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    Summary
    EudraCT Number:2013-005520-42
    Sponsor's Protocol Code Number:BCG-LPS
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-01-13
    Trial results View 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 number2013-005520-42
    A.3Full title of the trial
    The effects of BCG-vaccination on the innate immune response and immunoparalysis in healthy volunteers
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effects of BCG-vaccination on the immune response in healthy volunteers
    A.3.2Name or abbreviated title of the trial where available
    Effects of BCG on immune response
    A.4.1Sponsor's protocol code numberBCG-LPS
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRadboud University Nijmegen Medical Centre
    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 supportRadboud University Nijmegen Medical Centre
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboud University Nijmegen Medical Centre
    B.5.2Functional name of contact pointJenneke Leentjens
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein Zuid 10
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6525 GA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031243668420
    B.5.5Fax number0031243541612
    B.5.6E-mailjenneke.leentjens@radboudumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    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 γ-Irradiated BCG vaccine (BCG-Vaccin SSI [Nederlands Vaccin Instituut]) Danish strain 1331
    D.2.1.1.2Name of the Marketing Authorisation holderNederlands Vaccin Instituut
    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.3.1Product nameγ-Irradiated BCG vaccine
    D.3.2Product code Not applicable
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntradermal use
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSuspension for injection
    D.8.4Route of administration of the placeboIntradermal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    sepsis induced immunoparalysis
    sepsis geinduceerde immuunparalyse
    E.1.1.1Medical condition in easily understood language
    subjects with impaired immune functions due to bacterial bloodstream infections
    personen met een verminderde afweer door bloedvergiftiging
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Single endotoxemia
    To determine the effects of γ-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the Lipopolysacharide (LPS)-induced cytokine response between γ-irradiated BCG-vaccined subjects and placebo-treated control subjects.

    2. Repeated endotoxemia
    To determine the effects of γ-irradiated BCG-vaccination on endotoxin tolerance induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response following the first and second endotoxemia, between γ-irradiated BCG-vaccined and placebo-treated control subjects.
    1. eenmalige LPS toediening
    Om de effecten van γ-bestraalde BCG-vaccinatie te bepalen op de immuunrespons na LPS toediening in vivo bij gezonde vrijwilligers.

    2. herhaalde LPS toediening
    Om de effecten van-γ bestraald BCG-vaccinatie op endotoxine tolerantie veroorzaakt door menselijke endotoxinemie te bepalen.
    E.2.2Secondary objectives of the trial
    1. To determine the effects of γ-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli.

    2. To determine the effects of γ-irradiated BCG-vaccination on the phenotype of circulating monocytes (e.g. expression pattern of cell-surface receptors by use of flow cytometry).

    3. To determine the effects of γ-irradiated BCG-vaccination on inflammatory transcriptional pathways (by use of qPCR/microarrays).

    4. To determine the effects of γ-irradiated BCG-vaccination on epigenetic changes, including H3K4 trimethylation, in circulating immune cells.

    5. To determine the effects of γ-irradiated BCG-vaccination on LPS-induced clinical symptoms (illness score) and hemodynamic/temperature changes.
    1. Om de effecten van γ-bestraalde BCG-vaccinatie op de ex vivo respons van leukocyten te bepalen op verschillende inflammatoire stimuli.

    2. Om de effecten van γ-bestraalde BCG-vaccinatie op het fenotype van circulerende monocyten (bijv. expressiepatroon van celoppervlakte receptoren door gebruik van flowcytometrie) te bepalen.

    3. Om de effecten van γ-bestraalde BCG-vaccinatie op de inflammatoire cascade (met behulp van qPCR / microarrays) te bepalen.

    4. Om de effecten van γ-bestraalde BCG-vaccinatie op epigenetische veranderingen, waaronder H3K4 trimethylatie, van circulerende immuuncellen te bepalen

    5. Om de effecten van-γ bestraald BCG-vaccinatie op LPS-geïnduceerde klinische symptomen (ziekte score) en hemodynamische / temperatuurveranderingen te bepalen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent
    - Age ≥18 and ≤35 yrs
    - Male
    - Healthy
    - Schriftelijk informed consent
    - Leeftijd ≥ 18 en ≤ 35 jaar
    - Man
    - Gezond
    E.4Principal exclusion criteria
    - Use of any medication
    - History of BCG-vaccination
    - Vaccination other than BCG, within 3 months prior to study or within study period
    - Smoking
    - Previous spontaneous vagal collapse
    - History of atrial or ventricular arrhythmia
    - (Family) history of myocardial infarction or stroke under the age of 65 years
    - Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
    - Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
    - Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
    - Renal impairment (defined as plasma creatinin >120 μmol/l)
    - Liver enzyme abnormalities or positive hepatitis serology
    - Medical history of any disease associated with immune deficiency
    - CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration
    - Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
    - Use of recreational drugs within 21 days prior to experiment day
    - Recent hospital admission or surgery with general anaesthesia (<3 months)
    - Het gebruik van medicatie
    - Vooreschiedenis van BCG - vaccinatie
    - Vaccinatie anders dan BCG binnen 3 maanden voorafgaand aan de studie of binnen onderzoeksperiode
    - Roken
    - Voorgeschiedenis van spontane vagale collaps
    - Voorgeschiedenis van atriale of ventriculaire aritmie
    - ( Familiale ) voorgeschiedenis van myocardinfarct of beroerte onder de leeftijd van 65 jaar
    - Hartgeleidingsstoornissen op het ECG bestaande uit een 2e graads AV- blok of een complex bundeltakblok
    - Hypertensie ( gedefinieerd als systolische RR > 160 of diastolische RR > 90 )
    - Hypotensie ( gedefinieerd als systolische RR < 100 of RR diastolische < 50 )
    - Verminderde nierfunctie ( gedefinieerd als plasma creatinine > 120 micromol / l )
    - Afwijkingen in de leverenzymen of positieve hepatitis serologie
    - Medische voorgeschiedenis van een ziekte geassocieerd met immuundeficiëntie
    - CRP > 20 mg / L , WBC > 12x109 / L of klinisch significante acute ziekte, waaronder infecties, binnen 4 weken voor endotoxine toediening
    - Deelname aan een geneesmiddelenstudie of bloeddonatie 3 maanden voorafgaand aan de LPS toediening
    - Het gebruik van recreatieve drugs binnen 21 dagen voorafgaand aan de dag van LPS toediening
    - Recente ziekenhuisopname of operatie onder algehele anesthesie ( <3 maanden )
    E.5 End points
    E.5.1Primary end point(s)
    Single endotoxemia: the primary study endpoint is the differences in LPS-induced plasma concentration of TNF-α following endotoxemia, between γ-irradiated BCG-vaccined subjects and placebo-treated controls.

    Repeated endotoxemia: the primary study endpoint is the difference in the LPS-induced TNF-α concentration following the first and second endotoxemia, between γ-irradiated BCG-vaccined and placebo-treated control subjects.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Single endotoxemia:
    0, 60, 90, 120, 180, 240, 360 and 480 minutes after endotoxin administration

    Repeated endotoxemia:
    0, 60, 90, 120, 180, 240, 360 and 480 minutes after both endotoxin administrations
    E.5.2Secondary end point(s)
    Secondary study parameters include various other inflammatory cytokines, including IL-6 and IL-10, the ex vivo production of inflammatory mediators by stimulated leukocytes, the phenotype of circulating monocytes, inflammatory transcriptional pathways (by use of qPCR/microarrays), epigenetic changes in leukocytes including H3K4 trimethylation, illness score, mean arterial pressure, heart rate and temperature
    E.5.2.1Timepoint(s) of evaluation of this end point
    Single endotoxemia:
    0, 60, 90, 120, 180, 240, 360 and 480 minutes after endotoxin administration

    Repeated endotoxemia:
    0, 60, 90, 120, 180, 240, 360 and 480 minutes after both endotoxin administrations
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned 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.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    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 state36
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Geen
    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 Decision2014-01-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-10-31
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