| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing forms of multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063400 |
| E.1.2 | Term | Secondary progressive multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| 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 |
|
| 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 the study is to evaluate the efficacy of BIIB033
in subjects with active relapsing MS when used concurrently with
Avonex. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study in this study population are to assess
the safety, tolerability, and population PK of BIIB033 when used
concurrently with Avonex. |
|
| 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 |
Optional lumbar puncture substudy: CSF will be collected to assess the
modulation of potential PD/other biomarker that may be related to
BIIB033 activity or MS disease activity.
Exploratory Exploratory Multifocal Visual Evoked Potential (mfVEP)
Substudy in Czech Republic (protocol version 3.1.1, dated 10 March
2015), Poland (protocol version 3.2, dated 10 March 2015) and Serbia
(Version 3.3, dated 10 March 2015).
Efficacy Endpoint for mfVEP Substudy:
• Change from baseline to Week 72 in mfVEP latency and amplitude for
the right and left visual pathways. |
|
| E.3 | Principal inclusion criteria |
1. Ability to understand the purpose and risks of the study and provide
signed and dated Informed Consent Form (ICF) and authorization to use
protected health information (PHI) in accordance with national and local
subject privacy regulations.
2. Aged 18 to 58 years old, inclusive, at the time of informed consent.
3. Diagnosis of RRMS per the 2005 McDonald's criteria or onset of SPMS
per the Lublin and Reingold criteria.
4. For RRMS, subjects must have disease activity as defined by 2 or more
distinct occurrences of any of the following 3 events within 12 months of
enrollment: Clinical relapse Gd+ lesion on MRI (brain or spinal cord MRI)
New T2 lesion on MRI (brain or spinal cord MRI)
5. For SPMS, subjects must have disease activity as defined by 1 or more
distinct occurrences of any of the following 2 events within 12 months of
enrollment: Clinical relapse Gd+ lesion on MRI (brain or spinal cord MRI)
6. Baseline EDSS score of 2 to 6.
7. All male and female subjects of childbearing potential must practice
effective contraception during the study and be willing and able to
continue contraception for at least 6 months after their last dose of
study treatment (BIIB033 plus Avonex or placebo plus Avonex). |
|
| E.4 | Principal exclusion criteria |
1. History of abnormal laboratory results that in the opinion of the
Investigator, are indicative of an significant cardiac, endocrine,
hematologic, immunologic, metabolic, urologic, pulmonary,
gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than
MS) and/or other major disease that would preclude administration of
BIIB033 and/or Avonex.
2. Any of the following abnormal blood tests at screening: hemoglobin ≤
9.0 g/dL platelets ≤100 X 109/L lymphocytes ≤1.0 X 109/L neutrophils
≤1.5 X 109/L alanine aminotransferase/serum glutamate pyruvate
transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic
oxaloacetic transaminase (AST/SGOT), or gamma-glutamyl-transferase
≥ 2 times the upper limit of normal (ULN) serum creatinine ≥ULN
3. Treatment with Botox for limb spasticity within 6 months before Day
1/Baseline.
4. Plans to undergo elective major procedures/surgeries at any time
during the study.
5. Simultaneous participation in another study protocol.
6. Treatment with any investigational MS drugs within 3 weeks or 5 t1/2
(whichever is longer) prior to Day 1/Baseline.
7. Treatment with high dose oral or IV steroids ≤30 days before Day
1/Baseline.
8. History of suicidal ideation or an episode of clinically severe
depression (as determined by the Investigator) within 3 months of
enrollment. Note: subjects receiving ongoing antidepressant therapy will
not be excluded from the study unless the medication has been
increased within the 6 months prior to enrollment.
9. RRMS subjects with any history of inadequate response to any
approved (in country of residence) interferon β preparation (e.g.,
Avonex, Rebif, interferon β-1b, or any generic interferon β). (Inadequate
response definition: 2 or more distinct occurrences of clinical relapse
and/or Gd+ lesion on MRI and/or new or non-enhancing lesion on MRI
within any 12-month period while compliant with interferon β.)
10. History of human immunodeficiency virus or other immunodeficient
conditions.
11. History of positive test result for hepatitis C virus Ab or Hepatitis B
virus (defined as positive for hepatitis B surface antigen or hepatitis B
core Ab).
12. History of drug or alcohol abuse (as defined by the Investigator)
within 2 years prior to randomization.
13. History of seizure disorder or unexplained blackouts OR history of a
seizure within 6 months prior to Baseline.
14. Female subjects who have a positive pregnancy test, are pregnant,
or currently breast feeding.
15. T25FW >30 seconds (any of the 2 tests at Screening).
16. History of malignancy; however subjects with a history or excised or
treated basal cell carcinoma or fewer than 3 squamous cell carcinomas
are eligible to participate in this study.
17. Renal impairment with a creatinine clearance <80 mL/minute at
Screening (creatinine clearance estimated by Cockcroft-Gault equation).
18. In the opinion of the Investigator, a history of clinically significant
persistent neutralizing Ab against interferon β.
19. Known intolerance, contraindication to, or history of noncompliance
with Avonex.
20. Treatment with fingolimod or investigational sphingosine 1-
phosphate receptor 1 (S1P1) agonists within 3 months prior to Day
1/Baseline.
21. Treatment with natalizumab within 3 months prior to Day
1/Baseline.
22. Initiation of treatment or dose adjustment of commercially available
4-aminopyridine (4-AP) or related products within the last 28 days.
Note: subjects who have been on a stable dose of commercially available
4-AP for longer than 28 days are not excluded.
23. Treatment with any chemotherapeutic agents (e.g., mitoxantrone,
cyclophosphamide, cladribine) or cell depleting mAbs (e.g., rituximab,
ocrelizumab, alemtuzumab) within 6 months prior to Day 1/Baseline,
unless treatment with the chemotherapeutic agent/cell depleting mAbs
occurs no earlier than 3 months of Day 1/Baseline (i.e., between 3 and 6
months of Day 1/Baseline) and the subject's white blood cell (WBC)
count is determined to be within normal range at Screening.
24. An MS relapse that has occurred within the 90 days prior to Day
1/Baseline and/or the subject has not stabilized from a previous relapse
prior to Screening.
25. Inability to comply with study requirements.
26. Other unspecified reasons that, in the opinion of the Investigator or
Biogen Idec, make the subject unsuitable for enrollment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Percentage of subjects experiencing confirmed improvement of
neurophysical
and/or cognitive function over 72 weeks (approximately 18
months) of treatment as measured by a composite endpoint comprising
the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk
(T25FW), 9-Hole Peg Test (9HPT), and (3-Second) Paced Auditory Serial
Addition Test (PASAT).
Improvement on neuro-physical and/or cognitive function is defined as
at least 1 of the following: A ≥1.0 point decrease in EDSS from a baseline
score of ≤6.0 (decrease sustained for 3 months or greater). A ≥15%
improvement from baseline in T25FW (improvement sustained for 3
months or greater). A ≥15% improvement from baseline in 9HPT
(improvement sustained for 3 months or greater). A ≥15% improvement
from baseline in PASAT (improvement sustained for 3 months or
greater). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
Percentage of subjects experiencing confirmed worsening of
neurophysical
and/or cognitive function and/or disability over 72 weeks
(approximately 18 months) of treatment as measured by a composite
endpoint of the EDSS, T25FW, 9HPT, and PASAT.
Progression of disability or worsening of neuro-physical and/or cognitive
function is defined as at least 1 of the following: A ≥1.0 point increase in
EDSS from a baseline score of ≤5.5 or a ≥0.5 point increase from a
baseline score equal to 6.0 (increase sustained for 3 months orgreater).
A ≥15% worsening from baseline in T25FW (worsening sustained for 3
months or greater). A ≥15% worsening from baseline in 9HPT
(worsening sustained for 3 months or greater). A ≥15% worsening from
baseline in PASAT (worsening sustained for 3 months or greater).Safety Endpoints
The following safety parameters will be used to address the safety and
tolerability portion of the secondary objectives: Adverse events (AEs)
Serious adverse events (SAEs) Clinical laboratory test results Physical
examination findings Electrocardiogram (ECG) Vital signs results Weight
Serum antibodies (Ab) to BIIB033 Disease activity by brain MRI metrics
MS signs and symptoms Columbia Suicide Severity Rating Scale (C-SSRS)
score
Pharmacokinetic Endpoint
The PK portion of the secondary objectives will be addressed by the
following: BIIB033 population PK assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Assessments: Quarterly over 72 weeks
Safety Assessments and PK/PD Sampling: at specified timepoints during
the treatment period (day 1 to week 72) and follow up period (through
EOS ~week 84) |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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 | 5 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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