Please select the eligibility criteria that correspond to the clinical trial below.
Title: Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)
Brief Summary: Background:

- Secondary-progressive multiple sclerosis (SP-MS) is the chronic phase of multiple sclerosis (MS). The majority of people who have relapsing-remitting MS eventually develop SP-MS. There are currently no effective treatments for SP-MS. Researchers are interested in determining whether the drug rituximab, which is used to treat rheumatoid arthritis and some types of cancer, is able to target certain white blood cells that are thought to play a role in the progression of SP-MS. To ensure that the rituximab will reach the brain and spinal cord, participants will receive it by intravenous drip and by intrathecal injection (through a lumbar puncture into the cerebrospinal fluid).

Objectives:

- To evaluate the safety and effectiveness of combined intravenous and intrathecal rituximab in individuals with secondary-progressive multiple sclerosis.

Eligibility:

- Individuals between 18 and 65 years of age who have been diagnosed with SP-MS and have been off any form of immunosuppressive therapy for at least 3 months.

Design:

- The study will involve a 1-year pretreatment baseline series of visits, followed by a 2-year treatment period. Participants will provide blood samples throughout treatment as directed by the study researchers, and additional studies may be performed during the study period if participants consent to further investigation.


Options:
A: Inclusion Criteria:

* 18 through 55 years of age
* Patients with CIS demonstrating one unifocal neurological event AND at least 2 T2-weighted brain lesions measuring a minimum of 6mm in diameter by MRI analysis; or a definite diagnosis of RMS, as defined by the 2005 revised McDonald criteria(1, 2), and have had at least one clinically defined relapse within the past year OR one GEL on an MRI within the past year
* Women of child-bearing potential must agree to practice an acceptable method of birth control
* No evidence of progressive multifocal leukoencephalopathy (PML) or primary central nervous system (PCNS) lymphoma
* Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to randomization
* Subject must be able and willing to give meaningful, written informed consent prior to participation in the trial, in accordance with local regulatory requirements.

Exclusion Criteria:

* ≥ 15 GELs on baseline MRI
* Treatment with interferon β, natalizumab, or fingolimod within three months of randomization
* Treatment with mitoxantrone, cyclophosphamide, or any other chemotherapeutic agent for MS or malignancy within 12 months of randomization
* Attenuated live virus vaccination within 4 weeks of randomization
* Positive urine and serum pregnancy test at screening or baseline visit
* Any prior treatment with alemtuzumab or cladribine
* Unable to tolerate GA
* History of cardiac arrhythmias, angina or any other significant cardiac abnormalities
* History of clinically significant chronic disease of the immune system or a known immunodeficiency syndrome (HIV) other than MS
* White Blood Cell count of less than 2.5\*10\^9/L or lymphocyte count below 0.4\*10\^9/L
* Positive for any evidence of past, or current, hepatitis B and/or C infection
* History or presence of malignancy (except basal cell carcinoma)
* Clinically significant alcohol or drug abuse within past two years
* Any medical, psychiatric or other condition that could result in a subject not being able to give fully informed consent, or to comply with the protocol requirements
* Inability to undergo MRI scans or history of hypersensitivity to gadolinium- diethylenetriamine penta-acetic acid (DTPA)
* Participation in any clinical study evaluating another investigational drug or therapy within three months prior to randomization
* Any other condition that, in the Investigator's opinion, makes the subject unsuitable for participation in the study
B: 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)
C: * 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
D: Inclusion Criteria:

* Participant is in the center to receive an infusion for rituximab for a non-oncology indication during the study period
* Aged 18 years or older

Exclusion Criteria:

* Has previously already completed the rituximab survey
* Has participated in the past 12 months in a clinical trial in which rituximab was one of the treatments being evaluated.

Answer: C