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

NCT01212094 | Terminated Phase 1 Results DMC

• 2 other identifiers: 10021210-N-0212
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis

Keywords

Rituximab; Multiple Sclerosis; Intrathecal; MS; Secondary-Progressive Multiple Sclerosis; SP-MS

Outcome Measures

Primary Outcomes (2)

• Analysis of Changes in CSF CXCL13 Induced by Active Treatment (Rituximab) Measured 3 Months After 1st Drug Administration

  This outcome is for interim analysis of the efficacy of B cell depletion from the CSF 3 months after giving rituximab or placebo into the cerebrospinal fluid (CSF). It compares concentration of chemokine CXCL13 before and 3 months after administration of drug into the CSF. We averaged two time-points before treatment (CSF collected 1 year apart, at month -12 and month 0) and compared it to the single time-point (month 3), which was 3 months from the initiation of drug dosing. CXCL13 is released by activated B cells, T cells and by follicular dendritic cells and has been linked previously with MS inflammation in the brain and spinal cord. The protocol-stipulated threshold for trial continuation was at least 25% decrease in CSF CXCL13 induced by active treatment with significance level p=0.025.

  3 months

• Analysis of Changes in CSF BAFF Induced by Active Treatment (Rituximab) Measured 3 Months After 1st Drug Administration

  This outcome is for interim analysis of the efficacy of B cell depletion from the CSF 3 months after giving rituximab or placebo into the cerebrospinal fluid (CSF). It compares concentration of B-cell activating factor (BAFF) before and 3 months after administration of drug into the CSF. We averaged two time-points before treatment (CSF collected 1 year apart, at month -12 and month 0) and compared it to the single time-point (month 3), which was 3 months from the initiation of drug dosing. BAFF is consumed by B cells, therefore effective B cell depletion increases levels of BAFF. The protocol-stipulated threshold for trial continuation was at least 50% increase in CSF BAFF induced by active treatment with significance level p=0.025.

  3 months

Secondary Outcomes (11)

• Analysis of Changes in CSF B Cell Numbers Between Rituximab and Placebo

  3 months

• Expanded Disability Status Scale (EDSS)

  24 months

• Scripps Neurological Rating Scale (NRS)

  24 months

• Timed 25 Foot Walk

  24 months

• 9-Hole Peg Test

  24 months

Study Arms (3)

Rituximab

EXPERIMENTAL

Patients received 25mg of rituximab into the CSF and 200mg of rituximab intravenously at Month 0, followed by additional 200mg of rituximab intravenously at Month 0.5 and another 25mg of rituximab into CSF at months 1.5 and 12.

Drug: Rituximab

Placebo

PLACEBO COMPARATOR

Patients received normal saline into the CSF and intravenously at Month 0, followed by additional normal saline intravenously at Month 0.5 and another dose of normal saline into CSF at months 1.5 and 12.

Other: normal saline

Baseline

NO INTERVENTION

Patients in their first year baseline prior to study drug phase

Interventions

Rituximab DRUG

Rituximab

normal saline OTHER

normal saline

Also known as: saline

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• Serum alanine transaminase or aspartate transaminase levels which are greater than three times the upper limit of normal values.
• Total white blood cell count \< 3 000/mm(3)
• Platelet count \< 85 000/mm(3)
• Serum creatinine level \> 2.0 mg/dl and eGFR (glomerular filtration rate) \< 60
• Serological evidence of HIV, HTLV-1 or active hepatitis A, B or C
• Positive pregnancy test
• 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)
• 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

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Kosa P, Komori M, Waters R, Wu T, Cortese I, Ohayon J, Fenton K, Cherup J, Gedeon T, Bielekova B. Novel composite MRI scale correlates highly with disability in multiple sclerosis patients. Mult Scler Relat Disord. 2015 Nov;4(6):526-35. doi: 10.1016/j.msard.2015.08.009. Epub 2015 Aug 28.

  PMID: 26590659 RESULT

• Kosa P, Ghazali D, Tanigawa M, Barbour C, Cortese I, Kelley W, Snyder B, Ohayon J, Fenton K, Lehky T, Wu T, Greenwood M, Nair G, Bielekova B. Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment. Front Neurol. 2016 Aug 15;7:131. doi: 10.3389/fneur.2016.00131. eCollection 2016.

  PMID: 27574516 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Interventions

Rituximab; Saline Solution; Sodium Chloride

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

The trial was closed prematurely for futility, because pre-determined interim analysis demonstrated that selected dosing led to \<50% depletion of B cells from the brain/spinal cord. Therefore, only 5 patients per group finished trial.

Results Point of Contact

• Title: Dr. Bibiana Bielekova, Prinicipal Investigator
• Organization: NINDS, NIH

bibiana.bielekova@nih.gov

301-402-4488

Study Officials

• Bibiana Bielekova, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: September 29, 2010
• First Posted: September 30, 2010
• Study Start: September 1, 2010
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: March 28, 2016
• Results First Posted: March 28, 2016

Record last verified: 2016-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)