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:

* Given written/signed informed consent
* Age 18 to 50 years old (inclusive) as of the date the informed consent form (ICF) was signed
* Diagnosis of MS per updated McDonald criteria, and cranial magnetic resonance imaging (MRI) scan demonstrating white matter lesions attributable to MS within 5 years of screening
* Onset of MS symptoms (as determined by a neurologist, either at screening or retrospectively) within 5 years of the date the ICF was signed
* Expanded Disability Status Scale (EDSS) score 0.0 to 3.0 (inclusive) at screening
* Greater than or equal to (\>=) 2 MS attacks (first episode or relapse) occurring in the 24 months prior to the date the ICF was signed, with \>=1 attack in the 12 months prior to the date the ICF was signed, with objective neurological signs confirmed by a physician, nurse practitioner, or other Genzyme-approved health-care provider and the objective signs could be identified retrospectively

Exclusion Criteria:

* Received prior therapy for MS other than corticosteroids, for example, alemtuzumab, interferons, intravenous immunoglobulin, glatiramer acetate, natalizumab, and mitoxantrone
* Exposure to azathioprine, cladribine, cyclophosphamide, cyclosporine A, methotrexate, or any other immunosuppressive agent other than systemic corticosteroid treatment
* Any progressive form of MS
* History of malignancy (except basal skin cell carcinoma)
* CD4 + , CD8 + count, B cell, or absolute neutrophil count less than (\<) lower limit of normal (LLN) at screening
* Known bleeding disorder (for example, dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation, fibrinogen deficiency, or clotting factor deficiency)
* Significant autoimmune disease including but not limited to immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis
* Presence of anti-thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (that is, above the LLN)
* Active infection or at high risk for infection
B: Inclusion Criteria:

* Age 18 to 65 years
* PPMS according to the McDonald (2010) and Lublin (2014) criteria
* Disease duration at least one year
* EDSS ≤ 6.5
* Written informed consent to study participation
* No other signs of significant disease judged by the investigator
* Eligible for randomization to active treatment or placebo as assessed by CSF NFL levels above 380ng/L
* Not eligible for randomization as assessed by CSF biomarker studies but accepts follow-up and open-label treatment per protocol
* Patients not eligible for randomization due to low NFL concentrations in CSF at screening can be followed up after 48 weeks, and are eligible for open-label treatment if they fulfil one of the following clinical criteria of disease progression:
* 1 point increase in EDSS score from screening to week 48 if screening EDSS \<6
* 0.5 point increase in EDSS score from screening to week 48 if screening EDSS\>5.5
* 2 point increase in a physical functional system
* Worsening in SDMT, 9HPT or T25FW \>20% from screening to week 48

Exclusion Criteria:

* Pregnancy or breast feeding
* Lack of effective contraception for women of child-bearing potential
* Relapse within 6 months of inclusion
* Methylprednisolone treatment within 3 months of inclusion
* Treatment with interferon-beta, glatiramer acetate, immunoglobulin G or other immunomodulatory treatment within 6 months of inclusion
* Treatment with mitoxantrone, cyclophosphamide, azathioprine or other immunosuppressive treatment within 6 months of inclusion
* Findings on the screening MRI judged to preclude participation by the treating physician
* Other diseases associated with immunodeficiency
* Other diseases judged to be relevant by the treating physician
* Anticoagulant therapy other than platelet inhibitors
* Active malignant disease in the previous 5 years
* Renal insufficiency or blood creatinine \> 150 μmol/l
* Present or chronic infection with hepatitis B virus, hepatitis C virus, HIV (tested in the screening blood samples) or other infections found to be relevant by the treating physician.
* Psychiatric disorders or other disorders impairing the patient's ability to participate in the trial
* Contraindication to MRI
* Known allergy or hypersensitivity to dimethyl fumarate
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:

* Patients completed the core study BAF312A2201
* Written informed consent provided before any assessment of the extension study
* Female patients at risk of becoming pregnant must have a negative pregnancy test and use simultaneously two forms of effective contraception

Exclusion Criteria:

* Newly diagnosed systemic disease other than MS (which may require immunosuppressive treatment)
* Malignancies, diabetes, significant cardiovascular and pulmonary diseases and conditions
* Active infections

Answer: C