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

NCT01772199 | Completed Phase 2

• 1 other identifier: 116477
• Study Type: interventional
• Target: 131
• Locations: 8 countries
• Sites: 43

Brief Summary

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Keywords

GSK239512; remyelination; magnetic resonance imaging; Relapsing Remitting Multiple Sclerosis; Histamine 3 Receptor Antagonist; magnetization transfer ratio

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (23)

• 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

Study Arms (2)

GSK239512 Arm

EXPERIMENTAL

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

Placebo Arm

PLACEBO COMPARATOR

Placebo once daily orally

Drug: Placebo

Interventions

GSK239512 DRUG

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

GSK239512 Arm

Placebo DRUG

White to almost white, round tablets. Once daily orally.

Placebo Arm

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (43)

GSK Investigational Site

Sofia, 1113, Bulgaria

Location

GSK Investigational Site

Sofia, 1309, Bulgaria

Location

GSK Investigational Site

Sofia, 1431, Bulgaria

Location

GSK Investigational Site

Calgary, Alberta, T2N 2T9, Canada

Location

GSK Investigational Site

Edmonton, Alberta, T6G 1Z1, Canada

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Gatineau, Quebec, J9J 0A5, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3A 2B4, Canada

Location

GSK Investigational Site

Jihlava, 586 33, Czechia

Location

GSK Investigational Site

Olomouc, 775 20, Czechia

Location

GSK Investigational Site

Teplice, 415 29, Czechia

Location

GSK Investigational Site

Ulm, Baden-Wurttemberg, 89073, Germany

Location

GSK Investigational Site

Alzenau in Unterfranken, Bavaria, 63755, Germany

Location

GSK Investigational Site

Unterhaching, Bavaria, 82008, Germany

Location

GSK Investigational Site

Hamburg, Hamburg, 20249, Germany

Location

GSK Investigational Site

Hamburg, Hamburg, 22083, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 50935, Germany

Location

GSK Investigational Site

Münster, North Rhine-Westphalia, 48149, Germany

Location

GSK Investigational Site

Dresden, Saxony, 01069, Germany

Location

GSK Investigational Site

Leipzig, Saxony, 04103, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 10961, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 12163, Germany

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

Madrid, 28034, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Madrid, 28046, Spain

Location

GSK Investigational Site

Majadahonda (Madrid), 28222, Spain

Location

GSK Investigational Site

Málaga, 29010, Spain

Location

GSK Investigational Site

Seville, 41009, Spain

Location

GSK Investigational Site

Stockholm, SE-141 86, Sweden

Location

GSK Investigational Site

Donetsk, 83099, Ukraine

Location

GSK Investigational Site

Ivano-Frankivsk, 76008, Ukraine

Location

GSK Investigational Site

Kharkiv, 61068, Ukraine

Location

GSK Investigational Site

Kyiv, 04107, Ukraine

Location

GSK Investigational Site

Lutsk, 43005, Ukraine

Location

GSK Investigational Site

Lviv, 79010, Ukraine

Location

GSK Investigational Site

Poltava, 36024, Ukraine

Location

GSK Investigational Site

Vinnitsa, 21005, Ukraine

Location

GSK Investigational Site

London, NW1 2BU, United Kingdom

Location

GSK Investigational Site

London, SE5 9RS, United Kingdom

Location

GSK Investigational Site

Romford, RM7 0AG, United Kingdom

Location

GSK Investigational Site

Sheffield, S10 2JF, United Kingdom

Location

Related 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.

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

GSK239512

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2013
• First Posted: January 21, 2013
• Study Start: February 1, 2013
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: August 16, 2016

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will share

Locations

CA (5); CZ (3); SE (1); UA (8); BU (3); GB (4); ES (8); DE (11)