B-cell Depletion in Offspring to Women With MS Under Immunomodulatory Treatment

NCT06711354 | Not Yet Recruiting

• 1 other identifier: 142682
• Study Type: observational
• Target: 111
• Locations: 0 countries
• Sites: N/A

Brief Summary

The overall aim of the study is to gain knowledge about consequences for the child´s humoral immunosystem in mothers with multiple sclerosis and due to their immunomodulating treatments. Of special interest is when the mother is treated with monoclonal CD20-antibody like rituximab, ocrelizumab and ofatumumab shortly before (within six months prior to conception) and during pregnancy. Specific aims of the study are to:

• Investigate if the humoral immunosystem is fully functioning at birth in children born to mothers with MS
• Investigate if the humoral immunosystem at birth in children born to mothers with MS is influenced by the mothers immunomodulating treatment
• Investigate if monoclonal CD20-antibodies are fully eliminated in women treated with monoclonal CD20-antibodies within 12 months prior to conception.
• Determine if children who have been exposed to monoclonal CD20-antibody in utero have reduced markers of successful B-cell production at birth.
• Investigate the response to the Rota virus vaccine, a life-vaccine that is offered 6 weeks after birth to all children born after September 2019, in children to women treated with rituximab before or during pregnancy.
• Investigate the response to other vaccines (DTP, Polio, HiB, pneumococcus given at 3 and 5 months after birth) the earliest one months after vaccination.
• Investigate the occurrence of infections in the first-year post-partum for the mother and child due to hypogammaglobulinemia, b-cell depletion, and exposure to monoclonal CD20-antibody.
• Investigate if oral exposure to rituximab through mother´s breastmilk is resulting in B-cell reduction in the child.

Conditions

Multiple Sclerosis; B-Cell Deficiency; Offspring, Adult; Immunosuppression; Pregnancy Related

Outcome Measures

Primary Outcomes (5)

• KREC and CD19 of B-cells in offspring to mothers with MS exposed to monoclonal anti-CD20 antibodies

  Measurement of KREC and CD19 reflecting B-cells in offspring to women with MS who are exposed to monoclonal anti-CD20 antibodies before or during pregnancy compared to controls with MS and other DMT as well as MS without DMT.

  2 years (2022-2023)

• Antibody production post vaccination in offspring to mothers with MS exposed to monoclonal anti-CD20 antibodies

  Measurement of antibody response to vaccination 1-12 months post vaccination in children of of mothers with MS exposed to anti-CD20 antibodies compared to control groups with other DMT and no DMT respectively.

  4 years (2022-2025)

• Frequency and severity of infections in mothers with MS exposed to monoclonal anti-CD20 antibodies and their offspring

  Evaluation through history at clinical follow up and measurement of hypogammaglobulinemia in mother at every trimester and 3 months post partum as part of routine follow up.

  4 years (2022-2025)

• Blood levels of monoclonal anti-CD20 antibodies in offspring to mothers with MS exposed to monoclonal anti-CD20 antibodies before or during pregnancy

  Measurement of anti-CD20 antibodies in dry blood spot from blood samples collected and stored at birth in offspring to mothers with MS

  4 years (2022-2025)

• Levels of monoclonal anti-CD20 antibodies in breastmilk of breastfeeding mothers treated with monoclonal anti-CD20 antibodies in addition to measurement of anti-CD20 antibodies and evaluation of B-cells in blood from the breastfed child

  Mothers with MS exposed to monoclonal anti-CD20 antibodies who choose to breastfeed may transfer antibodies to their child. Measurements of monoclonal anti-CD20 antibodies as well as a potential effect on childs B-cells one month post treatment hold potential to clarify this.

  4 years (2022-2025)

Study Arms (3)

Mother exposed to anti-CD20 ab

Mothers with MS exposed to monoclonal anti-CD20 antibody (Rituximab 500 mg iv alternatively Ofatumumab 20 mg sc or Ocrelizumab 300-600 mg iv) within 12 months before pregnancy or during pregnancy.

Drug: Anti-CD20 Monoclonal Antibody

Mother exposed to other DMT

Mothers with MS exposed to disease modifying therapy other than Rituximab, Ofatumumab or Ocrelizumab within 6 months before pregnancy

Mother without DMT exposure

Mothers with MS without exposure to disease modifying therapy within 6 months before pregnancy

Interventions

Anti-CD20 Monoclonal Antibody DRUG

Injection of monoclonal anti-CD20 antibody as immunomodulatory treatment of multiple sclerosis

Also known as: Rituximab, Ocrelizumab, Ofatumumab

Mother exposed to anti-CD20 ab

Eligibility Criteria

• Age: Up to 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Women with definite diagnosis of multiple sclerosis who are pregnant are divided in study groups based on treatment 12 months prior to pregnancy. Study groups consist of treatment with monoclonal anti-CD20 antibodies, other immunomodulatory treatment and absence of immunomodulatory treatment respectively. Population also consist of offspring to women as described above with informed consent provided by both parents for participation.

You may qualify if:

• Definite diagnosis of multiple sclerosis in mother AND
• Administration of Rituximab, Ocrelizumab or Ofatumumab within 12 months or during established pregnancy OR
• Administration of other immunomodulatory treatment within 12 months or during established pregnancy OR
• No administration of immunomodulatory treatment within 12 months or during established pregnancy

You may not qualify if:

• Treatment with stem cell transfusion

Sponsors & Collaborators

• Region Stockholm: lead
• Haukeland University Hospital: collaborator

Related Publications (18)

• Ahlgren C, Oden A, Lycke J. High nationwide incidence of multiple sclerosis in Sweden. PLoS One. 2014 Sep 29;9(9):e108599. doi: 10.1371/journal.pone.0108599. eCollection 2014.

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• Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, Lu E, McElrath TF, Smyth P, Tremlett H, Sadovnick AD. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol. 2014 Dec;124(6):1157-1168. doi: 10.1097/AOG.0000000000000541.

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• Langer-Gould AM. Pregnancy and Family Planning in Multiple Sclerosis. Continuum (Minneap Minn). 2019 Jun;25(3):773-792. doi: 10.1212/CON.0000000000000745.

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• Bearak J, Popinchalk A, Alkema L, Sedgh G. Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. Lancet Glob Health. 2018 Apr;6(4):e380-e389. doi: 10.1016/S2214-109X(18)30029-9. Epub 2018 Mar 5.

  PMID: 29519649 BACKGROUND

• Salzer J, Svenningsson R, Alping P, Novakova L, Bjorck A, Fink K, Islam-Jakobsson P, Malmestrom C, Axelsson M, Vagberg M, Sundstrom P, Lycke J, Piehl F, Svenningsson A. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Nov 15;87(20):2074-2081. doi: 10.1212/WNL.0000000000003331. Epub 2016 Oct 19.

  PMID: 27760868 BACKGROUND

• Klink DT, van Elburg RM, Schreurs MW, van Well GT. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol. 2008;2008:271363. doi: 10.1155/2008/271363.

  PMID: 18596903 BACKGROUND

• Kumpfel T, Thiel S, Meinl I, Ciplea AI, Bayas A, Hoffmann F, Hofstadt-van Oy U, Hoshi M, Kluge J, Ringelstein M, Aktas O, Stoppe M, Walter A, Weber MS, Ayzenberg I, Hellwig K. Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany. Neurol Neuroimmunol Neuroinflamm. 2020 Dec 17;8(1):e913. doi: 10.1212/NXI.0000000000000913. Print 2021 Jan.

  PMID: 33334856 BACKGROUND

• Smith JB, Hellwig K, Fink K, Lyell DJ, Piehl F, Langer-Gould A. Rituximab, MS, and pregnancy. Neurol Neuroimmunol Neuroinflamm. 2020 May 1;7(4):e734. doi: 10.1212/NXI.0000000000000734. Print 2020 Jul.

  PMID: 32358226 BACKGROUND

• Perrotta K, Kiernan E, Bandoli G, Manaster R, Chambers C. Pregnancy outcomes following maternal treatment with rituximab prior to or during pregnancy: a case series. Rheumatol Adv Pract. 2021 Jan 4;5(1):rkaa074. doi: 10.1093/rap/rkaa074. eCollection 2021.

  PMID: 33521513 BACKGROUND

• Hollen C, Rice J, Park M, Yadav V. Rituximab for treatment of refractory multiple sclerosis relapses during pregnancy. Mult Scler. 2021 Sep;27(10):1620-1623. doi: 10.1177/1352458521998937. Epub 2021 Apr 30.

  PMID: 33929267 BACKGROUND

• Routes JM, Grossman WJ, Verbsky J, Laessig RH, Hoffman GL, Brokopp CD, Baker MW. Statewide newborn screening for severe T-cell lymphopenia. JAMA. 2009 Dec 9;302(22):2465-70. doi: 10.1001/jama.2009.1806.

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• Borte S, von Dobeln U, Fasth A, Wang N, Janzi M, Winiarski J, Sack U, Pan-Hammarstrom Q, Borte M, Hammarstrom L. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012 Mar 15;119(11):2552-5. doi: 10.1182/blood-2011-08-371021. Epub 2011 Nov 30.

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• Schrezenmeier E, Jayne D, Dorner T. Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives. J Am Soc Nephrol. 2018 Mar;29(3):741-758. doi: 10.1681/ASN.2017040367. Epub 2018 Jan 11.

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• Kruger R, Borte S, von Weizsacker K, Wahn V, Feiterna-Sperling C. Positive Kappa-Deleting Recombination Excision Circles (KREC) Newborn Screening in a Neonate With Intrauterine Exposure to Rituximab. Scand J Immunol. 2018 Jan;87(1):54-56. doi: 10.1111/sji.12627. No abstract available.

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• Barbaro M, Ohlsson A, Borte S, Jonsson S, Zetterstrom RH, King J, Winiarski J, von Dobeln U, Hammarstrom L. Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study. J Clin Immunol. 2017 Jan;37(1):51-60. doi: 10.1007/s10875-016-0347-5. Epub 2016 Nov 21.

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• Serana F, Chiarini M, Zanotti C, Sottini A, Bertoli D, Bosio A, Caimi L, Imberti L. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. J Transl Med. 2013 May 9;11:119. doi: 10.1186/1479-5876-11-119.

  PMID: 23656963 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Venous blood samples from mother analyzing immunoglobulin levels and B-cell levels as part of clinical routine. Additional analysis of anti-CD20 medication concentration as part of present study. Capillary blood samples from child analyzing antibodies produced through vaccination or infection. Dry blood spot from existing blood samples from child, obtained during routine screening, with complementary analysis of CD19, KREC and anti-CD20 medication concentration. Breast milk analysis of anti-CD20 medication concentration.

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Rituximab; ocrelizumab; ofatumumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Sofia Ernestam, MD, PhD

  Karolinska Institutet

  STUDY DIRECTOR

Central Study Contacts

Katharina Fink, MD, PhD

CONTACT

+46706571789; katarina.fink@ki.se

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: OTHER
• Target Duration: 2 Years
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2024
• First Posted: December 2, 2024
• Study Start: June 1, 2025
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: December 2, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: 2025-2035
• Access Criteria: Access to researchers who are part of the study project through approval from Dr Katharina Fink