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

NCT04902690 | Unknown

• 1 other identifier: VEGF Study
• Study Type: observational
• Target: 21
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Multiple Sclerosis Relapse

Keywords

Neuroprotective effect; Ocrelizumab; Multiple sclerosis; Vascular Endothelial Growth Factor

Outcome Measures

Primary Outcomes (1)

• VEGF protein levels

  To evaluate the expression of VEGF protein in PBMCs from patients with RMS

  Month 12 versus baseline (T0)

Secondary Outcomes (6)

• VEGF protein levels

  Month 6 versus baseline (T0)

• VEGF mRNA levels

  Change from baseline (T0) to Month 6 and Month 12

• PKCβ protein levels

  Change from baseline (T0) to Month 6 and Month 12

• PKCβ mRNA levels

  Change from baseline (T0) to Month 6 and Month 12

• Expanded Disability Status Scale (EDSS)

  Change from baseline (T0) to Month 6 and Month 12

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation: lead

Related Publications (13)

• Amadio M, Bucolo C, Leggio GM, Drago F, Govoni S, Pascale A. The PKCbeta/HuR/VEGF pathway in diabetic retinopathy. Biochem Pharmacol. 2010 Oct 15;80(8):1230-7. doi: 10.1016/j.bcp.2010.06.033. Epub 2010 Jul 1.

  PMID: 20599775 BACKGROUND

• Di Girolamo F, D'Amato A, Lante I, Signore F, Muraca M, Putignani L. Farm animal serum proteomics and impact on human health. Int J Mol Sci. 2014 Sep 1;15(9):15396-411. doi: 10.3390/ijms150915396.

  PMID: 25257521 BACKGROUND

• Girolamo F, Coppola C, Ribatti D, Trojano M. Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol Commun. 2014 Jul 22;2:84. doi: 10.1186/s40478-014-0084-z.

  PMID: 25047180 BACKGROUND

• Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.

  PMID: 28002679 BACKGROUND

• Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat A, Fillatreau S, Bar-Or A; Canadian B cells in MS Team. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015 Oct 21;7(310):310ra166. doi: 10.1126/scitranslmed.aab4176.

  PMID: 26491076 BACKGROUND

• Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21.

  PMID: 28002688 BACKGROUND

• Moran EP, Wang Z, Chen J, Sapieha P, Smith LE, Ma JX. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications. Am J Physiol Heart Circ Physiol. 2016 Sep 1;311(3):H738-49. doi: 10.1152/ajpheart.00005.2016. Epub 2016 Jul 29.

  PMID: 27473938 BACKGROUND

• Pascale A, Govoni S. The complex world of post-transcriptional mechanisms: is their deregulation a common link for diseases? Focus on ELAV-like RNA-binding proteins. Cell Mol Life Sci. 2012 Feb;69(4):501-17. doi: 10.1007/s00018-011-0810-7. Epub 2011 Sep 10.

  PMID: 21909784 BACKGROUND

• Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000 Dec;27(6 Suppl 12):17-24.

  PMID: 11225995 BACKGROUND

• Roscoe WA, Welsh ME, Carter DE, Karlik SJ. VEGF and angiogenesis in acute and chronic MOG((35-55)) peptide induced EAE. J Neuroimmunol. 2009 Apr 30;209(1-2):6-15. doi: 10.1016/j.jneuroim.2009.01.009. Epub 2009 Feb 23.

  PMID: 19233483 BACKGROUND

• Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sorensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sa M, Salemi G, Savettieri G, Hillert J, Compston DA. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005 Apr 12;64(7):1144-51. doi: 10.1212/01.WNL.0000156155.19270.F8.

  PMID: 15824338 BACKGROUND

• Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003 Oct 20;22(47):7359-68. doi: 10.1038/sj.onc.1206939.

  PMID: 14576843 BACKGROUND

• Theoharides TC, Konstantinidou AD. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci. 2007 Jan 1;12:1615-28. doi: 10.2741/2174.

  PMID: 17127408 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Peripheral blood mononuclear cells (PBMCs) will be isolated from the blood of MS patients. Whole blood will be collected by venipuncture in Vacutainer tubes containing EDTA (BD). Samples will be collected without need for fasting. Whole blood will be collected at T0, T6 and T12. The protein content of all the samples will be determined by the Bradford protein assay method, employing bovine serum albumin as standard. RNA will be extracted from total PBMCs homogenates by using RNeasy Micro Plus Kit from Qiagen (Valencia, CA).

MeSH Terms

Conditions

Multiple Sclerosis

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Roberto Bergamaschi, MD

  IRCCS Mondino Foundation, Pavia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cinzia Fattore, MD

CONTACT

0382 380385; cinzia.fattore@mondino.it

Giulia Mallucci, MD

CONTACT

0382 380381; giulia.mallucci@mondino.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2021
• First Posted: May 26, 2021
• Study Start: May 31, 2021
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: May 26, 2021

Record last verified: 2021-05