E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-Remitting Multiple Sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029205 |
E.1.2 | Term | Nervous system disorders |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
The primary objective of Part I of the study is to determine the efficacy of BG00012 on inflammatory brain MRI lesion activity (Gd-enhancing lesions) when compared with placebo from 4 scans performed at Weeks 12, 16, 20, and 24 in subjects with RRMS including subjects from the Asia-Pacific region.
The primary objective of part II of this study is to evaluate the long-term safety profile of BG00012 in eligible subjects from part 1.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of Part I of this study in this study population are to determine whether BG00012, when compared with placebo over 24 weeks, is effective in:
1. Reducing the cumulative number of new Gd-enhancing lesions from Baseline (Day 1) to Week 24
2. Reducing the number of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Week 24 compared with Baseline (Day 1)
There are no secondary objectives for part II of the study. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part I:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
2. Men and women from the Asia-Pacific region (with ethnic origin from those respective countries) or from other countries, aged 18 to 55 years old, inclusive, at the time of informed consent.
3. Must have a diagnosis of RRMS, as defined by the revised McDonald criteria 1 through 4 [Polman 2005]. All other possible neurologic diagnoses must have been reasonably excluded.
4. Must have a brain MRI performed at any time prior to randomization that demonstrates lesion(s) consistent with MS.
5. Must have an EDSS score between 0.0 and 5.0, inclusive.
6. Must have experienced disease activity within the 12 months prior to randomization as evidenced by at least 1 relapse or Gd-enhancing lesion of the brain on an MRI performed within the 6 weeks prior to randomization.
7. Female subjects of childbearing potential and male subjects who are not surgically sterile must practice effective contraception during their participation in the study and be willing and able to continue contraception for 12 weeks after their last dose of study treatment.
Part II:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use PHI in accordance with national and local subject privacy regulations.
2. Subjects who participated in and completed Part I per protocol including those subjects who prematurely discontinued study treatment but completed the visit schedule.
3. Female subjects of childbearing potential and male subjects who are not surgically sterile must practice effective contraception during their participation in the study and be willing and able to continue contraception for 12 weeks after their last dose of study treatment. |
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E.4 | Principal exclusion criteria |
Part I:
Primary progressive, secondary progressive, or progressive relapsing MS (as defined by Lublin and Reingold [1996]), with continuous clinical disease worsening over a period of at least 3 months. Subjects may also have superimposed relapses, but are distinguished from RRMS subjects by the lack of clinically stable periods or clinical improvement.
Diagnosis or history of NMO, eg, a long spinal lesion extending over ≥3 vertebral bodies was detected, or the subject has a history of positive tests for anti-AQP4 antibodies. Subjects whose anti-AQP4 antibody test result from Screening is positive and available prior to enrollment will be excluded from study participation.
A relapse that has occurred within the 50 days prior to randomization and/or the subject has not stabilized from a previous relapse prior to randomization.
History of:
• Malignancy, except subjects with basal cell carcinoma that has been completely excised prior to Screening will remain eligible.
• Severe allergic or anaphylactic reactions or known drug hypersensitivity.
• Clinically significant cardiovascular, pulmonary, GI, dermatologic, psychiatric, neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study.
• Abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or other major disease that would preclude participation in a clinical study.
• HIV.
• Hepatitis C virus antibody or hepatitis B virus, or positive test result at Screening.
• Drug or alcohol abuse (as defined by the Investigator) within 2 yrs prior to randomization.
Any of the following abnormal blood tests at Screening:
• ALT/ SGPT, or aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), or gamma-glutamyl-transferase (GGT) ≥2 times the upper limit of normal (ULN)
• Leukocytes <3500/mm3
• Eosinophils >0.7 × 103/L or >0.7 GI/L
Any of the following abnormal urine tests at Screening confirmed by a second urinalysis approx. 2 weeks later:
• Proteinuria (1+ or greater)
• Hematuria, without known etiology
• Glycosuria, without known etiology
• Note: If a subject has a positive test at Screening and the etiology is known (eg, due to menses or urinary tract infection in the case of hematuria, or due to recent steroid use or elevated serum glucose in the case of glycosuria), a repeat test is not required.
Prior treatment or procedures with any of the following:
• BG00012 or fumaric acid esters.
• Total lymphoid irradiation, Cladribine, T-cell or T-cell receptor vaccination, any therapeutic monoclonal antibody, with the exception of natalizumab.
• Mitoxantrone or cyclophosphamide within 1 year prior to randomization.
• Cyclosporine, Azathioprine, Methotrexate, Natalizumab, Fingolimod, Mycophenolate mofetil, Laquinimod, IV immunoglobulin, Plasmapheresis or cytapheresis within the 6 months prior to randomization.
• IFN-α, IFN-β, Glatiramer acetate within the 3 months prior to randomization.
• IV steroids or oral corticosteroid treatment, including agents that may act through the corticosteroid pathway; new or changed dosing of 4-aminopyridine or related products within the 50 days prior to randomization
• Other investigational drugs or approved therapy for investigational use within the 6 months prior to randomization.
• Use at the time of randomization or anticipated ongoing use of Traditional or Unlicensed Medicines or Traditional Therapies or herbal preparations.
Female subjects considering becoming pregnant or breast feeding while in the study or who are currently pregnant or breast feeding.
Current enrollment in any other investigational drug study or participation in any other investigational study within 6 months prior to randomization.
Unwillingness or inability to comply with the requirements of the protocol, or presence of any condition that is likely to affect the subject’s ability to comply with the protocol.
Additionally for Part II (at baseline visit):
• Any significant change in medical history including laboratory tests, cardiovascular risk factors, • or current clinically significant condition that in the opinion of the Investigator would have excluded the subject’s participation in Part I of the study.
• Subjects from Part I who discontinued study treatment due to an AE or due to reasons other than protocol defined relapse or disability progression.
• History of malignancy, except subjects with basal cell carcinoma that has been completely excised prior to entry into the Part II Extension Period will remain eligible.
• ALT/SGPT, AST/SGOT, or GGT >3 × ULN.
• Previous participation in Part II of this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in Part I is the total number of new Gd-enhancing lesions over 4 scans at Weeks 12, 16, 20, and 24, calculated as the sum of these 4 MRI scans.
The primary endpoints in Part II are as follows:
- incidence of treatment emergent AEs
- incidence of treatment-emergent SAEs
- clinical laboratory reported values
- clinically significant changes in vital sign measurements |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I: Weeks 12, 16, 20, and 24, calculated as the sum of these 4 MRI scans.
Not defined for Part II. |
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E.5.2 | Secondary end point(s) |
Part I: the following brain MRI Parameters:
1. the cumulative number of new Gd-enhancing lesions
2. the number of new or newly enlarging T2 hyperintense lesions
Part II: No secondary endpoints defined. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part I:
1. Baseline (Day 1) to Week 24
2. at Week 24 compared with Baseline (Day 1)
Part II: not applicable. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part I of the trial is controlled, randomised, double-blind; part II is open-label, uncontrolled. |
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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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Czech Republic |
Japan |
Korea, Republic of |
Poland |
Taiwan |
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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
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LVLS: The end of study is last subject, last visit for final collection of data for the primary outcome (i.e. the safety follow-up visit). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |