Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicenter Study of BG00002 in Japanese Subjects With RRMS, Consisting of a Multiple-Dose, Open-Label Evaluation of Its Safety, Tolerability, Pharmacokinetics and Pharmacodynamics (Part A) and a Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Evaluation of Safety and Efficacy (Part B)
Brief Summary: The primary objective of Part A is to determine the safety and tolerability of natalizumab administered over 24 weeks in Japanese participants with relapsing-remitting multiple sclerosis (MS). The endpoints for this will include assessment of adverse evetns (AEs), changes in laboratory evaluations, vital signs, Expanded Disability Status Scale (EDSS) scores, and changes in physical and neurological examination findings. The secondary objectives of Part A are to characterize the pharmacokinetics (PK) profile and pharmacodynamics (PD) of natalizumab.

The primary objective of Part B is to determine if natalizumab, when compared to placebo, is effective in treating Japanese participants with relapsing-remitting MS, as measured by new active lesions on cranial magnetic resonance imaging (MRI) scans over 24 weeks. New active lesions are the sum of the gadolinium-enhancing (Gd+) lesions and any new or newly-enlarging T2-hyperintense lesions that do not enhance. The primary endpoint is the rate of development of new active lesions over 24 weeks.

Secondary objectives of Part B are to determine over 24 weeks whether natalizumab, when compared to placebo, is effective in reducing the frequency of clinical exacerbations, reducing the number of Gd+ lesions, reducing the number of new or newly-enlarging T2-hyperintense lesions on brain MRI scans, increasing the proportion of relapse-free participants, and improving outcomes on visual analog scale (VAS) assessing the participant's global impression of his/her well-being. Additional objectives are to assess the safety and tolerability, the incidence of serum antibodies to natalizumab and the PK profile of natalizumab.


Options:
A: Inclusion Criteria:

1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria with a relapsing-remitting disease course.
2. Subjects must be ambulatory with an EDSS score of 0-5.5 in both screening and baseline visits.
3. Subjects must be in a relapse-free, stable neurological condition and free of corticosteroid treatment \[intravenous (IV), intramuscular (IM) and/or per os (PO)\] or ACTH 30 days prior to screening (month -1) and between screening and baseline (month 0) visits.
4. Subjects must have experienced one of the following:

   At least one documented relapse in the 12 months prior to screening, or At least two documented relapses in the 24 months prior to screening, or One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening.
5. Subjects must be between 18 and 55 years of age, inclusive.
6. Women of child-bearing potential must practice an acceptable method of birth control.
7. Subjects must be able to sign and date a written informed consent prior to entering the study.
8. Subjects must be willing and able to comply with the protocol requirements for the duration of the study

Exclusion Criteria:

1. Subjects with progressive forms of MS.
2. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
3. Use of immunosuppressive (including Mitoxantrone and Fingolimod) or cytotoxic agents within 6 months prior to the screening visit.
4. Use of natalizumab (Tysabri®) or any other monoclonal antibodies within 2 years prior to screening.
5. Use of cladribine within 2 years prior to screening.
6. Previous treatment with immunomodulators (including IFNβ 1a and 1b, and IV Immunoglobulin (IVIg) within 2 months prior to screening.
7. Previous use of GA or any other glatiramoid.
8. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit.
9. Previous total body irradiation or total lymphoid irradiation.
10. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
11. Pregnancy or breastfeeding.
12. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical exams, ECG, abnormal laboratory tests and chest X-ray. Such conditions may include hepatic, renal or metabolic diseases, systemic disease, acute infection, current malignancy or recent history (5 years) of malignancy, major psychiatric disorder, history of drug and/or alcohol abuse and allergies that could be detrimental according to the investigator's judgment.
13. A known history of sensitivity to Gadolinium.
14. Inability to successfully undergo MRI scanning.
15. A known drug hypersensitivity to Mannitol.
B: Inclusion Criteria:

1. The subject must have undergone a single clinical attack.
2. The subject must have a unifocal clinical presentation.
3. The subject should be enrolled within the period of 90 days after onset of a single unifocal clinical attack (index attack).
4. There must be 2 or more cerebral lesions highly suspicious of multiple sclerosis (MS) on the screening Magnetic Resonance Imaging (MRI), measuring 6mm or more in diameter.
5. Subjects must be between the ages of 18 and 45 years inclusive.
6. Subjects must not have taken corticosteroids within the 30 days prior to the MRI at the baseline visit.
7. Subjects may be male or female. Women of child-bearing potential must practice a medically acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, or double-barrier method (condom or intrauterine device with spermicide).
8. The subjects must be willing and able to give written informed consent, prior to entering the study.

Exclusion Criteria:

1. Multifocal clinical presentation.
2. Diseases other than MS responsible for the clinical/MRI presentation. The following laboratory tests must be part of the subject's medical history for differential diagnosis of clinically isolated syndrome (CIS): erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), complement (C3, C4) and anticardiolipin IgG - IgM. In the event that the results of these tests are inconclusive, the following additional tests may be requested by the Eligibility Evaluation Committee: syphilis screening, vitamin B12 and folic acid. In the case of spinal cord CIS presentation, a spinal cord MRI is required for confirmation of diagnosis in the medical history of the subject.
3. Use of experimental or investigational drugs, including IV immunoglobulin, and/or participation in an investigational drug study within 6 months prior to study entry.
4. Use of interferon agents within 6 months prior to the screening visit.
5. Chronic corticosteroid treatment (more than 30 consecutive days) in the 6 months prior to study entry.
6. Pregnancy or breast feeding.
7. Subjects who experience a relapse between the screening (month -1) and baseline (month 0) visits.
8. Life-threatening or other clinically significant disease.
9. A medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or if the subject is considered by the treating neurologist/physician to be, for any other reason, an unsuitable candidate for this study.
10. A known history of sensitivity to mannitol.
11. A known history of sensitivity to gadolinium.
12. Inability to successfully undergo MRI scanning.
C: Part A

Key Inclusion Criteria:

* Must give written informed consent and any authorizations required by local law.
* Must have a diagnosis of relapsing-remitting MS, as defined by the revised McDonald criteria 1 through 4 (Polman et al, 2005). All other possible neurologic diagnoses must have been reasonably excluded by means of laboratory and/or imaging studies, in the opinion of the Investigator.
* Japanese men and women aged 18 to 65, inclusive, at the time of informed consent.
* All male subjects and female subjects of childbearing potential must practice effective contraception during the study and be able to continue contraception for 12 weeks after their last dose of study treatment.
* Must have an Expanded Disability Status Scale (EDSS) score between 0.0 and 6.0, inclusive.
* Must have experienced at least 1 medically documented clinical exacerbation within 12 months of enrollment.
* Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon beta \[IFNβ\] and chronic systemic corticosteroids) for the duration of the study.
* Must have a baseline MRI, conducted within 35 calendar days prior to enrollment.

Key Exclusion Criteria:

* Diagnosis or history of neuromyelitis optica (NMO), e.g., a long spinal lesion extending over 3 or more vertebral bodies was detected, or the subject has a history of positive tests for anti-aquaporin-4 (anti-AQP4) antibodies.
* The subject is considered by the Investigator to be immunocompromised, based on medical history, physical examination, laboratory testing, or prior immunosuppressive or immunomodulating treatment.
* An MS exacerbation (relapse) within 30 days prior to enrollment or, in the opinion of the Investigator, the subject has not stabilized from a relapse prior to enrollment at Week 0.
* History of malignancy.
* Known history of, or positive test result for human immunodeficiency virus (HIV) infection.
* Known history of or positive test result for hepatitis C virus or hepatitis B virus within the year prior to enrollment.
* History of severe allergic or anaphylactic reactions or known drug hypersensitivity.
* A clinically significant infectious illness within 30 days prior to enrollment.
* Abnormal liver function test results at screening: alanine aminotransferase (ALT), or aspartate aminotransferase (AST) \>2 times of the upper limit of normal (ULN) or bilirubin \>1.5 times of the ULN during screening.
* Previous treatment with natalizumab, any murine protein, or any other therapeutic monoclonal antibody.
* Any prior treatment with any of the following medications: total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination.
* Treatment with immunosuppressant medications, e.g., azathioprine, cyclophosphamide, methotrexate, and fingolimod within 6 months prior to enrollment, or mitoxantrone and cyclosporine within 12 months prior to enrollment.
* Treatment with any of the following medications or procedures within 6 months prior to enrollment: intravenous immunoglobulin (IVIg), plasmapheresis, or cytapheresis.
* Treatment with immunomodulatory medications (including IFNβ and glatiramer acetate \[GA\]) within 2 weeks of enrollment.
* Treatment with any of the following medications within 30 days of enrollment: intravenous corticosteroid treatment, systemic corticosteroid treatment, 4-aminopyridine or related products.
* Participation in any other investigational treatment within the 6 months prior to enrollment or concurrent with this study.

Part B

Key Inclusion Criteria:

* Must give written informed consent and any authorizations required by local law.
* Must have a diagnosis of relapsing-remitting MS, as defined by the revised McDonald criteria 1 through 4 (Polman et al, 2005). All other possible neurologic diagnoses must have been reasonably excluded by means of laboratory and/or imaging studies, in the opinion of the Investigator.
* Japanese men and women aged 18 to 65, inclusive, at the time of informed consent.
* All male subjects and female subjects of childbearing potential must practice effective contraception during the study and be able to continue contraception for 12 weeks after their last dose of study treatment.
* Must have an EDSS score between 0.0 and 5.5, inclusive.
* Must have experienced at least 1 medically documented clinical exacerbation within 12 months of enrollment.
* Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including IFNβ and chronic systemic corticosteroids) for the duration of the study.
* Prior to enrollment all subjects must have: a screening MRI, or documentation of an MRI within the subject's medical record within 1 year of the screening visit, which reveals 3 or more T2 hyperintense lesions consistent with MS, and a baseline MRI, conducted within 7 calendar days prior to enrollment, which reveals at least 1 MRI lesion consistent with MS.

Key Exclusion Criteria

* Diagnosis or history of NMO, e.g., a long spinal lesion extending over 3 or more vertebral bodies was detected, or the subject has a history of positive tests for anti-AQP4 antibodies.
* The subject is considered by the Investigator to be immunocompromised, based on medical history, physical examination, laboratory testing, or prior immunosuppressive or immunomodulating treatment.
* An MS exacerbation (relapse) within 30 days prior to enrollment or, in the opinion of the Investigator, the subject has not stabilized from a relapse prior to enrollment at Week 0.
* History of malignancy.
* Known history, or positive test result of HIV infection.
* Known history of or positive test result for hepatitis C virus or hepatitis B virus within the year prior to Enrollment.
* History of severe allergic or anaphylactic reactions or known drug hypersensitivity.
* A clinically significant infectious illness within 30 days prior to Enrollment.
* Abnormal liver function test results at screening: ALT or AST \>2 times of the ULN or bilirubin \>1.5 times of the ULN during screening.
* Previous treatment with natalizumab, any murine protein, or any other therapeutic monoclonal antibody.
* Any prior treatment with any of the following medications: total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination.
* Treatment with immunosuppressant medications, e.g., azathioprine, cyclophosphamide, methotrexate, and fingolimod within 6 months prior to enrollment, or mitoxantrone and cyclosporine within 12 months prior to enrollment.
* Treatment with any of the following medications or procedures within 6 months prior to enrollment: IVIg, plasmapheresis, or cytapheresis.
* Treatment with immunomodulatory medications (including IFNβ and GA) within 2 weeks of enrollment.
* Treatment with any of the following medications within 30 days of enrollment: intravenous corticosteroid treatment, systemic corticosteroid treatment, 4-aminopyridine or related products.
* Participation in any other investigational treatment within the 6 months prior to enrollment or concurrent with this study.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.
D: Inclusion Criteria:

* Female or male patients with relapsing-remitting forms of multiple sclerosis (according to McDonald's criteria)
* Age between 18 and 60 years
* Natalizumab-treatment for at least 12 month following the current Swiss guidelines for treatment initiation
* Eligible patients are clinically stable (free from relapses and 6-month confirmed disability progression for at least 6 months) while on natalizumab-treatment
* Women of potential childbearing with active contraceptive methods
* Patients who are willing to undergo study procedures
* Patients who are willing and able to sign informed consent

Exclusion Criteria:

* Patients who have previously entered this study
* Natalizumab-treatment for less than 12 month following the current Swiss guidelines for treatment initiation
* Sign of clinical disease activity within the 6 month
* One or more relapses and/or 6-month confirmed disability progression during the 6 months prior to the study
* Any disease other than multiple sclerosis that would better explain the patient's signs and symptoms
* Secondary progressive MS
* Primary progressive MS
* Pregnancy - Urine pregnancy test at baseline visit - or breast feeding
* Uncontrolled, clinically significant heart diseases, such as arrhythmias, angina, or uncompensated congestive heart failure
* History of severe depression or attempted suicide or current suicidal ideation
* Medical or psychiatric conditions that compromise the ability to give informed consent, to comply with the protocol, or to complete the study
* Uncontrolled seizure disorder
* Myopathy or clinically significant liver disease
* Inability, in the opinion of the principal investigator or staff, to comply with protocol requirements for the duration of the study
* Known hypersensitivity to interferon-beta or other human proteins including albumin
* Any contraindication for MRI or contrast administration
* A history of drug abuse in the 6 months prior to screening
* Treatment with any of the following in the 30 days before day 1: systemic corticosteroids, ACTH, or other investigational drugs.
* Participation in any other study involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study
* Current participation on other clinical trials
* Treatment with drugs which might interfere with the evaluation of study drugs during the study protocol
* Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol

Answer: C