Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II/III, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis
Brief Summary: This is a Phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS. The study will enroll approximately 435 subjects at up to 60 sites in the United States and Canada.


Options:
A: Inclusion Criteria:

* Between the age of 18 and 65 years of age (nonfertile women or fertile women with effective contraceptive methods)
* Progressive MS since at least three years
* Some kind of documented progression of neurological symptoms during the previous two years.
* Expanded Disability Status Scale (EDSS) 4,0 - 7.0 (inclusive) (basically spared arm functions)
* Conventional therapy not indicated, contraindicated or failed
* Judged as compliant with the protocol

Exclusion Criteria:

* Eligible for any of the conventional MS therapies
* Relapsing remitting multiple sclerosis (RRMS)
* Bleeding diathesis or medication contraindicating neurosurgical procedures or lumbar puncture
* Cognitive defect making informed consent unreliable
* Any medical condition contraindicating minor surgical procedures, as judged by anaesthesiologist
* Severe, uncontrolled heart disease
* Pregnant or lactating women
* Patients having contraindication for or otherwise not compliant with MRI investigations
* Documented vulnerability to infections
* Simultaneous treatment with other immunosuppressive drugs
* Documented allergy or intolerance to Rituximab
* Severe psychiatric condition
B: Inclusion Criteria:

* Definitive diagnosis of PPMS
* Disease duration of ≥ 1 year
* EDSS at baseline between 2.0 and 6.5 points, inclusive
* Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings
* Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months:
* For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug

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, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex 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, syphilis)
* History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas)
* History of alcohol or drug abuse within 6 months prior to screening
* History of or currently active primary or secondary immunodeficiency
* Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
* Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation
* History or presence of MS relapse or exacerbation
* History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, 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 central nervous system 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 myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities)
* History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 \[HTLV-1\], or herpes zoster myelopathy)
* History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis)
* Neuromyelitis optica
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease)
* History or presence of sarcoidosis
* Previous treatment with rituximab (MabThera(R)/Rituxan(R))
* Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization
* Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization
* Receipt of a live vaccine within 30 days prior to randomization
* Systemic corticosteroid therapy within 30 days prior to randomization
* Treatment with IFN-\&#x3B2;, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization
* Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil \[MMF\], cyclosporine) within 90 days prior to randomization
* Statins or hormone replacement therapy started within 30 days prior to randomization
C: 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)
D: * INCLUSION CRITERIA:

MS as defined by the modified McDonald s criteria (Polman, Reingold et al. 2005)

SP-MS as documented by lack of MS relapse for the past 1 year and non-remitting/sustained (\> 3 months) progression of disability

Age 18-65, inclusive, at the time of the first screening baseline visit

EDSS 3.0 to 7.0, inclusive, at the time of the first screening baseline visit

Able to provide informed consent

Willing to participate in all aspects of trial design and follow-up

Lack of CEL on all MRIs performed within the last 12 months or if patient has CEL, then documentation that they tried and failed or could not tolerate FDA approved disease modifying therapies (DMTh)

Not receiving any DMTh (such as IFN-beta preparation, glatiramer acetate, corticosteroid, natalizumab, fingolimod, immunosuppressive agents or experimental therapeutics) for a period of at least 1 month before enrollment in the study, allowing for at least a 1-year

period off therapy prior to the first study dose

Agreeing to commit to the use of a reliable/accepted method of birth control (i.e. hormonal contraception (birth control pills, injected hormones, vaginal ring), intrauterine device, barrier methods with spermicide (diaphragm with spermicide, condom with spermicide) or they have undergone surgical sterilization (such as hysterectomy, tubal ligation, or vasectomy)) during enrollment in the study and through 12 months after the last dose of study drug

EXCLUSION CRITERIA:

RR-MS or PP-MS

Evidence of clearly documented MS relapse within the last 1 year

Alternative diagnoses that can explain neurological disability and MRI findings

Clinically significant medical disorders that, in the judgment of the investigators could cause CNS tissue damage, limit its repair, expose the patient to undue risk of harm or prevent the patient from completing the study (such as, but not limited to cerebrovascular disease, ischemic cardiomyopathy, clotting disorder, brittle diabetes, neurodegenerative disorder)

Pregnant or breastfeeding female

History or sign of congenital or acquired immunodeficiency or chronic infections, such as HIV/AIDS, Hepatitis A, B or C, HTLV-1 carrier and others that would expose patient to risks of pathogen reactivation associated with rituximab treatment

Abnormal screening/baseline blood tests exceeding any of the limits defined below:

1. Serum alanine transaminase or aspartate transaminase levels which are greater than three times the upper limit of normal values.
2. Total white blood cell count \< 3 000/mm(3)
3. Platelet count \< 85 000/mm(3)
4. Serum creatinine level \> 2.0 mg/dl and eGFR (glomerular filtration rate) \< 60
5. Serological evidence of HIV, HTLV-1 or active hepatitis A, B or C
6. Positive pregnancy test
7. Positive CSF or serum quantitative PCR for JC virus on CSF collected from the baseline spinal tap (test will be performed by CLIA certified laboratory of Gene Major, NINDS)
8. Total serum IgG \< 600mg/dl (nl 642-1730mg/dl) or total serum IgM \< 30mg/dl (nl 34-342mg/dl) as these Ig deficiencies would suggest underlying abnormalities with B cell function/maturation

Answer: B