The Possible Neuroprotective Effect of Ocrelizumab Via VEGF Protein Expression in Relapsing Multiple Sclerosis Patients

May 25, 2021 updated by: IRCCS National Neurological Institute "C. Mondino" Foundation

An Observation Monocentric Study to Analyse the Possible Neuroprotective Effect of Ocrelizumab Via VEGF Protein Expression in Relapsing Multiple Sclerosis Patients

Ocrelizumab (OCR) is a humanized anti-CD20 antibody approved for Relapsing Multiple Sclerosis (RMS) and Primary Progressive Multiple Sclerosis (PPMS), due to neuroprotective effects of partially unknown origin. While its mechanism of action is mainly thought to occur via B cell depletion, previous studies on rituximab, another anti-CD20 drug, showed that CD20 binding elicits several intracellular signalling pathways, also including Protein Kinase C (PKC) activation. Of interest, the β isoform of PKC is known to modulate, through the RNA-binding protein ELAV/HuR, the expression of Vascular Endothelial Growth Factor (VEGF), a signaling protein that has been suggested to play deleterious effects in the first phases of MS. Therefore, the hypothesis is that part of the neuroprotective effects exerted by OCR may also be due to the modulation of VEGF expression via PKCβ /HuR cascade. The primary objective is to evaluate the variation of the expression of VEGF (protein and mRNA) in Peripheral Blood Mononuclear Cells (PBMCs) induced by OCR therapy. No additional visits will be required outside of clinical practice. Additional laboratory testing (VEGF protein expression and PKCbeta/HuR cascade) will be performed on extra blood which will be taken during the routine blood exams.

This study is an observational, longitudinal, monocenter and single arm study, in patients with RMS who are newly prescribed with OCR as per clinical practice.

The study consists of the following visits as per clinical practice

  • T0 visit: at the first dose of OCR, blood sample and clinical/radiological MS data will be collected.
  • T6: after 6 months of OCR treatment, blood samples and clinical MS data will be collected.
  • T12 visit: after 12 months of OCR treatment, blood samples and clinical MS data will be collected.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

Ocrelizumab (OCR) is a humanized monoclonal anti-CD20 antibody approved by the FDA in 2017 and by the European Medicines Agency in 2018 for treatment of adult patients with Relapsing Multiple Sclerosis (RMS). In addition, having shown neuroprotective effects, OCR is the first drug ever approved for early treatment of Primary Progressive MS (PPMS). Currently, OCR is thought to mostly act via the rapid depletion of the B cells expressing CD20. Additionally, this depletion most likely causes long-lasting changes in the profile of B cells, characterized by a reduction of their pro-inflammatory phenotype, as demonstrated with other anti-CD20 antibodies.

Of interest, previous studies on other anti-CD20 drugs, mainly rituximab, have shown that anti-CD20 agents also exert interesting effects on additional intracellular signaling pathways, such as those involving serine/threonine and tyrosine kinases, as well as c-myc. Considering the structural, pharmacokinetic and pharmacodynamic similarities between OCR and rituximab, it can be hypothesized that the efficacy of OCR in delaying disease progression and neuroprotection might also stem from such intracellular effects.

Among the various intracellular effects elicited by rituximab through the binding with CD20, stimulation of the Protein Kinase C (PKC) pathway is of potential significance. The term PKC encompasses a family of several serine/threonine protein kinases of which the isoform β has been implicated in pathological processes, such as diabetic retinopathy, via a specific PKCβ/HuR/Vascular Endothelial Growth Factor (VEGF) pathway (Amadio et al. 2010). Notably, HuR belongs to a family of RNA-binding proteins, named ELAV, which are able to influence virtually any aspect of the post-synthesis fate of the targeted transcripts, including VEGF.

VEGF is a signaling molecule involved in vital processes such as angiogenesis, endothelial proliferation and cellular response to hypoxia. The possible role of VEGF in MS pathogenesis and evolution has not been explored until recently, but mounting evidence points to the conclusion that VEGF might play a significant noxious role in the relapsing stage of MS, for instance by mediating an increase in blood-brain barrier (BBB) permeability, while playing a beneficial, neuroprotective role in the late, progressive stage of the disease. Of note, VEGF has a primary role in promoting vascular hyperpermeability, indeed via phosphorylation of endothelial tight junction proteins modulates their degradation, finally leading to BBB disruption. Further, it also regulates vessel growth and is chemotactic for monocytes and lymphocytes, promoting neuroinflammation.

Of interest, a significant increase in VEGF was observed in mice in the acute phase of murine MOG-induced MS, which correlates to the clinical score, and in sera of MS patients during clinical disease relapses.

Based on these considerations, it can be possible that OCR exerts an additional beneficial effect in MS therapy by modulating VEGF content.

With this project, we aim to explore the effects of OCR on intracellular signaling pathways by assessing VEGF expression in Peripheral Blood Mononuclear Cells (PBMCs) of RMS patients at the beginning of OCR therapy, as well as at 6 and 12 months of ongoing treatment.

In particular, ther purpose of the study is to focus on the pro-angiogenic VEGF-A 165, which seems the isoform mainly involved as mediator of inflammation and cellular immunity.

Further, the PKCβ/HuR cascade will be investigated in the same conditions. Secondly, disease activity during OCR treatment will be examined at every step, and also compared with VEGF and PKC levels.

The results will also possibly demonstrate a necessity of further determining the extent and significance of intracellular effects of anti-CD20 therapy in MS.

This study is an observational (phase 4) , longitudinal, monocenter and single arm study, in patients with RMS who are newly prescribed with OCR as per clinical practice.

The study consists of the following visits as per clinical practice:

  • Baseline/start (T0): informed consent signature, inclusion/exclusion criteria verification, demographical characteristics, clinical medical history recording, concomitant therapies, neurological history recording (MS history), number of relapses from MS onset, neurological examination, the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), blood sample, ocrelizumab administration.
  • T6: (after 6 months of OCR treatment) adverse events (including relapses), neurological examination, therapies changes, EDSS, MSSS, blood sample, ocrelizumab administration.
  • T12 (after 12 months* of OCR treatment), adverse events (including relapses), neurological examination, therapies changes, EDSS, MSSS, blood sample, ocrelizumab administration.

Study Type

Observational

Enrollment (Anticipated)

21

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with RMS, who are newly prescribed with OCR as per clinical practice, are enrolled.

Description

Inclusion criteria

  • The participant must have a previous diagnosis of RMS in accordance with the 2017 revised McDonald criteria
  • The participant must have been newly prescribed to OCR treatment according to clinical practice
  • Absence of high dose of steroid treatment for at least 4 weeks
  • The participant must be capable of giving signed informed consent.

Exclusion criteria

  • Clinical MS relapse within four-week period prior to inclusion
  • Pregnant or nursing (lactating) women.
  • Chronic disease of the immune system, other than MS
  • Active systemic bacterial, viral or fungal infections
  • Allergy to OCR
  • Already included in other interventional trials

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
VEGF protein levels
Time Frame: Month 12 versus baseline (T0)
To evaluate the expression of VEGF protein in PBMCs from patients with RMS
Month 12 versus baseline (T0)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
VEGF protein levels
Time Frame: Month 6 versus baseline (T0)
To evaluate the expression of VEGF protein in PBMCs from patients with RMS before and after OCR treatment.
Month 6 versus baseline (T0)
VEGF mRNA levels
Time Frame: Change from baseline (T0) to Month 6 and Month 12
To evaluate the expression of VEGF mRNA in PBMCs from patients with RMS before and after OCR treatment
Change from baseline (T0) to Month 6 and Month 12
PKCβ protein levels
Time Frame: Change from baseline (T0) to Month 6 and Month 12
To evaluate the expression of PKCβ protein in PBMCs from patients with RMS before and after OCR treatment
Change from baseline (T0) to Month 6 and Month 12
PKCβ mRNA levels
Time Frame: Change from baseline (T0) to Month 6 and Month 12
To evaluate the expression of PKCβ mRNA in PBMCs from patients with RMS before and after OCR treatment
Change from baseline (T0) to Month 6 and Month 12
Expanded Disability Status Scale (EDSS)
Time Frame: Change from baseline (T0) to Month 6 and Month 12

To evaluate whether the expression of VEGF and PKCβ affects MS severity before and after OCR treatment.

The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.
Change from baseline (T0) to Month 6 and Month 12
Multiple Sclerosis Severity Score (MSSS)
Time Frame: Change from baseline (T0) to Month 6 and Month 12

To evaluate whether the expression of VEGF and PKCβ affects MS severity before and after OCR treatment.

The Multiple Sclerosis Severity Score (MSSS) relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations.
Change from baseline (T0) to Month 6 and Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS National Neurological Institute "C. Mondino" Foundation

Investigators

  • Principal Investigator: Roberto Bergamaschi, MD, IRCCS Mondino Foundation, Pavia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

May 31, 2021

Primary Completion (Anticipated)

July 31, 2024

Study Completion (Anticipated)

July 31, 2024

Study Registration Dates

First Submitted

May 20, 2021

First Submitted That Met QC Criteria

May 25, 2021

First Posted (Actual)

May 26, 2021

Study Record Updates

Last Update Posted (Actual)

May 26, 2021

Last Update Submitted That Met QC Criteria

May 25, 2021

Last Verified

May 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VEGF Study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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