Clinical trial NCT01772199: Study to Assess Whether GSK239512 Can Remyelinate Lesions in Subjects With Relapsing Remitting Multiple Sclerosis
Official title: Proof of Mechanism Study to Assess the Potential of GSK239512 to Remyelinate Lesions in Subjects With Relapsing Remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: GSK239512
remyelination
magnetic resonance imaging
Relapsing Remitting Multiple Sclerosis
Histamine 3 Receptor Antagonist
magnetization transfer ratio
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-01-21
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Up to Week 48
measure: Mean change in Delta MTR lesion MTR differences (calibrated to reference scan) from before lesion appearance to stable recovery (>=3 months post lesion appearance)
timeFrame: Up to Week 48
Secondary outcomes:
measure: Change from baseline in T2 lesion MTR at Week 48
timeFrame: Baseline and Week 48
measure: Cumulative new and enlarging Gd enhancing, T2 and Combined Unique Active lesions comparing placebo to GSK239512 treated subjects
timeFrame: Up to Week 48
measure: Change from baseline at Week 48 in total brain volume, white matter volume and grey matter volume comparing placebo to GSK239512 treated subjects
timeFrame: Baseline and Week 48
measure: 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
timeFrame: Up to Week 48
measure: 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
timeFrame: Up to Week 48
measure: Mean change from baseline in overall cognitive impairment and cognitive domains comparing placebo to GSK239512 treated subjects
timeFrame: Baseline and Week 48
measure: Comparison of Relapse Rates between placebo and GSK239512 treated subjects
timeFrame: Up to 50 Weeks
measure: Comparison of Time to First Relapse between placebo and GSK239512
timeFrame: Up to 50 Weeks
measure: Comparison of the proportion of subjects Relapse Free between placebo and GSK239512 treated subjects
timeFrame: Up to 50 Weeks
measure: Proportion of subjects with sustained worsening of Expanded Disability Severity Scale (EDSS) over 3 months comparing placebo to GSK239512 treated subjects
timeFrame: Up to 48 Weeks
measure: Mean change from baseline in the EDSS functional systems and a subset of component assessments comparing placebo to GSK239512 treated subjects
timeFrame: Up to 48 Weeks
measure: Safety and tolerability as assessed by frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by percentage of subjects withdrawing due to AEs
timeFrame: Up to Week 50
measure: 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)
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by summary of suicide behavior and ideation risk as assessed by Possible Suicidality Related Adverse Event (PSRAE)
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by change from baseline in clinical chemistry, hematology, and urinalysis parameters
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by frequency of clinical chemistry, hematology, and urinalysis parameters of potential clinical concern
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by change from baseline in blood pressure
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by change from baseline in heart rate
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by change from baseline in Electrocardiogram (ECG) parameters
timeFrame: Up to Week 50
measure: Safety and tolerability as assessed by frequency of vital signs and ECG parameters of potential clinical concern
timeFrame: Up to Week 50
measure: Trough concentration of GSK239512 at Week 4, Week 24, Week 36 and Week 48
timeFrame: Up to 48 weeks
measure: Sparse Pharmacokinetics (PK) sampling for concentration of GSK239512 at Week 8
timeFrame: 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
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Gatineau
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Jihlava
country: Czech Republic
facility: GSK Investigational Site
city: Olomouc
country: Czech Republic
facility: GSK Investigational Site
city: Teplice
country: Czech Republic
facility: GSK Investigational Site
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Alzenau
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Unterhaching
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Majadahonda (Madrid)
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Donetsk
country: Ukraine
facility: GSK Investigational Site
city: Ivano-Frankivsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Lutsk
country: Ukraine
facility: GSK Investigational Site
city: Lviv
country: Ukraine
facility: GSK Investigational Site
city: Poltava
country: Ukraine
facility: GSK Investigational Site
city: Vinnitsa
country: Ukraine
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Romford
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: