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    Summary
    EudraCT Number:2010-022693-14
    Sponsor's Protocol Code Number:METc2010.214
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2010-09-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2010-022693-14
    A.3Full title of the trial
    A study of humoral and cellular-mediated immune response in Monoclonal gammopathy of Undetermined Significance after vaccination with trivalent inactivated influenza vaccine (influvac)
    A.3.2Name or abbreviated title of the trial where available
    mgus-vacc respons
    A.4.1Sponsor's protocol code numberMETc2010.214
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsoruniversity medical centre groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Influvac
    D.2.1.1.2Name of the Marketing Authorisation holderSolvay
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNInfluenza Vaccine
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor code01
    D.3.9.3Other descriptive nameINFLUENZA VACCINE (SURFACE ANTIGEN, INACTIVATED)
    D.3.10 Strength
    D.3.10.1Concentration unit ml millilitre(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5 to ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Monoclonal Gammopathy of Undetermined significance
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10027522
    E.1.2Term MGUS
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level HLT
    E.1.2Classification code 10022005
    E.1.2Term Influenza viral infections
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of influenza vaccination in Monoclonal gammopathy of Undetermined Significance patients
    Is vaccination with trivalent inactivated influenza vaccine in MGUS patients useful?; Do these patients elicit adequate humoral and cellular T-cell responses after influenza vaccination?
    E.2.2Secondary objectives of the trial
    to find out what is the B-cell proliferation relation to clonal growth?; What happens to the plasma cell clones after vaccination?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    MGUS Patients/controls
    - (MGUS patients only)patients have to fulfill the diagnostic criteria for MGUS
    - serum M protein<30g/L
    - Clonal plasma cells in bone marrow <10%
    - No myeloma related dysfunction
    - No other B-cell proliferative disease
    - informed consent


    Multiple Myeloma inclusion criteria
    - patients who fulfill the diagnostic criteria for multiple myeloma
    - Monoclonal plasma cells in bone marrow >10% and/or presence of biopsy proven plasmacytoma
    - Monoclonal protein present in serum and/or urine
    - Myeloma related organ dysfunction
    o Calcium elevation in the blood S. Calcium >10.5 mg/l or upper limit of normal
    o Renal insufficiency: S. Creatinine > 2 mg/dl
    o Anemia Hemoglobin < 10 g/dl or 2 g < normal
    o Lytic bone lesions or osteoporosis
    - Patients with stage 1 myeloma (according to the International Staging System)
    o Serum β2-MG* ＜3.5 mg/L
    o Serum albumin ≥3.5 g/dl
    - Informed consent
    E.4Principal exclusion criteria
    MGUS Patients/controls
    - age under 18 years
    - current infection, defined as fever in combination with clinical focal signs of infection and the need for therapeutic antibiotic treatment
    - influenza vaccination within the 6 months prior to the study
    - pregnancy
    - malignancy
    - known allergy to or former severe reaction following Influvac®

    Multiple Myeloma Exclusion criteria
    - Patients in late stage disease
    - Patients who have undergone stem cell transplantation
    - current infection, defined as fever in combination with clinical focal signs of infection and the need for therapeutic antibiotic treatment
    - pregnancy
    - known allergy to or former severe reaction following Influvac®
    E.5 End points
    E.5.1Primary end point(s)
    Haemagglutinin Inhibition Test
    To detect the humoral immune response to influenza vaccination the haemagglutination inhibition (HAI) test will be performed at day 1, and 3-4 weeks following day 1.
    To evaluate the antibody responses, three parameters will be recorded:
    1. Fourfold titre rises, including seroconversions (defined as a serological outcome where the initial sample tests negative (below detection level of the assay) compared to a true positive result in the second sample i.e. fourfold above the detection limit)
    2. Achievement of titres 40, which are considered protective
    3. Geometric mean titres (GMT)

    Enzyme linked ImmunoSPOT (ELIspot) and memory B cell assay
    To enumerate the number of influenza specific plasma cells/ plasmablasts, an ELIspot assay will be performed on day 1, day 7 and 3-4 weeks following day 1.
    Memory b cells will be detected by culturing PBMCs for 6days with polyclonal mitogenic stimulants then quantifying by ELIspot.

    Analysis of clonality
    RNA will be isolated and to quantify clonality, variable genes will be sequenced from RNA of ASCs

    Cell-mediated responses
    Whole blood count, including lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/56) will be measured from all participants. T cell subsets will also be further defined (central/ effector memory) by flow cytometry. To evaluate the cellular immune response to influenza vaccination, PBMC will be isolated from venous blood. T Helper cell populations in the PBMC samples will be analysed for their capacity to respond with proliferation and produce cytokines after in vitro stimulation with common mitogens and Influenza vaccine-derived antigens.
    Cell mediated responses to the 3 influenza variants will be assessed by IFN ELISPOT, Intracellular Cytokine (i.e. IFN, IL-2 and TNFα) detection by Flow Cytometry and assessment of proliferation of CD4 and CD8 T cells using CFSE dye dilution and analysis by Flow Cytometry.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    healthy controls
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Measurement of cellular immuneresponse one year after vaccination.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state122
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-09-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-14
    P. End of Trial
    P.End of Trial StatusOngoing
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