Multiple SclerosisPhase 1NCT05078177
Safety and Efficacy of Intrathecal Rituximab in Patients With Multiple Sclerosis
A Phase 1 study testing Rituximab in people with Multiple Sclerosis, run by St. Petersburg State Pavlov Medical University at 1 site in Russia.
Trial summary
Considering the accumulated data on the pathogenesis of multiple sclerosis, indicating a significant role of B cells in the progression of the disease, the use of monoclonal antibodies to CD20 antigen, administered intrathecally to achieve adequate B-lymphodepletion in the barrier tissues can increase the duration of… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- 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
- 40 participants
- Where
- 1 siteRussia
- Study dates
- 21 Dec 2020to 21 Dec 2024
- 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 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-65;
- 1.0-7.5 points on the EDSS scale (for MS);
- Length of illness - any;
- Disease progression during the last 6 months while taking drugs of 1st and 2nd lines;
- An established and confirmed diagnosis of an autoimmune disease in the previous stages of treatment;
- Ineffectiveness, inaccessibility or intolerance of Disease-Modifying Therapies;
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- Relapse after AHSCT.
- Absence of severe concomitant somatic pathology;
- Left ventricular injection fraction > 50%;
- Karnofsky Performance Score (KPS) > 30%;
- The ability to take oral medications;
- Life expectancy is more than 1 month;
- Signed informed consent of the patient or legal representatives.
Who cannot join
- Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%
- Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted
- Respiratory distress >grade I
- Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits
- Creatinine clearance < 60 mL/min
- Uncontrolled bacterial or fungal infection at the time of enrollment
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- Requirement for vasopressor support at the time of enrollment
- Karnofsky performans status <30%
- Pregnancy
- Somatic or psychiatric disorder making the patient unable to sign informed consent
Trial locations and contacts
1 site in 1 country.
Russia1 site, 1 recruiting
- Recruiting
First Pavlov State Medical University of St. Petersburg
Saint Petersburg, 197022
Alexey Yu Polushin, MD, +79118167559, alexpolushin@yandex.ru
Yury R Zalyalov, MD, +79112193127, yz21@mail.ru
About this study
Official title: Trial of the Efficacy and Safety of Pathogenetic Therapy of Multiple Sclerosis and Other Autoimmune Diseases Using Intrathecal Rituximab
Considering the accumulated data on the pathogenesis of multiple sclerosis, indicating a significant role of B cells in the progression of the disease, the use of monoclonal antibodies to CD20 antigen, administered intrathecally to achieve adequate B-lymphodepletion in the barrier tissues can increase the duration of the recurrence-free course of autoimmune diseases, suspend their progression, and also prevent clinical relapse when memory B cells are detected.
Read the detailed description
Multiple sclerosis (MS) is a chronic progressive autoimmune-mediated inflammatory demyelinating disease of the central nervous system (CNS), clinically manifested by impaired sensory motor function and cognitive impairment. In the pathogenesis of MS, T-cells make the main contribution to the process of inflammatory demyelination; however, the accumulated data on the pathogenesis of MS indicate a significant role of B cells in the progression of the disease. In addition to differentiation into plasma cells that produce autoantibodies, B lymphocytes stimulate T cell activity through antigen presentation, production of proinflammatory cytokines that trigger demyelination and differentiation into memory B cells that promote CD4 + T cell autoproliferation. The presence of "oligoclonal bands" in cerebrospinal fluid and demyelination plaques of brain tissue in MS patients is the result of persistent intrathecal clonal expansion of various B cell populations that contribute to the production of autoreactive antibodies. Thus, B cells located in the central nervous system, protected by the blood-brain barrier (BBB) and, as a consequence, not undergoing complete eradication due to limited penetration of the BBB by immunosuppressive drugs, are a potential target for the treatment of patients with MS. Depletion of B cells through the use of monoclonal antibodies to the CD20 antigen, which is expressed predominantly on mature B lymphocytes, is a promising direction in the therapy of autoimmune diseases. The most readily available anti-CD20 monoclonal antibody is rituximab. The available data from numerous studies on the use of intravenous rituximab have demonstrated a decrease in MR activity and clinical activity in patients with RRMS. At the same time, rituximab does not affect clinical outcomes in patients with PPMS and SPMS with a long history of the disease, probably due to insufficient antibody concentration in intact BBB in the CNS tissue affected by tertiary lymphoid follicles, because the ratio of rituximab concentration in CSF and serum after intravenous infusion ranges from 0.1% to 1-1.7%. Thus, to ensure a sufficient therapeutic concentration of rituximab in the tissues of the central nervous system, the use of the intrathecal route of drug administration is justified. To date, sufficient data have been accumulated on the safety of using intrathecal rituximab in the treatment of both oncological and autoimmune diseases (including MS).
Thus, the use of an anti-CD20 monoclonal antibody injected intrathecally in order to achieve adequate B-lymphodepletion in the barrier tissues can increase the duration of the recurrence-free course of autoimmune diseases, suspend their progression, and also prevent clinical relapse when memory B cells are detected.
- Conditions
- Multiple Sclerosis
- Being tested
- Rituximab
- Keywords
- Autoimmune Diseases, Rituximab
- Medical subject headings
- Multiple Sclerosis, Autoimmune Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called Mabthera, Reditux, Acellbia
All patients receive AHSCT with RIC (Cyclophosphamide, Antithymocyte globulin/Rituximab). After resolution of cytopenia (approximately from about D+12 to D+14 AHSCT), patients will receive intrathecal Rituximab.
| Study group | Role | What they receive |
|---|---|---|
| AHSCT + intrathecal Rituximab | Experimental | AHSCT with reduced intensity condition regimen (RIC). Lumbar puncture with intrathecal injection of 25 mg Rituximab will be performed once from about D+12 to D+14 AHSCT, depending on the duration of cytopenia. Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Multiple sclerosis progression free survival
To evaluate safety and effectiveness of intrathecal Rituximab in patients with refractory multiple sclerosis after AHSCT. Multiple sclerosis progression free survival
Measured: 365 days
Secondary outcomes (10)
Overall survival
To evaluate overall survival after AHSCT in combination with intrathecal Rituximab in patients with autoimmune diseases.
Measured: 365 days
To evaluate adverse effects after intrathecal Rituximab
Toxicity based NCI CTCAE ver.5.0, including analysis of severe bacterial, fungal and viral infections incidence
Measured: 365 days
Quality of life status 1
Multiple sclerosis-specific questionnaire - HADS (Hospital Anxiety and Depression Scale) before and after AHSCT:
0-7 points - normal; 8-10 - subclinically expressed anxiety/depression; 11-21 - clinically expressed anxiety/depression.
Measured: 365 days
Quality of life status 2
Multiple sclerosis-specific questionnaire - The Short Form-36 (SF-36) before and after AHSCT:
The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role-physical functioning, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The indicators of each scale are compiled in such a way that the higher the value of the indicator (from 0 to 100), the better the score on the chosen scale. Of these, two parameters are formed: the psychological and physical components of health.
Measured: 365 days
Quality of life status 3
Multiple sclerosis-specific questionnaire - Multiple Sclerosis Impact Scale (MSIS-29) before and after AHSCT:
The MSIS-29 scale consists of 29 items and includes indicators observed over the previous two weeks, including 20 of which characterize physical condition, coordination and mobility, and 9 questions reflect the patient's mental state. Answers are ranked on a 5-point Likert scale from 1 to 5 (1 = none; 2 = little; 3 = moderate; 4 = significant; 5 = very strong) in one direction.
The total score is the sum of all 29 responses and can range from 29 to 145. A higher score means a higher degree of disability. The result is assessed on a scale from 0 to 100, where a higher result means worse health.
Measured: 365 days
Quality of life status 4
Multiple sclerosis-specific questionnaire - Functional Assessment of Multiple Sclerosis (FAMS) before and after AHSCT:
FAMS Total score (range=0-176) is derived by adding: 1) Mobility (r=0-28). 2) Symptoms (r=0-28). 3) Emotional well-being (r=0-28). 4) General contentment (r=0-28). 5) Thinking and fatigue (r=0-36). 6) Family/social wellbeing (r=0-28).
Higher scores indicate better quality of life.
Measured: 365 days
Neurological status 1
Multiple sclerosis-specific questionnaire - EDSS (Expanded Disability Status Scale) before and after AHSCT:
0 points - Normal neurologic exam; 1.0-1.5 - No disability, minimal signs in one or two Functional Systems (FS); 2.0-2.5 - Minimal disability in one or two FS; 3.0-3,5 - Moderate disability in one FS, fully ambulatory; 4.0-4.5 - Fully ambulatory without aid. Able to walk without aid or rest some 500 or 300 meters; 5.0-5.5 - Ambulatory without aid or rest for about 200 or 100 meters; 6.0 - Intermittent assistance required to walk about 100 meters; 6.5 - Constant bilateral assistance required to walk about 20 meters; 7.0-7.5 - Unable to walk beyond about 5 meters or more than a few steps; 8.0 - Essentially restricted to bed, but may be out of bed itself; 8.5 - Essentially restricted to bed; 9.0 - Helpless bed patient; can communicate and eat; 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; 10 - Death due to MS
Measured: 365 days
Evaluation of Immune system reconstitution after AHSCT 1
Determination of absolute and relative values of the subpopulation composition of T-lymphocytes (CD3, CD4, CD8, CD45) and the ratio of T-helpers/T-cytotoxic cells before and after AHSCT.
Measured: 365 days
Evaluation of Immune system reconstitution after AHSCT 2
Determination of the absolute and relative number of CD19 + B-lymphocytes and analysis of subpopulations of B-lymphocytes: B1-cells (CD19+CD5+), B-2 cells (CD19+CD5-), memory B-cells (CD19+CD5-CD27+) before and after AHSCT.
Measured: 365 days
Impact of autoHSCT+intrathecal Rituximab on brain structure anatomy
MRI 3,0 T
Measured: 365 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Oct 2021
- Study start21 Dec 2020
- Primary completion21 Dec 2022 (estimated)
- Study completion21 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- 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
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- St. Petersburg State Pavlov Medical University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ivan S Moiseev, St. Petersburg State Pavlov Medical University
- Investigators
- Ivan S Moiseev, MD, Ph.D, Principal investigator, Pavlov First Saint Petersburg State Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05078177
- Sponsor's protocol ID
- intrathecal_rtx_ms
- Status last verified
- Oct 2021
- First submitted
- 1 Oct 2021
- Last updated
- 14 Oct 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Trial of the Efficacy and Safety of Pathogenetic Therapy of Multiple Sclerosis and Other Autoimmune Diseases Using Intrathecal Rituximab
- ClinicalTrials.gov ID
- NCT05078177
- Acronym / sponsor ID
- intrathecal_rtx_ms
- Conditions
- Multiple Sclerosis
- Keywords
- Autoimmune Diseases, Rituximab
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- St. Petersburg State Pavlov Medical UniversityUniversity, hospital or other
- Study start
- 21 Dec 2020 (actual)
- Primary completion
- 21 Dec 2022 (estimated)
- Study completion
- 21 Dec 2024 (estimated)
- First posted
- 14 Oct 2021 (actual)
- 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.
Considering the accumulated data on the pathogenesis of multiple sclerosis, indicating a significant role of B cells in the progression of the disease, the use of monoclonal antibodies to CD20 antigen, administered intrathecally to achieve adequate B-lymphodepletion in the barrier tissues can increase the duration of the recurrence-free course of autoimmune diseases, suspend their progression, and also prevent clinical relapse when memory B cells are detected.
Detailed description
Multiple sclerosis (MS) is a chronic progressive autoimmune-mediated inflammatory demyelinating disease of the central nervous system (CNS), clinically manifested by impaired sensory motor function and cognitive impairment. In the pathogenesis of MS, T-cells make the main contribution to the process of inflammatory demyelination; however, the accumulated data on the pathogenesis of MS indicate a significant role of B cells in the progression of the disease. In addition to differentiation into plasma cells that produce autoantibodies, B lymphocytes stimulate T cell activity through antigen presentation, production of proinflammatory cytokines that trigger demyelination and differentiation into memory B cells that promote CD4 + T cell autoproliferation. The presence of "oligoclonal bands" in cerebrospinal fluid and demyelination plaques of brain tissue in MS patients is the result of persistent intrathecal clonal expansion of various B cell populations that contribute to the production of autoreactive antibodies. Thus, B cells located in the central nervous system, protected by the blood-brain barrier (BBB) and, as a consequence, not undergoing complete eradication due to limited penetration of the BBB by immunosuppressive drugs, are a potential target for the treatment of patients with MS. Depletion of B cells through the use of monoclonal antibodies to the CD20 antigen, which is expressed predominantly on mature B lymphocytes, is a promising direction in the therapy of autoimmune diseases. The most readily available anti-CD20 monoclonal antibody is rituximab. The available data from numerous studies on the use of intravenous rituximab have demonstrated a decrease in MR activity and clinical activity in patients with RRMS. At the same time, rituximab does not affect clinical outcomes in patients with PPMS and SPMS with a long history of the disease, probably due to insufficient antibody concentration in intact BBB in the CNS tissue affected by tertiary lymphoid follicles, because the ratio of rituximab concentration in CSF and serum after intravenous infusion ranges from 0.1% to 1-1.7%. Thus, to ensure a sufficient therapeutic concentration of rituximab in the tissues of the central nervous system, the use of the intrathecal route of drug administration is justified. To date, sufficient data have been accumulated on the safety of using intrathecal rituximab in the treatment of both oncological and autoimmune diseases (including MS).
Thus, the use of an anti-CD20 monoclonal antibody injected intrathecally in order to achieve adequate B-lymphodepletion in the barrier tissues can increase the duration of the recurrence-free course of autoimmune diseases, suspend their progression, and also prevent clinical relapse when memory B cells are detected.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AHSCT + intrathecal Rituximab | Experimental | Drug: RituximabAHSCT with reduced intensity condition regimen (RIC). Lumbar puncture with intrathecal injection of 25 mg Rituximab will be performed once from about D+12 to D+14 AHSCT, depending on the duration of cytopenia. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Age 18-65;
- 1.0-7.5 points on the EDSS scale (for MS);
- Length of illness - any;
- Disease progression during the last 6 months while taking drugs of 1st and 2nd lines;
- An established and confirmed diagnosis of an autoimmune disease in the previous stages of treatment;
Key exclusion criteria (10 listed)
- Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%
- Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted
- Respiratory distress >grade I
- Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits
- Creatinine clearance < 60 mL/min
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: Mabthera, Reditux, AcellbiaAll patients receive AHSCT with RIC (Cyclophosphamide, Antithymocyte globulin/Rituximab). After resolution of cytopenia (approximately from about D+12 to D+14 AHSCT), patients will receive intrathecal Rituximab. | Drug | AHSCT + intrathecal Rituximab |
Primary outcome
Multiple sclerosis progression free survival
Time frame: 365 days
To evaluate safety and effectiveness of intrathecal Rituximab in patients with refractory multiple sclerosis after AHSCT. Multiple sclerosis progression free survival
10 secondary outcomes
Overall survival
Time frame: 365 days
To evaluate adverse effects after intrathecal Rituximab
Time frame: 365 days
Quality of life status 1
Time frame: 365 days
Quality of life status 2
Time frame: 365 days
Quality of life status 3
Time frame: 365 days
Quality of life status 4
Time frame: 365 days
Neurological status 1
Time frame: 365 days
Evaluation of Immune system reconstitution after AHSCT 1
Time frame: 365 days
Evaluation of Immune system reconstitution after AHSCT 2
Time frame: 365 days
Impact of autoHSCT+intrathecal Rituximab on brain structure anatomy
Time frame: 365 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Oct 2021.
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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.
Ivan S Moiseev, MD, Ph.D principal investigator
Pavlov First Saint Petersburg State Medical 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 Multiple Sclerosis, run by St. Petersburg State Pavlov Medical University at 1 site in Russia.
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 13 inclusion and 10 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: status not confirmed, as of the sponsor's last update on 14 Oct 2021. 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 Russia. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alexey Yu Polushin, MD (+79118167559, alexpolushin@yandex.ru), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Multiple sclerosis progression free survival (time frame: 365 days). 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 14 Oct 2021.