E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067063 |
E.1.2 | Term | Progressive relapsing multiple sclerosis |
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 |
Part 1: evaluate effects of BIIB033 versus placebo on disability improvement over 72 weeks.
Part 2: evaluate long-term safety profile of BIIB033 as an add-on therapy in subjects with MS. |
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E.2.2 | Secondary objectives of the trial |
Part 1: evaluate effects of BIIB033 versus placebo on additional measures of disability improvement.
Part 2: investigate long term efficacy (disability improvement) and additional safety measures of BIIB033 as an add on therapy in subjects with MS. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A biomarker substudy will be included in Part 2 of the study, with the objective to explore remyelination/neurorepair biomarkers in optional Imaging substudy.
This imaging substudy will explore magnetization transfer saturation (MTsat) imaging and susceptibility weighted imaging (SWI) techniques. |
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E.3 | Principal inclusion criteria |
Part 1: Key Inclusion Criteria:
-Baseline Expanded Disability Status Scale (EDSS) of 2.0 to 6.0, have a diagnosis of relapsing-remitting multiple sclerosis (RRMS) per the 2010 McDonald’s criteria or onset of secondary progressive multiple sclerosis (SPMS) per the Lublin and Reingold criteria, and should have experienced their first MS symptom(s) within the previous 20 years.
-Subjects must have experienced at least 1 of the following within 24 months prior to Day 1/Baseline: a clinical relapse (but not within 24 weeks prior to Day 1/Baseline), gadolinium-enhancing lesions on brain or spinal cord magnetic resonance imaging (MRI), or new T2 lesion(s) on brain or spinal cord MRI.
-Subjects must be on a stable dose of a protocolspecified anti-inflammatory disease-modifying therapies
(DMT) (IFNβ [Avonex, Plegridy, Betaferon/Betaseron, or Rebif], dimethyl fumarate (DMF) [Tecfidera], or
natalizumab [Tysabri]) for at least 24 weeks prior to enrollment.
-In addition, subjects must have met protocol-defined MRI characteristics consistent with the presence of demyelination and relatively well-preserved tissue integrity. For enrollment, subjects must meet the following MRI criteria on the Screening/Baseline brain MRI: magnetization transfer ratio (MTR) in T2 lesions ≤-0.17 normalized MTR unit and diffusion tensor imaging (DTI) – radial diffusivity in T2 lesions ≤0.98 × 10-3 mm2/s
Part 2 Key Inclusion Criteria:
-Ability to understand purpose and risks of study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local subject privacy regulations.
-Subjects who complete study treatment (BIIB033 or placebo) at Part 1/Week 72 Visit.
3All female subjects of childbearing potential and all male subjects must practice effective contraception during study and continue contraception for at least 24 weeks after their last dose of BIIB033. In addition, subjects should not donate sperm or eggs during study and for at least 24 weeks after their last dose of study treatment. |
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E.4 | Principal exclusion criteria |
Part 1: Key Exclusion Criteria
-Primary progressive MS
-An MS relapse that has occurred within 24 weeks prior to Day 1/Baseline or the subject has not stabilized from a previous relapse at the time of Screening.
-Treatment with any chemotherapeutic agents (e.g., mitoxantrone, cyclophosphamide, cladribine), celldepleting
monoclonal antibodies (mAbs) (e.g., rituximab, ocrelizumab, alemtuzumab), total lymphoid irradiation, T-cell or T-cell receptor vaccination, or teriflunomide within 1 year prior to Day 1/Baseline.
-Treatment with other anti-inflammatory DMTs (e.g., GA, fingolimod, daclizumab) or plasmapheresis within 24 weeks prior to Day1/Baseline.
-Treatment with Botox for limb spasticity within 24 weeks before Day 1/Baseline.
-Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to gadolinium renal impairment, or claustrophobia that cannot be medically managed.
-History of human immunodeficiency virus or other immunodeficient conditions.
-History of malignancy; however, subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study.
Part 2 Key Exclusion Criteria:
- Subjects who did not complete study treatment in Part 1/Week 72 Visit
- Subjects who have a duration >12 weeks between their Part 1/Week 72 Visit and Part 2/Day 1.
- Any significant change in clinical status that would make the subject unsuitable to participate in Part 2, in the opinion of the Investigator. The Investigator must reassess the subject's medical fitness for participation
and consider any diseases that would preclude study treatment.
- A history of clinically significant and persistent neutralizing antibody against IFNβ or natalizumab, in the opinion of the Investigator, for subjects treated with an interferon or with natalizumab, respectively.
- Treatment with any investigational drug within 12 weeks prior to Part 2/Day 1.
- Treatment with 4-aminopyridine (4-AP) within 30 days prior to Part 2/Day 1, unless a stable dose has been maintained for at least 30 days prior to Part 2/Day 1. Treatment with medical marijuana for MS symptoms is not exclusionary, if it is consistent with local MS treatment guidelines and local regulations.
- Treatment with high-dose oral or IV steroids within 30 days before Part 2/Day 1.
-Contraindications to MRI, as presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to Gd, renal impairment, or claustrophobia that cannot be medically managed. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: Overall Response Score
Overall Response Score is a multicomponent score based on 4 components: Expanded Disability Status Scale (EDSS),
Timed 25-Foot Walk (T25FW), 9-Hole Peg Test in the dominant hand (9HPT-D), and 9HPT in the nondominant hand (9HPTND). It assesses overall changes in disability over time. Overall Score ranges from +4 to -4. At each visit, each
component is given a score relative to baseline: -1 if threshold is met for worsening, 0 if no changes meet threshold
criteria, or +1 if threshold is met for improvement. The thresholds for T25FW and 9HPT are defined by a 15%
change from baseline (≥15% decrease from baseline for improvement and ≥15% increase from baseline for worsening). For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a baseline score of ≤6.0, and worsening is defined as a ≥1-point increase from a baseline score of ≤5.5 or a ≥0.5-point increase from a baseline score equal to 6.0.
Part 2: Incidence of AEs and SAEs over 96 weeks in Part 2 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Overall Response Score, assessed over 72 weeks of the study.
Part 2: AEs and SAEs over 96 weeks in Part 2 of the study. |
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E.5.2 | Secondary end point(s) |
Part 1:
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3)
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and without confirmed worsening in any of the 4 assessments during the 72 weeks of the study
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT)
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% thresholds for T25FW and 9HPT)
Part 2:
• Overall Response Score over 96 weeks in Part 2
• Proportion of subjects with 24-week confirmed improvement in at
least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND
(improvement in T25FW and 9HPT is defined as a ≥15% decrease from
BIIB033 Treatment Baseline)
• Proportion of subjects with 24-week confirmed improvement in at
least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT ND,
PASAT-3 (improvement in PASAT-3 is defined as a ≥15% increase from
BIIB033 Treatment Baseline)
• Proportion of subjects with 24-week confirmed improvement in at
least 1 of the following assessments: EDSS, T25FW, 9HPT-D, or 9HPT ND,
and without confirmed worsening in any of the 4 assessments during the
96 weeks of the study
• Proportion of subjects with 24-week confirmed improvement in at
least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT ND,
SDMT (improvement in SDMT is defined as a ≥4-point increase from
BIIB033 Treatment Baseline)
• Proportion of subjects with 24-week confirmed improvement in at
least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT ND
(20% thresholds for T25FW and 9HPT)
• Potentially clinically significant abnormal laboratory, ECG, vital signs,
and weight values over 96 weeks in Part 2
• C SSRS score over 96 weeks in Part 2 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: Assessed every 12 weeks from Baseline to Week 72
Part 2: Assessed over 96 weeks in Part 2 |
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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 | No |
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 | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 92 |
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 |
Australia |
Canada |
Israel |
United States |
Belgium |
Czechia |
France |
Germany |
Hungary |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 6 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 9 |