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

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.

Trial also included interim analysis for the efficacy of B cell depletion from the
intrathecal compartment with pre-defined stopping criteria for futility: if less than 50% of
intrathecal B cells were depleted by active treatment (measured by <25% decrease in CSF
CXCL13 and <50% increase in CSF BAFF), then trial was deemed to be underpowered to
demonstrate efficacy on clinical or MRI outcomes and would be stopped.

- 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