Study to Assess Whether GSK239512 Can Remyelinate Lesions in Subjects With Relapsing Remitting Multiple Sclerosis

Proof of Mechanism Study to Assess the Potential of GSK239512 to 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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: GSK239512; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1431
    • GSK Investigational Site
  • Sofia, Bulgaria, 1113
    • GSK Investigational Site
  • Sofia, Bulgaria, 1309
    • GSK Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • GSK Investigational Site
    • Edmonton, Alberta, Canada, T6G 1Z1
      • GSK Investigational Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • GSK Investigational Site
  • Quebec
    • Gatineau, Quebec, Canada, J9J 0A5
      • GSK Investigational Site
    • Montreal, Quebec, Canada, H3A 2B4
      • GSK Investigational Site
• Czech Republic
  • Jihlava, Czech Republic, 586 33
    • GSK Investigational Site
  • Olomouc, Czech Republic, 775 20
    • GSK Investigational Site
  • Teplice, Czech Republic, 415 29
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 10961
    • GSK Investigational Site
  • Berlin, Germany, 12163
    • GSK Investigational Site
  • Hamburg, Germany, 20249
    • GSK Investigational Site
  • Hamburg, Germany, 22083
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany, 89073
      • GSK Investigational Site
  • Bayern
    • Alzenau, Bayern, Germany, 63755
      • GSK Investigational Site
    • Unterhaching, Bayern, Germany, 82008
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50935
      • GSK Investigational Site
    • Muenster, Nordrhein-Westfalen, Germany, 48149
      • GSK Investigational Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01069
      • GSK Investigational Site
    • Leipzig, Sachsen, Germany, 04103
      • GSK Investigational Site
• Spain
  • Barcelona, Spain, 08036
    • GSK Investigational Site
  • Barcelona, Spain, 08035
    • GSK Investigational Site
  • Madrid, Spain, 28040
    • GSK Investigational Site
  • Madrid, Spain, 28046
    • GSK Investigational Site
  • Madrid, Spain, 28034
    • GSK Investigational Site
  • Majadahonda (Madrid), Spain, 28222
    • GSK Investigational Site
  • Malaga, Spain, 29010
    • GSK Investigational Site
  • Sevilla, Spain, 41009
    • GSK Investigational Site
• Sweden
  • Stockholm, Sweden, SE-141 86
    • GSK Investigational Site
• Ukraine
  • Donetsk, Ukraine, 83099
    • GSK Investigational Site
  • Ivano-Frankivsk, Ukraine, 76008
    • GSK Investigational Site
  • Kharkiv, Ukraine, 61068
    • GSK Investigational Site
  • Kyiv, Ukraine, 04107
    • GSK Investigational Site
  • Lutsk, Ukraine, 43005
    • GSK Investigational Site
  • Lviv, Ukraine, 79010
    • GSK Investigational Site
  • Poltava, Ukraine, 36024
    • GSK Investigational Site
  • Vinnitsa, Ukraine, 21005
    • GSK Investigational Site
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • GSK Investigational Site
  • London, United Kingdom, NW1 2BU
    • GSK Investigational Site
  • Romford, United Kingdom, RM7 0AG
    • GSK Investigational Site
  • Sheffield, United Kingdom, S10 2JF
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GSK239512 Arm; GSK239512 once daily orally, started at 10 mcg and titrated to the maximum tolerated dose, Up to the highest dose of 80 mcg (10 mcg first week, 20 mcg second week, 40 mcg third week, 80 mcg fourth week) followed by 44 week maintenance treatment period	Drug: GSK239512; White to almost white, round tablets. Once daily orally, started at 10 mcg and titrated to the maximum tolerated dose, Up to the highest dose of 80 mcg (10 mcg first week, 20 mcg second week, 40 mcg third week, 80 mcg fourth week) followed by 44 week maintenance treatment period
Placebo Comparator: Placebo Arm; Placebo once daily orally	Drug: Placebo; White to almost white, round tablets. Once daily orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in gadolinium (Gd) enhanced (GdE) lesion magnetization transfer ratio (MTR) differences (calibrated to reference scan) from before enhancement to stable recovery (>=3 months post new GdE lesion)	A single Baseline magnetic resonance image (MRI) prior to randomization. Following randomization, a total of 8 MRIs at approximate 6 week intervals: Week 6, Week 12, Week 18, Week 24, Week 30, Week 36, Week 42, Week 48. Reference MRI: In order to accommodate variations in MTR images acquired using different scanners, the images must be normalized to eliminate intensity shifts and contrast variations. For each scanner, images from a normal subject will be obtained and processed to serve as a calibration for each scanner prior to initiating scanning for subjects participating in the study	Up to Week 48
Mean change in Delta MTR lesion MTR differences (calibrated to reference scan) from before lesion appearance to stable recovery (>=3 months post lesion appearance)	A single Baseline MRI prior to randomization Following randomization, a total of 8 MRIs at approximate 6 week intervals: Week 6, Week 12, Week 18, Week 24, Week 30, Week 36, Week 42, Week 48. Reference MRI: In order to accommodate variations in MTR images acquired using different scanners, the images must be normalized to eliminate intensity shifts and contrast variations. For each scanner, images from a normal subject will be obtained and processed to serve as a calibration for each scanner prior to initiating scanning for subjects participating in the study	Up to Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in T2 lesion MTR at Week 48		Baseline and Week 48
Cumulative new and enlarging Gd enhancing, T2 and Combined Unique Active lesions comparing placebo to GSK239512 treated subjects		Up to Week 48
Change from baseline at Week 48 in total brain volume, white matter volume and grey matter volume comparing placebo to GSK239512 treated subjects		Baseline and Week 48
Cumulative number of persistent black holes and new unenhancing T1 lesion counts comparing placebo to GSK239512 treated subjects over treatment duration up to Week 48		Up to Week 48
Proportion of new GdE lesions evolving into chronic (unenhancing) T1 lesions (black holes) comparing placebo to GSK239512 treated subjects over treatment duration up to Week 48		Up to Week 48
Mean change from baseline in overall cognitive impairment and cognitive domains comparing placebo to GSK239512 treated subjects	A cognitive battery (computerized battery) is included in this study to assess the impact, if any, on several cognitive functional domains. The battery will be executed twice during the screen visit to familiarize the subject with the use of the tool	Baseline and Week 48
Comparison of Relapse Rates between placebo and GSK239512 treated subjects	A relapse in this protocol is defined as: "patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS), current or historical". It must occur in the absence of fever or infection and should - follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours	Up to 50 Weeks
Comparison of Time to First Relapse between placebo and GSK239512	A relapse in this protocol is defined as: "patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS), current or historical". It must occur in the absence of fever or infection and should - follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours	Up to 50 Weeks
Comparison of the proportion of subjects Relapse Free between placebo and GSK239512 treated subjects	A relapse in this protocol is defined as: "patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS), current or historical". It must occur in the absence of fever or infection and should - follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours	Up to 50 Weeks
Proportion of subjects with sustained worsening of Expanded Disability Severity Scale (EDSS) over 3 months comparing placebo to GSK239512 treated subjects	The EDSS is an assessment of disability specifically associated with Multiple Sclerosis. The assessment will be captured in the medical records including the detailed assessment and scoring for each functional system and domain	Up to 48 Weeks
Mean change from baseline in the EDSS functional systems and a subset of component assessments comparing placebo to GSK239512 treated subjects	The EDSS is an assessment of disability specifically associated with Multiple Sclerosis. The assessment will be captured in the medical records including the detailed assessment and scoring for each functional system and domain	Up to 48 Weeks
Safety and tolerability as assessed by frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)		Up to Week 50
Safety and tolerability as assessed by percentage of subjects withdrawing due to AEs		Up to Week 50
Safety and tolerability as assessed by summary of suicide behavior and ideation risk as assessed by the electronic Columbia Suicide Severity Rating Scale (eC-SSRS)		Up to Week 50
Safety and tolerability as assessed by summary of suicide behavior and ideation risk as assessed by Possible Suicidality Related Adverse Event (PSRAE)		Up to Week 50
Safety and tolerability as assessed by change from baseline in clinical chemistry, hematology, and urinalysis parameters		Up to Week 50
Safety and tolerability as assessed by frequency of clinical chemistry, hematology, and urinalysis parameters of potential clinical concern		Up to Week 50
Safety and tolerability as assessed by change from baseline in blood pressure		Up to Week 50
Safety and tolerability as assessed by change from baseline in heart rate		Up to Week 50
Safety and tolerability as assessed by change from baseline in Electrocardiogram (ECG) parameters		Up to Week 50
Safety and tolerability as assessed by frequency of vital signs and ECG parameters of potential clinical concern		Up to Week 50
Trough concentration of GSK239512 at Week 4, Week 24, Week 36 and Week 48		Up to 48 weeks
Sparse Pharmacokinetics (PK) sampling for concentration of GSK239512 at Week 8	1 pre-dose and 3 post-dose samples. No samples should be collected within 30 minutes of the previous sample	Pre-dose, and 30 minutes (15 min to 1 hour), 2 hours (1 to 4 hours) and 6 hours (4 to 8 hours) post dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: January 17, 2013
• First Submitted That Met QC Criteria: January 17, 2013
• First Posted (Estimate): January 21, 2013

Study Record Updates

• Last Update Posted (Estimate): August 16, 2016
• Last Update Submitted That Met QC Criteria: August 12, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: magnetic resonance imaging; remyelination; Relapsing Remitting Multiple Sclerosis; GSK239512; Histamine 3 Receptor Antagonist; magnetization transfer ratio
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: 116477

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Study Protocol
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Clinical Study Report
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Annotated Case Report Form
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Dataset Specification
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 116477
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register