to be driven by a Th1 cytokine reaction and
`to therapeutically respond to either immunosuppression or Th2 suppression (Weiner
`and Selkoe, 2002). Putative effects of BG00012 include suppression of circulating T
`cell population, down regulation of adhesion molecule expression, modulation of the
`Th1/Th2 cytokine expression profile, inhibition of neutrophil burst, and TNF-induced
`CD62E expression through suppression of NF-kB nuclear translocation.
`
`Methyl fumaric acid esters (FUMADERMÒ) have been shown to reduce peripherally
`in vivo circulating CD4+, CD8+ and CD52+ mononuclear cells (Hoxtermann et al,
`1998). This circulatory reduction has been associated with a decrease in
`intradermal mononuclear cell infiltration in psoriasis patients (another T
`cell-mediated disease) (Vandermeeren et al, 1997). DMF was recently shown to
`induce substantial plasma membrane alterations potentially linked to the
`deactivation via apoptosis of lymphocytes (Sebök et al, 2000).
`
`Methylfumarates have been shown to modulate in vitro T cell cytokine profile from
`Th1 to Th2 (Ockenfels et al, 1998). DMF and MMF inhibit the proliferation of
`keratinocytes, possibly due to a temporary rise in the intracellular calcium
`concentration (Nibbering et al, 1993). Methylfumarates have been shown to prevent
`acute and chronic rejection in rat kidney transplantation models (Risch et al, 2001).
` It is difficult to assess the validity of some in vitro data that have been derived using
`doses that exceed serum levels found in human trials (Mrowietz et al, 1999).
`
`In summary, the putative immunomodulatory effects, the psoriasis efficacy of
`FUMADERM®, and the efficacy data in the pilot MS study of BG00012 support a
`
`1 of 6
`
`4/29/2015 7:48 AM
`
`Page 1 of 6
`
`

`
`NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`proof of concept study in MS
`Detailed description
`The study will be divided into two parts: Part 1 will be a 24 week, blinded, placebo-
`controlled treatment phase followed by Part 2, a 24-week blinded, safety extension
`phase in which all subjects will receive BG00012.
`
`All investigational drug (BG00012 or placebo) will be given orally.
`
`In Part 1, subjects will be randomized in equal numbers to one of the following
`treatment groups:
`
`Treatment Group BG00012 Dosing Regimen BG00012 Total Daily Dose
`1 120 mg once a day (qd) 120 mg
`2 120 mg three times a day (tid) 360 mg
`3 240 mg tid 720 mg
`4 Placebo Placebo
`
`All subjects will be evaluated for tolerance to investigational drug after the first week
`of dosing. In addition, subjects in the highest dose group (Group 3) will dose at 120
`mg tid for the first week. After 1 week, Group 3 subjects who tolerate
`120 mg tid (as determined by the subject’s tolerance of flushing episodes and
`gastrointestinal [GI] disturbances) will have their dose increased to 240 mg tid.
`
`In Part 2, subjects who received BG00012 in Part 1 of the study will remain on the
`same BG00012 dose throughout the Part 2 extension phase. Subjects who
`received placebo in Part 1 of the study will receive BG00012 120 mg tid for one
`week in Part 2 and then, if well-tolerated, the BG00012 dose will be increased to
`240 mg tid.
`
`Dose reduction will be allowed for subjects who are unable to tolerate investigational
`drug. Dosing interruptions (or investigational drug discontinuation) will be required
`for significantly elevated liver or renal function tests or decreased white blood cell
`count (WBC). Any subject who prematurely discontinues BG00012 dosing should
`remain in the study for the time period specified in the protocol and continue
`protocol-scheduled evaluations.
`
`Subject treatment assignments will remain blinded throughout the study. Safety will
`be monitored during the study by the Advisory Committee and the Clinical Safety
`Committee.
`
`Phase
`Study type
`Study design
`Study design
`Study design
`Study design
`Study design
`Study design
`
`Phase 2
`Interventional
`Treatment
`Randomized
`Double Blind
`Placebo Control
`Parallel Assignment
`Safety/Efficacy Study
`
`2 of 6
`
`4/29/2015 7:48 AM
`
`Page 2 of 6
`
`

`
`NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`Primary outcome
`
`Secondary outcome
`Secondary outcome
`
`Secondary outcome
`
`Secondary outcome
`Secondary outcome
`
`Secondary outcome
`Secondary outcome
`
`Secondary outcome
`
`Condition
`Intervention
`
`Measure: The primary endpoint for the primary objective is
`the total number of Gd-enhancing lesions over four scans at
`Weeks 12, 16, 20, and 24 (calculated as the sum of these
`four MRI scans).
`Measure: Secondary MRI endpoints include:
`Measure: · the cumulative number of new Gd-enhancing
`lesions from baseline to Week 24, and
`Measure: · the number of new or newly-enlarging T2
`hyperintense lesions at Week 24 compared to baseline.
`Measure: Additional endpoints include:
`Measure: · the number of new T1 hypointense lesions at
`Week 24 compared to baseline
`Measure: · the incidence and severity of adverse events
`Measure: · EDSS scores and change from baseline in
`EDSS scores at Weeks 12, 24, 36, and 48, and
`Measure: · annualized relapse rate from Week 0 to Weeks
`24 and 48, and the proportion of relapse-free subjects at
`Weeks 24 and 48.
`Multiple Sclerosis
`Drug: BG00012
`
`Recruitment Information
`Status
`Start date
`Criteria
`Inclusion Criteria:
`1. Must give written informed consent and authorize the release and use of
`protected health information (PHI), as required by local law.
`
`No longer recruiting
`2004-10
`
`2. Must be 18 to 55 years old, inclusive, at the time of informed consent.
`
`3. Must have a confirmed diagnosis of relapsing-remitting MS according to
`McDonald criteria #1-4 (McDonald et al, 2001; Appendix 2).
`
`4. Must have a baseline EDSS between 0.0 and 5.0, inclusive.
`
`5. Must meet one of the following two criteria:
`
`a) have experienced at least one relapse within the 12 months prior to
`randomization, with a prior cranial MRI demonstrating lesion(s) consistent with MS (it
`is not necessary to obtain a current scan if a scan performed previously is available
`from the subject’s history; if a scan is not available from the subject’s history, then
`the baseline scan may be used). For inclusion purposes, a relapse is defined as
`neurologic signs and/or symptoms documented by a neurologist in the medical
`record and of at least 24-hours duration to be determined by the investigator or the
`treating neurologist. Time since relapse should be measured from the time of
`
`3 of 6
`
`4/29/2015 7:48 AM
`
`Page 3 of 6
`
`

`
`NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`relapse onset,
`
`OR
`
`b) show evidence of Gd-enhancing lesions of the brain on an MRI performed within
`the 6 weeks prior to randomization (if a scan is not available from the subject’s
`history, then the baseline scan may be used).
`
`6. Male and female subjects must be willing to take appropriate measures to prevent
`pregnancy while participating in this study. Male subjects and female subjects of
`child-bearing potential must use adequate contraception as appropriate (either intra-
`uterine device, oral or depot contraceptive, or barrier plus spermicide) and be willing
`and able to continue contraception for 30 days after their last dose of investigational
`drug. The rhythm method is not to be used as the sole method of contraception.
` Females who have not been stable on oral or depot contraceptives for 3 months
`prior to the first dose of investigational drug must also agree to use a barrier method
`throughout the study. Female subjects are exempt from contraceptive use if they
`are post-menopausal for at least 1 year prior to the start of the study or are
`surgically sterile (females need to have either no uterus or no ovaries to be
`considered surgically sterile; males or females who have tubes tied or cut are not
`considered surgically sterile).
`
`All female subjects who are not post-menopausal or surgically sterile must have a
`negative pregnancy test at screening and at various time points throughout the
`study to receive investigational drug.
`
`Exclusion Criteria:
`1. Primary progressive, secondary progressive, or progressive relapsing MS (as
`defined by Lublin and Reingold, 1996 [Appendix 3]). These conditions require the
`presence of continuous clinical disease worsening over a period of at least 3
`months. Patients with these conditions may also have superimposed relapses, but
`are distinguished from relapsing-remitting patients by the lack of clinically stable
`periods or clinical improvement.
`
`2. History of malignancy unless an exception is granted by the Biogen Idec Medical
`Director.
`
`3. History of severe allergic or anaphylactic reactions or known drug hypersensitivity.
`
`4. History of abnormal laboratory results indicative of any significant cardiac,
`endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary,
`gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than MS), and/or
`other major disease that would preclude administration of BG00012.
`
`5. History of human immunodeficiency virus (HIV).
`
`6. History of drug or alcohol abuse (as defined by the Investigator) within the 2 years
`prior to randomization.
`
`7. An MS relapse that has occurred within the 50 days prior to randomization
`
`4 of 6
`
`4/29/2015 7:48 AM
`
`Page 4 of 6
`
`

`
`NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`AND/OR the subject has not stabilized from a previous relapse prior to
`randomization.
`
`8. Body weight >100 kg.
`
`9. Positive for hepatitis C antibody and/or positive for hepatitis B surface antigen
`(HBsAg) at screening.
`
`10. Any of the following abnormal blood tests at screening:
`· alanine transaminate/serum glutamate-pyruvate transaminase (ALT/SGPT), or
`aspartate transaminase/serum glutamic-oxaloacetic transaminase (AST/SGOT), or
`gamma-glutamyl-transferase (GGT) >2 times the upper limit of normal (ULN)
`· leukocytes <3500/mm3
`· eosinophils >0.7 x 10³/mL or >0.7 GI/L, and
`· serum creatinine >ULN.
`11. Any previous treatment with FUMADERM®, FAG-201, or BG00012.
`
`12. Prior treatment with the any of the following:
`· total lymphoid irradiation
`· cladribine
`· T-cell or T-cell receptor vaccination
`· any therapeutic monoclonal antibody, with the exception of ANTEGREN®
`(natalizumab) (see exclusion #14)
`
`13. Prior treatment with any of the following within 1 year prior to randomization:
`· mitoxantrone
`· cyclophosphamide
`
`14. Prior treatment with any of the following medications or procedures within the 6
`months prior to randomization:
`· cyclosporine
`· azathioprine
`· methotrexate
`· natalizumab
`· intravenous immunoglobulin (IVIg)
`· plasmapheresis or cytapheresis.
`
`15. Prior treatment with any of the following within the 3 months prior to
`randomization:
`· subcutaneous or oral glatiramer acetate
`· interferon-alpha
`· interferon-beta (subjects who are positive for neutralizing antibodies to
`interferon-beta may receive interferon-beta treatment up to 2 weeks prior to
`randomization).
`
`16. Treatment with any of the following medications within the 30 days prior to
`randomization:
`· IV corticosteroid treatment
`· oral corticosteroid treatment
`· 4-aminopyridine or related products.
`
`5 of 6
`
`4/29/2015 7:48 AM
`
`Page 5 of 6
`
`

`
`NCT00168701 on 2005_09_14: ClinicalTrials.gov Archive
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`17. Treatment with another investigational drug or approved therapy for
`investigational use within the 6 months prior to randomization.
`18. Female subjects considering becoming pregnant while in the study.
`
`19. Female subjects who are currently pregnant or breast-feeding.
`
`20. Previous participation in this study.
`
`21. Current enrollment in any other investigational drug study or participation in any
`other investigational study within 6 months prior to randomization.
`
`22. Unwillingness or inability to comply with the requirements of the protocol
`including the presence of any condition (physical, mental, or social) that is likely to
`affect the subject’s ability to comply with the protocol.
`
`23. Any other reasons that, in the opinion of the Investigator and/or the Sponsor, the
`subject is determined to be unsuitable for enrollment in this study.
`Gender
`Both
`Minimum age
`18 Years
`Maximum age
`55 Years
`Healthy volunteers
`No
`Expected enrollment
`260
`
`Biogen Idec
`C-1900
`Biogen Idec
`United Kingdom: Medicines and Healthcare Products
`Regulatory Agency
`Germany: Federal Institute for Drugs and Medicinal Devices
`Netherlands: Medicines Evaluation Board (MEB)
`Czech Republic: State Institute for Drug Control
`Poland: Ministry of Health
`Hungary: National Institute of Pharmacy
`Switzerland: Swissmedic
`Turkey: Ministry of Health
`Sweden: Medical Products Agency
`Russia: Pharmacological Committee, Ministry of Health
`
`
`
`Administrative Data
`Organization name
`Organization study ID
`Sponsor
`Health Authority
`
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`Health Authority
`
`6 of 6
`
`4/29/2015 7:48 AM
`
`Page 6 of 6