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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis, Relapsing-Remitting; Vaccine Response Impaired
• Intervention / Treatment: Biological: Most recent vaccine to seasonal influenza

• Study Type: Observational
• Enrollment (Anticipated): 260

Contacts and Locations

• Study Contact: Name: Sven G Meuth, MD, PhD; Phone Number: 0049 211 81 19532; Email: svenguenther.meuth@med.uni-duesseldorf.de
• Study Contact Backup: Name: Leoni Rolfes, MD; Phone Number: 0049 211 81 19532; Email: leoni.rolfes@med.uni-duesseldorf.de

Study Locations

• Germany
  • Northrhine-Westphalia
    • Duesseldorf, Northrhine-Westphalia, Germany, 40225
      • Recruiting
      • Medical Faculty, Heinrich-Heine-University
      • Contact: Leoni Rolfes, MD; Phone Number: 0049 211 81 19532; Email: leoni.rolfes@med.uni-duesseldorf.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

52 patients per group/cohort, resulting in a theoretical maximum number of 260 patients. Patients will be screened until this number is reached.

Description

Inclusion Criteria:

1. Signed informed consent form (ICF)
2. Age 18 to 60 years old (inclusive) as of the date the ICF is signed
3. Diagnosis of RRMS according to the revised McDonald criteria
4. EDSS score of 0.0 to 7.0 (inclusive)
5. 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:

1. Previous treatment with B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)
2. Any previous treatment with alemtuzumab, cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation
3. 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
4. Patients that receive immunosuppressive treatment for diseases other than MS or that receive long-term corticosteroid treatment
5. Patients that received apheresis procedures 6 weeks prior to vaccination or in-between vaccination and DMT initiation
6. Systemic high dose corticosteroid therapy within 6 weeks prior to vaccination or in-between vaccination and DMT initiation
7. Patients with verified infection by human-immunodeficiency-virus or hepatitis-c-virus
8. Patients with major impairment of the blood coagulation system including therapy with anticoagulants
9. Patients with known chicken egg allergy

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Investigators: Principal Investigator: Sven G Meuth, MD, PhD, Heinrich-Heine-University Duesseldorf, Germany

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): April 30, 2022

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 24, 2021

Study Record Updates

• Last Update Posted (Actual): August 24, 2021
• Last Update Submitted That Met QC Criteria: August 19, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: cladribine; influenza vaccination
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Orthomyxoviridae Infections; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Influenza, Human
• Other Study ID Numbers: 2021-1474

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No