Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab (Mabthera/Rituxan) in Adults With Relapsing Remitting Multiple Sclerosis
Brief Summary: This is a Phase II, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of Rituximab in adults with RRMS.


Options:
A: Core Study

Inclusion Criteria:

* Diagnosis of relapsing multiple Sclerosis (MS)
* Patients with at least two documented relapses in the previous 2 years or one documented relapse in the last year
* Patients with an Expanded Disability Status Scale (EDSS) score of 0-6

Extension Study

* A positive Gd-enhanced MRI scan at screening (in case the first MRI scan obtained at screening was negative, a second scan could have been obtained 1 month later)
* Neurologically stable with no evidence of relapse within 30 days prior to randomization,or during the Screening and Baseline periods.
* Female patients either post-menopausal, surgically incapable of bearing children, or practicing an acceptable method of birth control. Females of childbearing potential with a negative pregnancy test at baseline prior to entry into the treatment period.

Exclusion Criteria:

Core Study

* Patients with other chronic disease of the immune system, malignancies, pulmonary or heart disease, etc
* Pregnant or nursing women

Extension Study

* Patients who had permanently discontinued study drug prior to the Month 6 visit of the core study
* Patients with diabetes mellitus (to reduce the risk of ME), and therefore ongoing patients with diabetes mellitus or who developed diabetes mellitus were discontinued from the study)

Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

* Single, first clinical event suggestive of MS within 60 days prior to study Day 1, which is the day of randomization (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction
* At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial
* EDSS 0 - 5.0 at least one time point during the screening period before start of treatment
* 18 and 50 years old, inclusive
* Willing to follow study procedures
* Written informed consent
* If female, subject must:

  * be neither pregnant nor breast-feeding nor attempting to conceive
  * use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is \[i.e.\] less than 1 percent \[%\] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner

Exclusion Criteria:

* Diagnosis of MS (per McDonald criteria 2005)
* Any other disease that could better explain the subject's signs and symptoms
* Complete transverse myelitis or bilateral optic neuritis
* Subject uses or has used any other approved MS disease-modifying drug (DMD)
* Any investigational drug or undergone an experimental procedure within 12 weeks prior to study Day 1
* Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to study Day 1
* Total bilirubin greater than 2.5 times upper limit of normal (ULN)
* Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN
* Inadequate bone marrow reserve, defined as a total white blood cell count less than 3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than 100 gram per liter (g/L)
* Current autoimmune disease
* Major medical or psychiatric illness (including history of or current severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
* History of seizures not adequately controlled by treatment
* Cardiac disease, such as angina, congestive heart failure or arrhythmia
* Known allergy to IFN-beta or the excipient(s) of the study medication
* Any condition that could interfere with the MRI evaluation;
* Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)
* Previously participated in this study
* Participated in any clinical trial within the past 6 months
* Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment, including, but not limited to, the following products: any IFN, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 \[CD4\]), intravenous, immunoglobulins (Igs), cytokines or anti-cytokine therapy
* Any experimental MS treatment prior to trial entry, including, but not limited to, any statins (if given to prevent MS) and pentoxyfylline
* History of alcohol or drug abuse
* Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
* Inability to administer subcutaneous injections either by self or by caregiver
* Moderate to severe renal impairment
C: 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.
D: Inclusion Criteria:

* Ability and willingness to provide written informed consent and to comply with the schedule of protocol assessments
* Age 18--55 years, inclusive
* Diagnosis of relapsing MS, as defined by McDonald Criteria 1--4
* History of at least one relapse in the subject's medical records during the 1 year prior to randomization
* EDSS at screening between 0 and 5.0 points, inclusive
* For subjects of reproductive potential (males and females), ability and willingness to use a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during the study, including the safety follow-up period, and for up to 1 year after their last dose of study drug, even if they have discontinued early from the study

Exclusion Criteria:

* Pregnancy or lactation
* Incompatibility with MRI
* Lack of peripheral venous access
* History of severe, allergic, or anaphylactic reactions to humanized or murine monoclonal antibodies
* Known active bacterial, viral, fungal, or mycobacterial infection, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes infections), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening
* History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, or syphilis)
* History of cancer, including solid tumors and hematologic malignancies (except fully resolved and resected cutaneous basal cell and squamous cell carcinomas of the skin)
* History of alcohol or drug abuse within 6 months prior to screening
* History of or currently active primary or secondary immunodeficiency
* Presence of significant, uncontrolled disease of the cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal systems
* Diagnosis of secondary progressive, primary progressive, or progressive relapsing MS
* History or presence of vascular disease potentially affecting brain or spinal cord (e.g., stroke, transient ischemic attack, severe carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation)
* History or presence of myelopathy due to spinal cord compression by disk or vertebral disease
* History of severe, clinically significant CNS trauma (e.g., cerebral contusion, spinal cord compression)
* History of intracranial or intraspinal tumor (e.g., meningioma, glioma)
* History or presence of potential metabolic cause of encephalopathy or myelopathy (e.g., untreated vitamin B12 deficiency, untreated thyroid deficiency)
* History or presence of infectious causes of encephalopathy or myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 \[HTLV-1\], herpes zoster myelopathy)
* Neuromyelitis optica
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, antiphospholipid antibody syndrome, Sjogren�s syndrome, Behcet disease)
* History or presence of sarcoidosis
* Relapse within 30 days prior to randomization
* Previous treatment with rituximab (MabThera(R)/Rituxan(R))
* Treatment with any investigational agent within 90 days of randomization or five half-lives of the investigational drug (whichever is longer)
* Receipt of a live vaccine within 30 days prior to randomization
* Previous treatment with lymphocyte-depleting therapies (e.g., Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation)
* Treatment with cyclophosphamide or mitoxantrone within 12 months of randomization
* Systemic corticosteroid therapy within 30 days of randomization
* Treatment with IFN-Beta; or Copaxone(R) within 60 days of randomization
* Treatment with IVIG within 60 days of randomization
* Plasmapheresis within 60 days of randomization
* Treatment with non-lymphocyte depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil, cyclosporine) within 90 days prior to randomization
* Statins or hormone replacement therapy started within 30 days of randomization
* Positive pregnancy test
* B-cell count \<1.1% (reported as percent CD19)
* Vitamin B12 below the lower limit of normal with an abnormal methylmalonic acid level
* Positive rapid plasma reagin
* Serum creatinine \>1.4 mg/dL for women or \>1.6 mg/dL for men
* Aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) \>2.5 x the upper limit of normal
* Platelet count \<100,000/mL
* Hemoglobin \<8.5 g/dL
* Neutrophils \<1.5 x 10\^3/mL
* Serum IgG levels below 5.65 mg/mL and serum IgM levels below 0.55 mg/mL
* Findings on brain MRI scan consistent with clinically significant conditions other than MS
* Electrocardiogram (ECG) showing significant abnormality that the treating investigator determines may jeopardize the subject's health (i.e., acute ischemia, left bundle branch, or bifascicular block)

Answer: D