Last updated: 11/07/2018 10:29:26
Study to assess whether GSK239512 can remyelinate lesions in subjects with Relapsing Remitting Multiple Sclerosis
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: Proof of Mechanism Study to Assess the Potential of GSK239512 to Remyelinate Lesions in Subjects with Relapsing Remitting Multiple Sclerosis
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Mean change in gadolinium enhanced (GdE) lesion magnetization transfer ratio (MTR) value post-Lesion (PoL) from pre-Lesion (PrL)
Timeframe: Up to Week 48
Mean change in Delta-MTR Lesions MTR value PoL from PrL
Timeframe: Up to Week 48
Secondary outcomes:
Change from Baseline in T2 lesion MTR at Week 48
Timeframe: Baseline and Week 48
Cumulative number of new GdE lesions, new enlarging T2 lesions and combined unique active lesions at Week 48
Timeframe: Week 48
Change from Baseline in whole brain volume at Week 48
Timeframe: Baseline and Week 48
Change from Baseline in white matter volume and grey matter volume at Week 48
Timeframe: Baseline and Week 48
Cumulative number of new unenhancing T1 lesions at Week 48
Timeframe: Week 48
Cumulative number of new GdE lesions evolving into black holes by Week 48
Timeframe: Week 48
Change from Baseline in CogState battery total score (TS), executive function composite score (EFCS), memory composite score (MCS) and attention composite score (ACS) at Week 48
Timeframe: Baseline and Week 48
Relapse rate during the treatment phase
Timeframe: Up to Week 48
Number of participants relapsing during the treatment phase
Timeframe: Up to Week 48
Analysis of the time to first relapse
Timeframe: Up to Week 48
Expanded Disability Status Scale (EDSS) score at Week 48
Timeframe: Week 48
Number of participants with the indicated change from the BL in EDSS score over 48 weeks
Timeframe: Baseline and Week 12, 24, 36 and 48
Number of participants with sustained worsening of the Expanded Disability Status Scale (EDSS) score at Week 48
Timeframe: Week 48
Change from Baseline at Week 48 in Multiple Sclerosis Quality of Life (MSQoL) Physical Function and Mental Function Composite Score
Timeframe: Early Withdrawal, Week 48
Number of participants with any adverse events (AEs) and any serious adverse events (SAEs)
Timeframe: Up to Week 50
Number of mild, moderate and severe AEs
Timeframe: Up to Week 50
Number of participants withdrawn due to AEs
Timeframe: Up to Week 50
Number of participants within each category of the Columbia Suicide Severity Rating Scale
Timeframe: Up to Week 50
Maximum on-treatment change from Baseline in the albumin and total protein values
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the alkaline phosphatase, alanine amino transferase, aspartate amino transferase and gamma glutamyl transferase values
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the calcium, glucose, potassium, sodium and Urea/Blood Urea Nitrogen (BUN) values
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, platelets, total neutrophils and white blood cell (WBC) count
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the creatinine clearance values
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the creatinine, direct and total bilirubin values
Timeframe: Up to 48 weeks
Maximum on-treatment change from Baseline in the red blood cell (RBC) and reticulocytes count
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the hemoglobin and mean corpuscular hemoglobin concentration (MCHC) value
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the mean corpuscular hemoglobin (MCH) value
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the mean corpuscular volume (MCV) value
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the hematocrit value
Timeframe: From Baseline up to Week 48
Urinalysis parameters at the indicated time points up to Week 50
Timeframe: From Baseline up to Week 50
Number of participants with chemistry laboratory values outside the clinical concern range at any time on-treatment
Timeframe: From Baseline up to Week 48
Number of participants with hematology laboratory values outside the clinical concern range at any time on-treatment
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the systolic blood pressure and diastolic blood pressure
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the heart rate
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the weight
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the heart rate as a measure of electrocardiogram (ECG) assessment
Timeframe: From Baseline up to Week 48
Maximum on-treatment change from Baseline in the PR Interval, QRS duration, QT interval, QTcB, QTcF and RR Interval as a measure of the ECG assessment
Timeframe: From Baseline up to Week 48
Number of participants with change in the indicated vital sign with respect to the reference range and Baseline value
Timeframe: From Baseline up to Week 48
Number of participants with indicated change from Baseline in the indicated potential clinical concern ECG values
Timeframe: From Baseline up to Week 48
Mean GSK2586184 trough plasma concentrations at Weeks 4, 8, 24, 36 and 48
Timeframe: Weeks 4, 8, 24, 36 and 48
Mean GSK2586184 plasma concentrations at Weeks 8
Timeframe: Weeks 8
Interventions:
Drug: GSK239512
Drug: Placebo
Enrollment:
131
Observational study model:
Not applicable
Primary completion date:
2014-12-09
Time perspective:
Not applicable
Clinical publications:
Schwartzbach C, Grove R, Brown R, Tompson D, Then Bergh F, Arnold D. Lesion Remyelinating Activity of GSK239512 versus Placebo In Patients with Relapsing Remitting Multiple Sclerosis: a Randomised, Single-Blind, Phase 2 Study. J Neurol. 2017;264(2):304-315.
Medical condition
Multiple Sclerosis, Relapsing-Remitting
Product
GSK239512
Collaborators
Not applicable
Study date(s)
February 2013 to September 2014
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 50 years
Accepts healthy volunteers
No
- 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.
- 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)
Inclusion and exclusion 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
Trial location(s)
Location
GSK Investigational Site
Calgary, Alberta, Canada, T2N 2T9
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Dresden, Sachsen, Germany, 01069
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Hamburg, Hamburg, Germany, 22083
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Ulm, Baden-Wuerttemberg, Germany, 89073
Status
Study Complete
Location
GSK Investigational Site
Ottawa, Ontario, Canada, K1H 8L6
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Muenster, Nordrhein-Westfalen, Germany, 48149
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Koeln, Nordrhein-Westfalen, Germany, 50935
Status
Terminated/Withdrawn
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
Protocol
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2014-12-09
Actual study completion date
2014-12-09
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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