Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)

• Quantitative MRI markers
• Clinical/paraclinical markers

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.
• Baseline Visits:
• Visit 1: Participants will provide blood samples and have a magnetic resonance imaging (MRI) scan of the brain.
• Visits 2 and 3: In addition to providing blood samples, participants will have an MRI scan of the spine, additional tests of vision and motor skills, and a lumbar puncture to collect a sample of cerebrospinal fluid.

Participants will be randomly assigned to receive either rituximab or a placebo.

• Visit 4: In addition to providing blood samples, participants will have an MRI scan of the brain and a skin biopsy.
• Treatment Visits:
• Visit 5: Participants will be admitted for a 2-day inpatient stay, and will have MRI scans, vision and motor skills tests, and blood samples on the first day. On the second day, participants will receive rituximab or placebo by both intravenous drip and through a lumbar puncture, and will be discharged on the following day after overnight monitoring.
• Visit 6: Two weeks after Visit 5, participants will have an overnight stay to receive rituximab or placebo by intravenous drip only.
• Visit 7: Six months after Visit 6, participants will have MRI scans and provide blood samples.
• Visit 8: One year after Visit 5, participants will have another 2-day inpatient stay. On the first day, the same procedures performed described for Visit 5 will be repeated; on the second day, participants will receive rituximab or placebo through a lumbar puncture only, and will be discharged on the following day after overnight monitoring.
• Visit 9: Six months after Visit 8, participants will have MRI scans and provide blood samples.
• Visit 10: Six months after Visit 9, participants will have MRI scans and provide blood samples.
• After the end of the study, participants will continue with standard care for SP-MS.

Objective: The primary goal of this study is to define the safety and efficacy of combined systemic and intrathecal (IT) B cell-depleting therapy (i.e. anti-CD20, rituximab) in patients with secondary-progressive multiple sclerosis (SP-MS). The secondary goals of this study are to collect longitudinal data to help identify the most sensitive outcome measures and trial design for future Phase II trials for SP-MS patients and to investigate the mechanism of action of rituximab on the human immune system.

Study Population: Patients with SP-MS and mild to moderate level of clinical disability, who have no medical contraindication to IT or intravenous (IV) administration of rituximab.

Design: This is double blind, placebo-controlled, single center, baseline versus treatment, Phase I/II clinical trial of IV and IT rituximab in SP-MS patients.

Outcome Measures: Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal cord) tissue destruction and clinical and functional (i.e. electrophysiological) measures of neurological disability will be collected every 6-12 months. Additionally, biomarkers focusing on analysis of cerebral spinal fluid (CSF) B cells and immunological responses to EBV will be collected at baseline and during treatment. The trial is currently powered using progression of brain atrophy as detected by SIENA methodology as the primary outcome measure. However, this may not be the most sensitive outcome available. In recognition of this, the trial has an adaptive design: it incorporates analysis of the progression of CNS tissue destruction, as measured by quantitative MRI markers, and clinical/paraclinical markers, defined as secondary outcome measures, in the first 30 enrolled patients during the year long pre-treatment baseline prior to randomization. All defined outcome measures collected in the first 30 enrolled patients will be transformed into z-scores and compared for the robustness of longitudinal change over the coefficient of variation. As a result, the primary outcome measure of this trial will be the comparison of individualized rates of brain atrophy progression between the rituximab and placebo groups after 2 years of treatment; unless the predetermined analysis establishes that one of the secondary outcome measures has a higher z-score than the brain atrophy measurement. In this case, the primary outcome would be the efficacy of rituximab versus placebo in inhibiting patient-specific slopes of functional or structural deterioration as measured by this more sensitive biomarker of CNS tissue destruction.

• Aggarwal A, Catlett JP. Rituximab: an anti-CD20 antibody for the treatment of chronic refractory immune thrombocytopenic purpura. South Med J. 2002 Oct;95(10):1209-12.
• Aggarwal A, Grewal R, Green RJ, Boggio L, Green D, Weksler BB, Wiestner A, Schechter GP. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia. 2005 Jan;11(1):13-9. Review.
• Akyuz C, Aydin GB, Cila A, Akalan N, Soylemezoglu F, Cengiz M, Yazici N, Buyukpamukcu M. Successful use of intraventricular and intravenous rituximab therapy for refractory primary CNS lymphoma in a child. Leuk Lymphoma. 2007 Jun;48(6):1253-5. No abstract available.

• 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