Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Placebo-controlled, Parallel-Group, Dose-Ranging Study to Investigate the MRI Efficacy and Safety of Six Months' Administration of Ofatumumab in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS)
Brief Summary: Ofatumumab is a novel Immunoglobulin 1ĸ ( IgG1ĸ) lytic monoclonal antibody (mAb) that specifically binds to the human Cluster of Differentiation 20 (CD20) antigen of which expression is restricted to B lymphocytes from the pre-B cell stage to the plasmacytoid immunoblast stage only. A recent trial with an anti-CD20 mAb (rituximab) demonstrated that targeting B-cells reduces the number of gadolinium-enhancing (GdE) T1 lesions and the relapse rate in relapsing-remitting multiple sclerosis (RRMS). Ofatumumab has been shown to be both well tolerated and efficacious in several indications, including a small, placebo-controlled trial in RRMS using an intravenous (IV) formulation.

This double-blind, placebo-controlled, parallel-group study will investigate the safety and efficacy of a subcutaneous formulation of ofatumumab in the treatment of subjects with RRMS. The primary objective of the study is to investigate the efficacy as assessed by magnetic resonance imaging. Other objectives will include evaluation of tolerability/safety, dose-response relationship, pharmacokinetics, pharmacodynamics, exposure-response, as well as other clinical endpoints.


Options:
A: Inclusion criteria:

* Written informed consent must be obtained before any assessment is performed
* Male and female patients 18 to 65 years of age, inclusive.
* Patients with RRMS, as defined by 2010 revised McDonald criteria.
* Patients must be neurologically stable with no onset of relapse within 30 days of randomization
* Patients with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years before randomization.
* Patients with an EDSS score of 0 to 6, inclusive, at Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk at least 100 meters with or without resting.

Exclusion criteria:

* Patients with a history of malignancy of any organ system (other than cutaneous basal cell carcinoma) in the last 5 years that do not have confirmation of absence of a malignancy prior to randomization
* Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren's syndrome, Crohn's disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency).
* Patients who have been treated with:
* High-dose intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization
* Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, cyclophosphamide, methotrexate) within 6 months before randomization
* Natalizumab within 2 months before randomization
* Previous treatment with lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab, ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization Previous treatment with mitoxantrone within 6 months before randomization
* Use of teriflunomide within 3.5 months prior to randomization, except if active washout (with either cholestyramine or activated charcoal) was done. In that case, plasma levels are required to be measured and be below 0.02 mg/L before randomization.

No washout period is necessary for patients treated with dimethyl fumarate, interferon (IFN) beta, or glatiramer acetate.

Patients being treated with dimethyl fumarate, glatiramer acetate, or IFN beta at the Screening visit can continue drug intake up to the day before Day 1 of this study (i.e., there is no need for a washout period).

* Patients who have been treated with systemic corticosteroids or adrenocorticotropic hormones in the past 30 days prior to the screening magnetic resonance imaging (MRI) procedure.
* Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin \>9%) or with diabetic neuropathy.
* Patients with a diagnosis of macular edema during Screening (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at Screening).
* Patients with severe active bacterial, viral, or fungal infections.
* Patients without acceptable evidence of immunity to varicella zoster virus (VZV) at randomization.
* Patients who have received any live or live-attenuated vaccines (including VZV, herpes simplex, or measles) within 1 month before randomization.
* Patients who have received total lymphoid irradiation or bone marrow transplantation.
* Patients with any unstable medical/psychiatric condition, as assessed by the primary treating physician at each site.
* Patients who in the last 6 months experienced any of the following cardiovascular conditions or findings in the screening electrocardiogram (ECG): myocardial infarction, unstable angina, stroke, transient ischemic attack or decompensated heart failure requiring hospitalization or Class III/IV heart failure.
B: Inclusion Criteria:

- Diagnosis of RMS (as per McDonald criteria, 2005) Other protocol-defined inclusion criteria could apply.

Exclusion Criteria:

* Have primary progressive multiple sclerosis (MS)
* Have secondary progressive MS without superimposed relapses
* Relevant cardiac, hepatic and renal diseases as specified in the protocol
* Pretreatment with immunosuppressants and immunomodulating drugs as specified in the protocol
* Clinical significant abnormalities in blood cell counts and immunoglobulin levels as specified in the protocol
* Clinical significant acute or chronic infections as specified in the protocol Other protocol-defined exclusion criteria could apply.
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:

* Able to provide signed, written informed consent to participate in the study
* 18-55 years of age.
* Definite diagnosis of MS according to the 2010 revisions of the McDonald diagnostic criteria for MS \[Polman, 2011\].
* Subjects do not have any manifestation of another type of MS other than RRMS.
* Subjects must have a relapsing-remitting course of disease with at least one of the following prior to screening:
* At least one confirmed relapse within the previous year or
* At least two confirmed relapses within the previous 2 years or
* At least one relapse in the previous 2 years, with a GdE brain lesion on an MRI scan in the past year.
* Expanded Disability Status Scale (EDSS) score of 0-5.5 (inclusive) at screening.
* Neurologically stable with no evidence of relapse for at least 30 days prior to start of Screening and during the Screening Phase (subjects who relapse during the screening Phase can be re-screened, once the relapse has resolved).
* A female subject is eligible to enter the study if she is:
* Of non-childbearing potential
* Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy test at screening, and agrees to one of the following:
* Complete abstinence from intercourse for the period from consent into the study until 6 months after the last dose of investigational product; or,
* Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 6 months after the last dose of investigational product:

Oral contraceptives (either combined or progesterone only) Injectable progesterone Levonorgestrel implants Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of \<1% per year Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; this male must be the sole partner for the subject Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

A female is considered "Non-childbearing potential" if she is status-post hysterectomy, status-post surgical removal of both ovaries, has current, documented tubal ligation, or is postmenopausal and \>2 years without menses. Female subjects who are post-menopausal \<2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol levels.

A female is considered "childbearing potential" if she has functional ovaries, ducts, and uterus with no impairment that would cause sterility. This includes women with oligomenorrhea (even severe), and women who are perimenopausal or who have just begun to menstruate.

* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

* Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media, or who lack adequate peripheral venous access).
* Any clinically significant brain abnormality other than MS found on MRI.
* Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) or confirmed PML (see Appendix 4, Section 11.4, for PML monitoring algorithm).
* Subjects whom experience a relapse during the Screening Phase. These subjects may be eligible for re-screening after consultation with GlaxoSmithKline (GSK).
* History of clinically significant Central Nervous System (CNS) trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
* Prior treatment with any of the following:
* Systemic glucocorticoids or Adrenocorticotrophic hormone (ACTH) within one month prior to screening
* Receipt of a live vaccine within 6 weeks prior to screening
* Glatiramer acetate (Copaxone) or Interferon (IFN)-β (Betaferon, Betaseron, Avonex, or Rebif) within 3 months prior to screening
* Any immunomodulatory therapies, excluding glatiramer acetate or IFN-β, within 6 months prior to screening including natalizumab and fingolimod (Gilenya), immunoglobulin, or plasma exchange/plasmapheresis
* Any monoclonal antibodies at any time, other than natalizumab (Tysabri)
* Any lymphocyte-depleting therapies, including, but not limited to: cladribine, anti-Cluster of Differentiation 4 (CD4), total body irradiation, or bone marrow transplantation
* Any immunosuppressive agents, including, but not limited to: mitoxantrone, azathioprine, cyclosporine, cyclophosphamide, or tacrolimus
* Past or current history of medically significant adverse effects (including allergic reactions) from:
* Cetirizine (or equivalent)
* Paracetamol/acetaminophen
* Corticosteroids
* Known hypersensitivity to components of the investigational product.
* Past or current malignancy, except for
* Cervical carcinoma Stage 1B (cancer is present but has not spread) or less
* Non-invasive basal cell and squamous cell skin carcinoma
* Cancer diagnoses with a duration of complete response (remission) \>5 years
* A history of hematologic malignancy excludes a subject from participation, regardless of response.
* Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average QT interval for heart rate corrected using Bazett's Formula (QTcB) or QT interval for heart rate corrected using Fridericia's Formula (QTcF) interval \>/=450 msec (\>/=480 msec for subjects with a Bundle Branch Block) over 3 consecutive ECGs.
* Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which in the opinion of the investigator could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by this protocol.
* History of severe, clinically significant CNS trauma (e.g. cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
* Chronic or ongoing active infectious disease requiring long term systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C.
* Previous serious opportunistic or atypical infections.
* Positive polymerase chain reaction (PCR) screening for John Cunningham (JC) Virus as measured by plasma John Cunningham Virus (JCV) DNA.
* Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
* Prior history, or suspicion, of tuberculosis (TB)
* Known history of positive serology for HIV.
* Any of the following screening laboratory values:
* White blood cells (WBC) \<3.8 GI/L.
* Neutrophils \<2 x 109/L.
* Platelets \<1.3 x 105 GI/L.
* Circulating IgG, Immunoglobulin M (IgM), or Immunoglobulin A (IgA) levels \< lower limit of normal (according to central laboratory range)
* Alanine aminotransferase (ALT) \>2.0 times the upper limit of normal
* Aspartate aminotransferase (AST) \>2.0 times the upper limit of normal
* Alkaline phosphatase (ALP) \>1.5 times the upper limit of normal
* Bilirubin \>1.5 times the upper limit of normal
* CD4 count \<500 cells/mm3.
* CD19+ B-lymphocyte counts \< lower limit of normal (according to central laboratory range)
* Creatinine clearance \<60 mL/minute (by Cockcroft and Gault).
* Subjects known or suspected of not being able to comply with a trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder).
* A documented history of attempted suicide over the 6 months prior to the screening visit, presents with suicidal ideation of type 4 or 5 on the C-Suicide Severity Rating Scale (SSRS) at the Screening visit, OR if in the investigator's judgment, the subject is at risk for a suicide attempt.
* Use of an investigational drug or other experimental therapy for a condition other than MS within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening. Any prior use of an investigational drug or other experimental therapy for MS at any time should be discussed with the GSK Medical Monitor.
* Current participation in any other interventional clinical trial. Participation in a non-interventional trial requires approval of the protocol by the GSK Medical Monitor
* French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days

Answer: D