Primary Progressive Multiple SclerosisPhase 1NCT02253264
A Phase 1 Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients
A Phase 1 study testing Rituximab in people with Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis, run by Johns Hopkins University at 1 site in United States.
Trial summary
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Primary Progressive Multiple Sclerosis, Secondary Progressive Multiple Sclerosis
- What is being tested?
- Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2014to Aug 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of PPMS by revised McDonald criteria or SPMS by Lublin and Reingold criteria
- Age ≥ 18 years
- MRI Brain demonstrating evidence of leptomeningeal enhancement on contrast enhanced FLAIR images within the past 12 months, which is now part of the routine clinical MS MRI protocol at the Johns Hopkins Hospital.
- Patients may be on no MS treatment or should have been on the same treatment for at least 6 months and are not expected to switch therapy in the next 6 months
Who cannot join
- Severe intolerance of lumbar puncture in the past
- Treatment with a chemotherapeutic agent in the past year or chronic infectious disease
- Peripheral CD19 counts below lower limit of normal in patients previously treated with rituximab
- Calculated creatinine clearance ≥ 70 ml/min calculated using Cockroft-Gault equation
- Female patients of childbearing potential not willing to use contraception (intrauterine device (IUD), oral contraceptive pill (OCP) or double barrier method)
- Corticosteroid treatment within the past 30 days
Show all 14Show fewer
- Known history of other neuroinflammatory or systemic autoimmune disease
- Known bleeding diathesis or ongoing anticoagulation (oral/ injectable)
- Receipt of live vaccination within 1 month prior to scheduled study drug dosing
- Hemoglobin < 10 mg/dL, or Platelet count < 100,000 /mm3 or white blood count (WBC) < 2,000 or > 15,000 /mm3
- Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) > 2.5× the site laboratory upper limit of normal (ULN) or Total bilirubin > 2.5 ULN
- Positive for Hepatitis B surface antigen (HBsAg) or Positive for Hepatitis C antibody (HCV Ab)
- Moderate or severe acute illness with or without fever
- Current use (or use within the past 3 months) of natalizumab as MS therapy
Trial locations and contacts
1 site in 1 country.
United States1 site
The Johns Hopkins Hospital
Baltimore, Maryland, 21287
About this study
Official title: A Phase 1 Open-label Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients With Magnetic Resonance Imaging Evidence of Leptomeningeal Enhancement
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. Intrathecal (IT) rituximab administration has been used in central nervous system (CNS) lymphoma to achieve greater cerebrospinal fluid (CSF) concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
Read more
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using magnetic resonance imaging (MRI) to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on MRI or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Read the detailed description
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. It has been shown to be effective when given intravenously in trials of Relapsing-Remitting Multiple Sclerosis (RRMS). However, the cerebrospinal fluid (CSF) penetrance of rituximab is minimal, such that CSF levels are < 1% of serum levels after the administration of intravenous (IV) rituximab. Indeed, IV rituximab failed to significantly slow disability in a clinical trial in progressive MS. Intrathecal (IT) rituximab administration has been used in CNS lymphoma to achieve greater CSF concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
A recently described finding is the presence of enhancing meningeal lesions on post-contrast FLAIR imaging in MS patients. These could possibly represent ectopic lymphoid follicles. This finding could serve as a biomarker to identify patients with ectopic meningeal lymphoid follicles who might be most likely to derive benefit from IT rituximab therapy.
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using post-contrast FLAIR imaging to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on post-contrast FLAIR imaging or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Progressive MS currently has no FDA approved treatments. There is a great need for new therapeutic modalities for patients with progressive forms of MS. The identification of a novel treatment for progressive MS would have a beneficial impact on tens of thousands of patients with progressive MS.
- Being tested
- Rituximab
- Medical subject headings
- Multiple Sclerosis, Chronic Progressive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called Rituxan
| Study group | Role | What they receive |
|---|---|---|
| Intrathecal rituximab | Experimental | 25 mg of rituximab will be administered intrathecally by direct infusion over 10 minutes at two time points, two weeks apart. Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of serious adverse events over the course of the study at least possibly related to intrathecal rituximab therapy, as determined by the principal investigator.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Oct 2014 (estimated)
- Study startNov 2014
- Primary completionAug 2017
- Study completionAug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Primary Progressive Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ellen M Mowry, MD, MCR, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02253264
- Sponsor's protocol ID
- IRB00027318
- Status last verified
- Aug 2017
- First submitted
- 29 Sep 2014
- Last updated
- 30 Aug 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Open-label Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients With Magnetic Resonance Imaging Evidence of Leptomeningeal Enhancement
- ClinicalTrials.gov ID
- NCT02253264
- Acronym / sponsor ID
- IRB00027318
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Study start
- Nov 2014
- Primary completion
- Aug 2017 (actual)
- Study completion
- Aug 2017 (actual)
- First posted
- 1 Oct 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. Intrathecal (IT) rituximab administration has been used in central nervous system (CNS) lymphoma to achieve greater cerebrospinal fluid (CSF) concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using magnetic resonance imaging (MRI) to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on MRI or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Detailed description
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. It has been shown to be effective when given intravenously in trials of Relapsing-Remitting Multiple Sclerosis (RRMS). However, the cerebrospinal fluid (CSF) penetrance of rituximab is minimal, such that CSF levels are < 1% of serum levels after the administration of intravenous (IV) rituximab. Indeed, IV rituximab failed to significantly slow disability in a clinical trial in progressive MS. Intrathecal (IT) rituximab administration has been used in CNS lymphoma to achieve greater CSF concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
A recently described finding is the presence of enhancing meningeal lesions on post-contrast FLAIR imaging in MS patients. These could possibly represent ectopic lymphoid follicles. This finding could serve as a biomarker to identify patients with ectopic meningeal lymphoid follicles who might be most likely to derive benefit from IT rituximab therapy.
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using post-contrast FLAIR imaging to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on post-contrast FLAIR imaging or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Progressive MS currently has no FDA approved treatments. There is a great need for new therapeutic modalities for patients with progressive forms of MS. The identification of a novel treatment for progressive MS would have a beneficial impact on tens of thousands of patients with progressive MS.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Intrathecal rituximab | Experimental | Drug: Rituximab25 mg of rituximab will be administered intrathecally by direct infusion over 10 minutes at two time points, two weeks apart. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of PPMS by revised McDonald criteria or SPMS by Lublin and Reingold criteria
- Age ≥ 18 years
- MRI Brain demonstrating evidence of leptomeningeal enhancement on contrast enhanced FLAIR images within the past 12 months, which is now part of the routine clinical MS MRI protocol at the Johns Hopkins Hospital.
- Patients may be on no MS treatment or should have been on the same treatment for at least 6 months and are not expected to switch therapy in the next 6 months
Key exclusion criteria (14 listed)
- Severe intolerance of lumbar puncture in the past
- Treatment with a chemotherapeutic agent in the past year or chronic infectious disease
- Peripheral CD19 counts below lower limit of normal in patients previously treated with rituximab
- Calculated creatinine clearance ≥ 70 ml/min calculated using Cockroft-Gault equation
- Female patients of childbearing potential not willing to use contraception (intrauterine device (IUD), oral contraceptive pill (OCP) or double barrier method)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: Rituxan | Drug | Intrathecal rituximab |
Primary outcome
Number of serious adverse events over the course of the study at least possibly related to intrathecal rituximab therapy, as determined by the principal investigator.
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Aug 2017.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ellen M Mowry, MD, MCR principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rituximab in people with Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis, run by Johns Hopkins University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of serious adverse events over the course of the study at least possibly related to intrathecal rituximab therapy, as determined by the principal investigator. (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Aug 2017.