Study to Assess Whether GSK239512 Can Remyelinate Lesions in Subjects With Relapsing Remitting Multiple Sclerosis
Study to Assess Whether GSK239512 Can Remyelinate Lesions in Subjects With Relapsing Remitting Multiple Sclerosis
This is a randomized, parallel group, placebo-controlled study designed to assess whether
 GSK239512 can enhance lesion remyelination in subjects with Relapsing Remitting Multiple
 Sclerosis (RRMS). Subjects with RRMS on stable background treatment with either Avonex
 (Interferon-beta1a) or Copaxone (Glatiramer Acetate) are eligible to participate. Subjects
 will be randomized in a 1:1 ratio between placebo and GSK239512, and will continue to be
 managed with their current standard of care therapy (Copaxone or Avonex). The total treatment
 period is 48 weeks, including a standard 4 week titration period and 44 week maintenance
 treatment period (which could be adapted to a 5-week titration and 43 week maintenance
 period, if needed). Titration doses start at 10 micrograms (mcg) and increase up to 80 mcg
 (10 mcg first week, 20 mcg second week, 40 mcg third week, 80 mcg fourth week). Subjects will
 be titrated to the maximum tolerated dose with the objective of titrating to the highest dose
 (80 mcg GSK239512), whenever possible, based on investigator judgement of tolerability. The
 post-treatment follow-up period will be a minimum of 2 weeks in duration following the end of
 treatment at Week 48 or early withdrawal, as appropriate.
Inclusion Criteria:

 -  18 to 50 years of age

 -  Diagnosed with a relapsing-remitting course of multiple sclerosis as defined by the
 appropriate McDonald criteria at the time of diagnosis.

 -  Diagnosis of RRMS made within approximately 10 years prior to the screening visit (as
 documented by year of diagnosis or duration of disease), and No physical
 manifestations of other forms of Multiple Sclerosis (MS) including signs of
 progression to secondary progressive MS (SPMS)

 -  Currently compliant with a stable dose regimen of Avonex (Interferon Beta1a) or
 Copaxone (Glatiramer Acetate) for management of MS for >= 1 year prior to the
 screening visit

 -  The occurrence of at least one of the following (within the year preceding the screen
 visit AND after >=2 months of stable treatment with Avonex OR Copaxone): a) 1 reported
 and/or documented relapse, OR b) 1 Gadolinium Enhanced (GdE) lesion on MRI

 -  Currently neurologically stable, in the investigator's judgment, and not actively
 experiencing or recovering from a recent relapse at the screening visit

 -  A Kurtzke Expanded Disability Status Scale (EDSS) score of 1 to 4.5 (inclusive) at the
 screening visit.

 -  Must agree not to participate in a clinical study involving another investigational
 drug or device throughout their participation in this study. Non-interventional study
 participation is allowed if the time involvement and scheduling will not interfere
 with compliance in this study in the opinion of the investigator

 -  A female subject is eligible to enter the study if she is a) Not pregnant or nursing,
 b) Of non-childbearing potential (i.e. women who have had a hysterectomy, are
 postmenopausal, which is defined as >2 years without menses [female subjects who have
 been post-menopausal for <2 years must be confirmed with Follicle Stimulating Hormone
 and estradiol levels], have both ovaries surgically removed or have current documented
 tubal ligation); or, c) Of childbearing potential and agrees to use the acceptable
 methods of birth control, for one month prior to the start of investigational product
 to 1 month after the last dose of investigational product.

 -  Informed Consent: Must be competent to understand the information given in the
 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved
 Informed Consent Form (ICF) and must sign the form prior to the initiation of any
 study procedures

 Exclusion Criteria:

 -  MRI: Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia,
 hypersensitivity to contrast media), Lacks adequate venous access for administration
 of Gd-enhancing agent, or Findings on brain MRI scan indicating any clinically
 significant brain abnormality other than MS (e.g. damage associated with prior
 traumatic brain injury)

 -  Past and Concurrent Medical Conditions: a) History of severe and clinically
 significant CNS trauma with current sequelae (e.g. traumatic brain injury, spinal cord
 compression), b) Significant concurrent, uncontrolled medical condition or disease
 which in the opinion of the investigator could (e.g. significant psychiatric disorder,
 etc), affect the subjects' safety, impair the subject's reliable participation in the
 trial, impair the evaluation of the endpoints, or necessitate the use of medication
 not allowed by this protocol, c) History or presence of myelopathy due to spinal cord
 compression by disk or vertebral disease or chronic progressive myelopathy, d)
 Diagnosis of any type epilepsy, e) At risk of suicide, as indicated by: A documented
 history of attempted suicide or significant suicidal ideation during the 6 months
 preceding the screening visit, OR If in the investigator's judgment the subject is at
 risk of a suicide attempt based on the screen visit assessment, including the eC-SSRS,
 f) Presence of significant and routine sleep disturbance (severe insomnia, nocturnal
 wandering, confusion, disorientation, agitation, or vivid dreams) that has a negative
 impact on quality of life that, in the judgement of the investigator, may increase the
 risk of tolerability issues during dose escalation, g) Presence or history of
 hallucinations that, in the judgement of the investigator, may increase the safety
 risk to the subject, h) Known diagnosis or history consistent with positive human
 immunodeficiency virus (HIV)

 -  Past and Current Medications and Therapies: Have had treatment with the following to
 manage their MS: a) Within 1 year: fingolimod (e.g. Gilenya), Rebif (interferon
 beta1a), interferon beta1b (e.g. Betaseron), mycophenolate mofetil (e.g. CellCept), or
 Recently approved medication or formulation indicated for the management of MS.
 Consult with GlaxoSmithKline (GSK) Medical Monitor if there are specific questions
 regarding eligible treatments b) Within 2 years: natalizumab (e.g. Tysabri),
 alemtuzumab (e.g. Campath), daclizumab (e.g. Zenapax), rituximab (e.g. Rituxan),
 mitoxantrone (e.g. Novantrone), cladribine (e.g. Leustatin), or azathioprine (e.g.
 Imuran)

 -  Have used corticotropin to manage a relapse within 6 months prior to Screen Visit.

 -  Have had treatment with the following and were unable to discontinue and refrain from
 treatment for the specified time period and are not able to discontinue use throughout
 participation in the clinical trial: dalfampridine /fampridine (e.g. Ampyra) - 1 month
 prior to Screen Visit, nabiximols (e.g. Sativex) - 1 month prior to Screen Visit,
 amantadine (e.g. Symmetrel) - 3 months prior to Screen Visit, or leflunomide (e.g.
 Arava) - 1 year prior to Screen Visit

 -  Have used the following medications within the last 30 days or 5 half-lives (whichever
 is longer) prior to screening and are not able to discontinue use throughout
 participation in the clinical trial: Any CNS stimulants (e.g., modafinil,
 dexamphetamine, methylphenidate), Known potent P-glycoprotein inhibitors (e.g.
 itraconazole, ketoconazole, cyclosporin, loperamide, diltiazem, verapamil,
 spironolactone, quinidine, bepridil, quinine, carvedilol), Known potent inhibitors or
 inducers of the CYP3A4 enzyme (e.g., verapamil, ketoconazole, cimetidine, rifampin,
 modafinil), CNS-penetrant antihistamines (e.g. bromopheniramine, chlorpheniramine,
 clemastine, diphenhydramine, hyrdoxyzine),

 -  History of medically significant adverse effects (including allergic reactions and
 hypersensitivities) following treatment with: Histamine H3 receptor antagonist or
 inverse agonist, Gadolinium enhancing agent, Relapse medication: glucocorticoids
 (e.g., methylprednisolone) OR A known hypersensitivity to components of the
 investigational product, relapse medication, or Gadolinium enhancing agent.

 -  Electrocardiogram (ECG) showing a clinically significant abnormality at screening.
 Including a QT interval corrected using Bazett's and Fridericia's formulas (QTcB or
 QTcF) interval of >=450 msec or >=480 msec for patients with a Bundle Branch Block.

 -  Infectious Disease Status at Screening a) Subjects with no documented record of
 vaccination against Hepatitis B (primary and secondary immunization and booster) AND a
 positive test for hepatitis B surface antigen (HBsAg and Hepatitis B Core Antibody
 [IgM anti-HBc]), b) Subjects with serologic evidence of active Hepatitis C, as
 indicated by a positive Hepatitis C Virus(HCV) RNA test and anti-HCV antibody test

 -  Laboratory Values at Screening: Hematology: Total white cell count <2.0 x 109/L,
 Neutrophils <1.0 x 109/L, Platelets <75 x 109/L (If out of range, platelet count can
 be repeated to exclude platelet clumping), or Haemoglobin < 80 g/L.

 -  Screening clinical chemistry liver function test: Alanine aminotransferase (ALT) >2.0
 x upper limit of normal (ULN), Aspartate aminotransferase (AST) >2.0 x ULN, Alkaline
 phosphatise (ALP) >1.5 x ULN, or Bilirubin >1.5 x ULN.

 -  Documented renal insufficiency or laboratory results indicative of renal insufficiency
 (due to risks associated with administration of Gadolinium based contrast agents to
 subjects with moderate to severe kidney disease): Estimated Creatinine Clearance
 (Cockroft-Gault) <60 mL/minute

 -  If known, or according to investigator judgement, subject is suspected of not being
 able to comply with the study protocol requirements. Contributing factors to this
 assessment by the investigator could be, but not limited to: job demands, substance
 abuse, alcoholism, drug dependency or psychological disorder

 -  Prior participation in a clinical trial or use of an investigational product for a non
 approved intervention: Prior use of an investigational drug for MS or a condition
 other than MS within 4 weeks or 5 half-lives (whichever is longer) prior to screening.
 The GSK Medical Monitor should be consulted to confirm eligibility