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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
131
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
White to almost white, round tablets. Once daily orally.
GSK Investigational Site
Sofia, Bulgaria
GSK Investigational Site
Sofia, Bulgaria
GSK Investigational Site
Sofia, Bulgaria
GSK Investigational Site
Calgary, Alberta, Canada
GSK Investigational Site
Edmonton, Alberta, Canada
GSK Investigational Site
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
Time frame: 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
Time frame: Up to Week 48
Change from baseline in T2 lesion MTR at Week 48
Time frame: Baseline and Week 48
Cumulative new and enlarging Gd enhancing, T2 and Combined Unique Active lesions comparing placebo to GSK239512 treated subjects
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 48 Weeks
Safety and tolerability as assessed by frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Up to Week 50
Safety and tolerability as assessed by percentage of subjects withdrawing due to AEs
Time frame: 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)
Time frame: 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)
Time frame: Up to Week 50
Safety and tolerability as assessed by change from baseline in clinical chemistry, hematology, and urinalysis parameters
Time frame: Up to Week 50
Safety and tolerability as assessed by frequency of clinical chemistry, hematology, and urinalysis parameters of potential clinical concern
Time frame: Up to Week 50
Safety and tolerability as assessed by change from baseline in blood pressure
Time frame: Up to Week 50
Safety and tolerability as assessed by change from baseline in heart rate
Time frame: Up to Week 50
Safety and tolerability as assessed by change from baseline in Electrocardiogram (ECG) parameters
Time frame: Up to Week 50
Safety and tolerability as assessed by frequency of vital signs and ECG parameters of potential clinical concern
Time frame: Up to Week 50
Trough concentration of GSK239512 at Week 4, Week 24, Week 36 and Week 48
Time frame: 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
Time frame: 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
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Ottawa, Ontario, Canada
GSK Investigational Site
Gatineau, Quebec, Canada
GSK Investigational Site
Montreal, Quebec, Canada
GSK Investigational Site
Jihlava, Czechia
GSK Investigational Site
Olomouc, Czechia
...and 33 more locations