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 | 21.1 |
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 main objectives of Part 1 are as follows:
• To evaluate the safety, tolerability, and efficacy on the disease course
of BG00012 (dimethyl fumarate) in subjects with RRMS, as compared
with a disease modifying treatment..
• To assess health outcomes and evolution of disability
The primary objective of Part 2 is to evaluate the long-term safety of
BG00012 in subjects who completed week 96 in Part 1 of Study 109MS306. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key inclusion criteria:
1. Ability of parents or legal guardians 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. Subjects will provide assent in addition to the parental or guardian consent, as appropriate, as per local regulations.
2. Males and females aged from 10 to less than 18 years old (from 14 to less than 18 years old in Poland) at the time of informed consent or assent.
3. Must have a body weight of ≥30 kg (≥40 kg in Poland).
4. Must have a diagnosis of RRMS (consensus definition for pediatric RRMS [Krupp 2007]).
5. Must be ambulatory with a baseline EDSS score between 0 and 5.5, inclusive.
6. Must have experienced at least 1 relapse within the last 12 months prior to Day 1 or at least 2 relapses within the last 24 months prior to Day 1, with a prior brain MRI demonstrating lesions consistent with MS, or evidence of Gd-enhancing lesions of the brain on an MRI performed within the 6 weeks prior to Day 1.
7. Must be neurologically stable, with no evidence of relapse within 50 days prior to Day 1 and no evidence of corticosteroid treatment within 30 days prior to Day 1.
8. Subjects of childbearing potential who are sexually active must be willing to practice effective contraception during the study and be willing and able to continue contraception for at least 30 days after their final dose of study treatment.
Part 2;
- Subjects who have completed week 96 in Part 1
NOTE: Other protocol defined inclusion criteria may apply |
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E.4 | Principal exclusion criteria |
Key exclusion criteria:
Medical history
1. Primary progressive, secondary progressive, or progressive relapsing MS (as defined by [Lublin and Reingold 1996]). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Subjects with these conditions may also have superimposed relapses but are distinguished from relapsing-remitting subjects by the lack of clinically stable periods or clinical improvement.
2. Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
3. History of premalignant or malignant disease. Subjects with basal cell carcinoma that has been completely excised prior to screening will remain eligible
4. History of severe allergic or anaphylactic reactions, or known drug hypersensitivity to DMF,fumaric acid esters or interferon β-1a (IFN β-
1a)
5. History of abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or any other major disease that would preclude participation in a clinical study
6. History of clinically significant cardiovascular, pulmonary, GI, dermatologic, growth, developmental, psychiatric (including depression), neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study
7. History of human immunodeficiency virus
8. History of drug or alcohol abuse (as defined by the Investigator) within the 2 years prior to Day 1.
9. An MS relapse that has occurred within 50 days prior to Day 1 AND/OR the subject has not stabilized from a previous relapse prior to Day 1
10. History or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb]). Subjects with immunity to hepatitis B from either active vaccination (defined as negative HBsAg, positive hepatitis B surface antibody [HBsAb] and negative HBcAb) or from previous natural infection (defined as negative HBsAg, positive HBsAb IgG, and positive HBcAb) are eligible to participate in the study (definitions are based on the Centers for Disease Control and Prevention [CDC]’s interpretation of the hepatitis B serology panel [CDC 2007]; Appendix 4, Section 25]).
11. Any of the following abnormal blood test results at Screening:
ALT, AST, or gamma-glutamyl-transferase (GGT) ≥2 × ULN
leukocytes <3500/mm3
eosinophils >0.7 × 103/μL or >0.7 GI/L
absolute lymphocyte count <LLN
12. Any of the following abnormal urine tests at Screening confirmed by a second urinalysis approximately 2 weeks later:
proteinuria (1+ or greater) and/or spot protein/creatinine ratio (with AM void) >0.2 mg. Note: Documented benign proteinuria is not exclusionary.
hematuria, without known etiology
glycosuria, without known etiology
Note: If a subject has a positive test at Screening and the etiology is known (e.g., 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.
Treatment history
13. Any previous treatment with Fumaderm® or BG00012.
14. Prior treatment with any of the following:
total lymphoid irradiation
cladribine
T-cell or T-cell receptor vaccination
any therapeutic monoclonal antibody, with the exception of rituximab (see Exclusion Criterion 15) or natalizumab (see Exclusion Criterion 16)
15. Prior treatment with any of the following medications within the 12 months prior to Day 1:
mitoxantrone
cyclophosphamide
rituximab
16. Prior treatment with any of the following medications or procedures within 6 months prior to Day 1:
fingolimod
teriflunomide
natalizumab
cyclosporine
azathioprine
methotrexate
mycophenolate mofetil
laquinimod
IV immunoglobulin
plasmapheresis or cytapheresis
17. Prior treatment with any of the following within 3 months prior to Day 1:
glatiramer acetate
interferon-alpha
interferon-β (subjects who are positive for neutralizing antibodies to interferon-β may receive interferon-β treatment up to 2 weeks prior to Day 1)
18. Treatment with any of the following medications within 30 days prior to Day 1:
steroids (IV or oral corticosteroid treatment, including agents that may act through the corticosteroid pathway [e.g., low dose naltrexone])
4-aminopyridine or related products (except subjects on a stable dose of controlled-release fampridine for 3 months)
Part 2;
- Any significant changes in medical history occurring after enrollment in
Part 1
- Subjects who could not tolerate BG00012 in Part 1
Note: Other protocol-defined inclusion/exclusion criteria may apply
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of Part 1 is the proportion of subjects free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Week 96.
The primary endpoint of the Part 2 is the incidence of adverse events, serious adverse events and discontinuations of BG00012 due to an adverse event |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 - Day 1 (baseline visit), weeks 24, 48, 72, 96
Part 2 - up to week 244 |
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E.5.2 | Secondary end point(s) |
English The secondary endpoints of Part 1 are as follows:
• Number of new/newly enlarging T2 hyperintense lesions on brain MRI
scans at Weeks 24 and 96
• Proportion of participants free of new/newly enlarging T2
hyperintense lesions on brain MRI scans at Weeks 24 and 48
• Proportion of participants free of new MRI activity as measured by
brain MRI scans (new MRI activity includes: Gd enhancing MRI lesion on
brain MRI scans; new T2 MRI lesions on brain MRI scans and newly
enlarging LRI lesions on brain MRI scans) at Weeks 24, 48, and 96
• Time to first relapse up to week 96
• Proportion of participants who do not experience relapse up to Week
96
• Annualized relapse rate at Weeks 48 and 96
• Number of participants that experience adverse events (AEs) and
serious adverse events (SAEs), including prospective and follow up of
flushing, nausea, abdominal pain, and diarrhea up to week 96
• Participants receiving BG00012 who consent to participate in the
PD/PK subset - PK parameters derived from PK subset data analysis:
area under the concentration time curve from time 0 to 10 hours (AUC0
10), maximum observed plasma concentration (Cmax), time to reach
maximum observed plasma concentration (Tmax), lag time, elimination
half-life (t½), apparent clearance (Cl/F), and apparent volume of
distribution (V/F) up to week 4
• Participants receiving BG00012 who consent to participate in the
PD/PK subset - PD parameters, derived from PD subset data analysis:
changes in the nuclear factor (erythroid derived 2) like 2 activation
pathway markers quinone 1 (NQO 1) and heme oxygenase 1 (HO 1)up
to week 4
• Fatigue as measured by the Pediatric Quality of Life Inventory
(PedsQL) Multidimensional Fatigue Scale scores (Multidimensional
Fatigue Scale scores designed as a generic symptomspecific instrument
to measure fatigue in patients with acute and chronic health conditions
as well as healthy school and community populations.) up to week 96
• Quality of Life as measured by the PedsQL up to week 96
• Change from baseline to Week 96 in the Expanded Disability Status
Scale (EDSS score; The EDSS measures the disability status of people
with multiple sclerosis on a scale that ranges from 0 to 10. The first
levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability
and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory
ability. The range of main categories include (0) = normal neurologic
exam; to (5) = ambulatory without aid or rest for 200 meters; disability
severe enough to impair full daily activities; to (10) = death due to MS.)
up to week 96
• Vital signs, electrocardiograms (ECGs) and changes in clinical
laboratory data, including monitoring of liver function, renal function,
hematologic and coagulation parameters up to week 96
• Other pre-specified outcomes |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
English
Part 1 - The various secondary endpoints will be measured throughout the study as defined by the Schedule of Events. Specifically there are visits at Day 1 (baseline) weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 and a safety follow-up visit at week 100. There is also a safety telephone call at week2. |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 2 is open label with all subjects receiving BG00012 |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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 | 50 |
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 |
Belgium |
Bulgaria |
Canada |
Czechia |
Denmark |
France |
Hungary |
Israel |
Italy |
Kuwait |
Poland |
Serbia |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |