| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing Remitting Multiple Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsing Remitting Multiple Sclerosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048393 |
| E.1.2 | Term | Multiple sclerosis relapse |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Estimation of the effects of GSK239512 on lesion remyelination in
subjects with Relapsing Remitting Multiple Sclerosis on stable treatment
with Avonex [interferon-beta1a] or Copaxone [glatiramer acetate]. |
|
| E.2.2 | Secondary objectives of the trial |
| Objectives Endpoints Evaluate the effects of GSK239512 on alternate potential marker of remyelination of lesions. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age: 18 to 50 years of age, inclusive
2. RRMS Diagnosis and Treatment:
• Diagnosed with a relapsing-remitting course of multiple sclerosis as defined by the appropriate McDonald criteria at the time of diagnosis, most recently updated by Polman (2011) and:
• Diagnosis 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 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):
• 1 reported and/or documented relapse, OR
• 1 Gadolinium Enhanced (GdE) lesion on MRI,
Example: If treatment with Avonex initiated at 12 months prior to screen the earliest a lesion or relapse could occur to qualify for the study would be 10 months prior to screen.
• Currently neurologically stable, in the investigator’s judgment, and not actively experiencing or recovering from a recent relapse at the screening visit.
3. MS Disability: A Kurtzke Expanded Disability Status Scale (EDSS) (Kurtzke 1983) score of 1 – 4.5 (inclusive) at the screening visit.
4. Clinical Trial Commitment: 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.
5. Female Reproduction and lactation: 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 postmeznopausal, 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 (FSH) and estradiol levels), have both ovaries surgically removed or have current documented tubal ligation); or,
c. Of childbearing potential (i.e. women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhea [even severe], women who are perimenopausal or have just begun to menstruate. Subject has a negative serum pregnancy test at screening and agrees to one of the following:
1. Complete abstinence from intercourse for one month prior to administration of the first dose of investigational product until 1 month
after the last dose of investigational product; or,
2. Consistent and correct use of one of the following 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
• Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of <1% per year
• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject’s entry into the study, and this male is the sole partner for the subject
• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent(foam/gel/film/cream/suppository).
• Consistent and correct use of one of the following acceptable methods of birth control WITH a single barrier method (condom, occlusive cap, or vaginal spermicidal agent) for one month prior to the start of investigational product to 1 month after the last dose of investigational product:
• Oral contraceptives (either combined or progesterone only)
• Injectable progesterone
• Implants of levonorgestrel
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
6. Informed Consent: Must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures. |
|
| E.4 | Principal exclusion criteria |
1. 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.
• Findings on brain MRI scan indicating any clinically significant brain
abnormality other than MS (e.g. damage associated with prior traumatic brain injury).
2. Past and Concurrent Medical Conditions:
• History of severe and clinically significant CNS trauma with current sequelae (e.g. traumatic brain injury, spinal cord compression)
• 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.
• History or presence of myelopathy due to spinal cord compression by disk or vertebral disease or chronic progressive myelopathy
• Diagnosis of any type epilepsy.
• 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
• Presence of significant and routine sleep disturbance 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. Examples of significant sleep disturbances may be: severe insomnia, nocturnal wandering, confusion, disorientation, agitation, or vivid dreams.
• Presence or history of hallucinations that, in the judgement of the investigator, may increase the safety risk to the subject.
• Known diagnosis or history consistent with positive human immunodeficiency virus (HIV).
3. Past and Current Medications and Therapies:
• Have had treatment with the following to manage their MS within 1 or 2 years prior to the Screen Visit:
• One 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 GSK Medical Monitor if there are specific questions regarding eligible treatments.
• Two 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 (see Section 5.10.2 for information regarding reason for exclusion):
• 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 [Clinical Investigator Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012), relapse medication, or Gadolinium enhancing agent.
4. Cardiovascular Status at Screening: Electrocardiogram (ECG) showing a
clinically significant abnormality at screening. Including a QTcB or QTcF interval of ≥450 msec or ≥480 msec for patients with a Bundle Branch Block.
(For the full section on Exclusion criteria, please refer to the Protocol on Page 28-31) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Changes in lesion myelination using two exploratory
magnetization transfer ratio (MTR) endpoints comparing
placebo to GSK239512 treated subjects in:
1) Mean change in gadolinium (Gd) enhanced
(GdE) lesion MTR differences (calibrated to reference scan [Section 6.3.1.1]) from before enhancement to stable recovery (≥3 months post new GdE lesion), and
2) Mean change in Delta MTR lesion MTR differences (calibrated to reference scan) from before lesion appearance to stable recovery (≥3 months post lesion appearance) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks for MRI assessment, with a minimum of 5 MRI scans required to assess the endpoints. |
|
| E.5.2 | Secondary end point(s) |
Change from baseline in T2 lesion MTR at Week 48. Cumulative new and enlarging Gd enhancing, T2 and Combined Unique Active lesions comparing placebo to GSK239512 treated subjects.
Change from baseline at Week 48 in total brain volume, white matter volume and grey matter volume comparing placebo to GSK239512 treated subjects.
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.
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.
Mean change from baseline in overall Cognitive impairment and cognitive domains comparing placebo to GSK239512 treated subjects.
Comparison of Relapse Rates between placebo and GSK239512 treated subjects.
Comparison of Time to First Relapse between placebo and GSK239512 treated subjects.
Comparison of the proportion of subjects Relapse Free between placebo and GSK239512 treated subjects.
Proportion of subjects with sustained worsening of Expanded Disability Severity Scale (EDSS) over 3 months comparing placebo to GSK239512 treated subjects.
Mean change from baseline in the EDSS functional systems and a subset of component assessments comparing placebo to GSK239512 treated subjects. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Imaging endpoints are assessed every 6 weeks, relapse is assessed every 4 weeks, cognition is assessed at 3 and 6 month intervals, and disability progression is assessed every 12 weeks. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Canada |
| Czech Republic |
| Germany |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 21 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 21 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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