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Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, no 20, p. E1893-E1901Article in journal (Refereed) Published
Abstract [en]

Objectives To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a1-year follow-up period. Methods Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months. Results Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers. Conclusions Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy. ClinicalTrials.gov identifier NCT01719159. Classification of evidence This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.

Place, publisher, year, edition, pages
Wolters Kluwer, 2018. Vol. 91, no 20, p. E1893-E1901
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-154850DOI: 10.1212/WNL.0000000000006500ISI: 000452514700006PubMedID: 30305449Scopus ID: 2-s2.0-85056314572OAI: oai:DiVA.org:umu-154850DiVA, id: diva2:1275196
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2020-03-31Bibliographically approved
In thesis
1. Studies of the Biology of Intrathecal Treatment in Progressive MS
Open this publication in new window or tab >>Studies of the Biology of Intrathecal Treatment in Progressive MS
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av biologin vid intratekal behandling vid progressiv MS
Abstract [en]

Background: Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease, affecting the central nervous system (CNS). About 85% of afflicted present with a relapsing-remitting form of the disease (RRMS), for which a breakthrough in treatment was made in 2008 with rituximab, an antibody directed towards CD20, a surface antigen on B-cells. These findings also contributed to cementing the importance of the B-cell’s role in MS pathophysiology. However, MS also exist as a progressive phenotype, affecting most MS patients either from onset or after a transition from RRMS, and for progressive MS the same treatment effect of anti-CD20 has not been observed. Still, studies have found follicle-like structures containing B-cells in meninges and subarachnoid space of the cortex in progressive MS brains, supporting the involvement of B-cells. Evidence also support the existence of a chronic, low-grade inflammatory process compartmentalised within the CNS that correlates with the progressive phase of MS, which may present a treatment barrier towards anti-CD20. Peripherally administrated therapeutic antibodies cross the intact blood-brain barrier with low efficiency with only 0.1-0.5% of the plasma concentration occurring in the cerebrospinal fluid (CSF). Intrathecal (IT) administration circumvents the blood-brain barrier, presenting an opportunity to better target the CNS B-cells.

Aims: To evaluate the safety and feasibility of intrathecal anti-CD20 therapy with rituximab in progressive MS, its effect on disease progression through clinical parameters, and impact on biomarkers in CSF. Furthermore, this thesis aimed to evaluate the effect on biomarkers representative of cell injury related to insertion of a ventricular catheter for drug administration and to examine the interstitial milieu in the brain through microdialysis (MD).

Methods: The thesis is based on the open-label, phase IIb, multicentre clinical trial Intrathecal Treatment Trial in Progressive Multiple Sclerosis (ITT-PMS; EudraCT 2008-002626-11), in which 23 participants received IT treatment with rituximab, and the extended follow-up study, ITT-PMS extension (EudraCT 2012-000721-53). All participants received a ventricular catheter and an Ommaya reservoir for drug administration through a neurosurgical procedure, and 10 participants received a MD catheter in parallel to the ventricular catheter for 10 days. The treatment effect was evaluated by regular clinical evaluations and analyses of CSF. The clinical outcome was evaluated through walking and upper-limb function tests, and by clinical evaluation scales. Levels of selected CSF biomarkers were analysed from the same time-points as the clinical evaluations.

Results: After the completion of the extension trial, one clinical parameter (cognitive performance) showed improvement but could most likely be explained by a learning effect. Worsening of walking speed was observed, while the remaining clinical parameters showed no change. Two severe adverse events occurred in the form of low-virulent bacterial meningitis caused by Propionibacterium, but both were treated effectively with antibiotics without residual symptoms. A ‘spike’ was noticed in the level of lumbar CSF neurofilament light (NFL) following surgery but returned to pre-surgery baseline within 6-12 months. No change was observed for any of the other lumbar CSF biomarkers. No meaningful correlation of protein levels was observed when comparing MD samples, ventricular CSF, and lumbar CSF.

Conclusions: Intrathecal treatment through intraventricular administration was well tolerated but not without risks. A continued progression was observed in gait impairment. The insertion of the ventricular catheter caused white matter injury, measured through an increase in NFL in lumbar CSF, in direct association with the surgical procedure. No impact was observed on other CSF biomarkers. There was a poor correlation between different CNS compartments regarding protein levels, arguing for caution in drawing conclusions about brain pathophysiology from lumbar CSF samples.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2020. p. 68
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2082
Keywords
Progressive Multiple Sclerosis, intrathecal treatment, Ommaya reservoir, anti-CD20 therapy, microdialysis, cerebrospinal fluid, CNS compartments, Progressiv Multipel Skleros, intratekal behandling, Ommaya reservoar, anti-CD20 terapi, mikrodialys, ryggmärgsvätska, sektioner i centrala nervsystemet
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-169322 (URN)978-91-7855-232-0 (ISBN)978-91-7855-233-7 (ISBN)
Public defence
2020-04-24, DBS-enhetens bibliotek, NUS, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
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Ny lokal: På spikbladet anges tidigare fastslagna lokal. 

Available from: 2020-04-03 Created: 2020-03-31 Last updated: 2021-02-10Bibliographically approved

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Bergman, JoakimGilthorpe, Jonathan D.Bergenheim, TommySvenningsson, Anders

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