Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the antibody response to seasonal influenza vaccine, in patients with active RRMS, treated with cladribine, compared to control individuals with basic immunomodulatory treatment. Serum antibody titers against the respective pathogen will be assessed prior to and 6 to 8 months following vaccination.

Official Title
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A Non-interventional Observation Study to Evaluate Immune Responses Following Seasonal Influenza Vaccine in Participants With Relapsing Multiple Sclerosis Treated With Cladribine Tablets

Conditions
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Multiple Sclerosis, Relapsing-Remitting, Vaccine Response Impaired

Intervention / Treatment
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* Biological: Most recent vaccine to seasonal influenza


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form (ICF) Age 18 to 60 years old (inclusive) as of the date the ICF is signed Diagnosis of RRMS according to the revised McDonald criteria EDSS score of 0.0 to 7.0 (inclusive) In case of participants who are subjected to influenza vaccination by the treating physicians prior to cladribine the first or second cycle of cladribine (cohort 1 + cohort 3), this should be performed at least 4 to 6 weeks before the start of cladribine. Definition of control group: Patients with active RRMS treated with cladribine will be compared to sex and age matched control individuals, with RRMS under basic treatment either with interferon beta, glatiramer acetate, dimethyl fumarate or teriflunomide, who provide sample material prior to and 6 to 8 months after routine seasonal influenza vaccination during the same period. Exclusion Criteria: Previous treatment with B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) Any previous treatment with alemtuzumab, cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation Medical, psychiatric, cognitive, or other conditions that, in the investigator's opinion, compromise the patient's ability to understand the patient information, to give informed consent, or to complete the study Patients that receive immunosuppressive treatment for diseases other than MS or that receive long-term corticosteroid treatment Patients that received apheresis procedures 6 weeks prior to vaccination or in-between vaccination and DMT initiation Systemic high dose corticosteroid therapy within 6 weeks prior to vaccination or in-between vaccination and DMT initiation Patients with verified infection by human-immunodeficiency-virus or hepatitis-c-virus Patients with major impairment of the blood coagulation system including therapy with anticoagulants Patients with known chicken egg allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| vaccination prior to first cladribine exposition<br> | Biological: Most recent vaccine to seasonal influenza<br>* Seasonal Influenza vaccine: according to the latest SmPC and according to national guidelines (published by the Standing Committee on Vaccination (STIKO)).<br>|
| vaccination shortly after first cladribine exposition<br> | Biological: Most recent vaccine to seasonal influenza<br>* Seasonal Influenza vaccine: according to the latest SmPC and according to national guidelines (published by the Standing Committee on Vaccination (STIKO)).<br>|
| vaccination prior to second cladribine exposition<br> | Biological: Most recent vaccine to seasonal influenza<br>* Seasonal Influenza vaccine: according to the latest SmPC and according to national guidelines (published by the Standing Committee on Vaccination (STIKO)).<br>|
| vaccination following completion of cladribine treatment<br> | Biological: Most recent vaccine to seasonal influenza<br>* Seasonal Influenza vaccine: according to the latest SmPC and according to national guidelines (published by the Standing Committee on Vaccination (STIKO)).<br>|
| vaccination in patients with RRMS not subjected to cladribine<br> | Biological: Most recent vaccine to seasonal influenza<br>* Seasonal Influenza vaccine: according to the latest SmPC and according to national guidelines (published by the Standing Committee on Vaccination (STIKO)).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion who achieve seroprotection | The capacity of influenza vaccine to elicit a measurable immune response (immunogenicity) when it is administered (i) shortly (at least 4-6 weeks) before cladribine initiation (cohort 1), (ii) 3 to 4 months after cladribine initiation (cohort 2) (iii) shortly (at least 4-6 weeks) before second cladribine administration (cohort 3) and (iv) in patients who have already received the second cycle of cladribine tablets (3 to 4 months after second cycle; cohort 4), compared to RRMS patients treated with basic DMTs (cohort 5). Efficacy is measured as proportion of patients who achieve seroprotection (specific hemagglutination inhibition (HI) titers > 1:40)). | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction with 2-fold increase of HI titers | Proportion of patients who achieve a 2-fold increase in specific HI titers at 6 to 8 months post-immunization | 6 months | 
| Fraction with 4-fold increase of HI titers | Proportion of patients who achieve a 4-fold increase in specific HI titers at 6 months post-immunization | 6 months | 
| Seroconversion rate | Proportion of patients with seroconversion (i.e., a pre-vaccination antibody titer < 10 and a post-vaccination HI titer > 40) | 6 months | 
| Mean antibody titers | Geometric mean antibody titers (GMTs) and geometric mean antibody ratios (GMRs, post-vaccination:pre-vaccination) prior and 6 months after vaccination | 6 months | 
| Cellular immune responses | Flow cytometry analysis, which will include (but is not limited to) the following cells: Total B cells (CD19 positive), B-cell subsets, e.g., memory B cells, naïve B cells, plasma cells; Total T cell (CD3 positive) and T cell subsets, e.g. T helper cells, cytotoxic lymphocyte T cells | 6 months | 
| Serum immunoglobulin subtypes | Analysis of quantitative Ig levels (including total Ig, IgG, IgG subtypes, IgM, and IgA) | 6 months | 
| Influenza infections | Incidence of infections caused by influenza | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza vaccination, cladribine