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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Individualized brain atrophy progression between the rituximab and placebo groups after 2 years of treatment or predetermined analysis shows the secondary outcome measures has higher zscore than brain atrophy measurement
Bibiana Bielekova, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|