Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)
|ClinicalTrials.gov Identifier: NCT01212094|
Recruitment Status : Terminated (The efficacy on CSF biomarkers failed to reach criteria for continuation of the trial)
First Posted : September 30, 2010
Results First Posted : March 28, 2016
Last Update Posted : March 28, 2016
|First Submitted Date ICMJE||September 29, 2010|
|First Posted Date ICMJE||September 30, 2010|
|Results First Submitted Date||March 9, 2016|
|Results First Posted Date||March 28, 2016|
|Last Update Posted Date||March 28, 2016|
|Start Date ICMJE||September 2010|
|Primary Completion Date||December 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT01212094 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)|
|Official Title ICMJE||Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)|
- 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).
- To evaluate the safety and effectiveness of combined intravenous and intrathecal rituximab in individuals with secondary-progressive multiple sclerosis.
- 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.
- 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.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
|Condition ICMJE||Multiple Sclerosis|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Terminated|
|Completion Date||December 2015|
|Primary Completion Date||December 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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
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:
|Ages||18 Years to 65 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01212094|
|Other Study ID Numbers ICMJE||100212
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )|
|Study Sponsor ICMJE||National Institute of Neurological Disorders and Stroke (NINDS)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||March 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP