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    Summary
    EudraCT Number:2016-001971-61
    Sponsor's Protocol Code Number:SALYCENDO
    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:2016-07-01
    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 number2016-001971-61
    A.3Full title of the trial
    The effects of acetylsalicylic acid on immunoparalysis following human endotoxemia.
    Het effect van acetylsalicylzuur op immuunparalyse na humane endotoxemie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of aspirin on the attenuated immune system following human endotoxemia.
    Het effect van aspirine op het verzwakte immuun systeem geïnduceerd door humane endotoxemie.
    A.3.2Name or abbreviated title of the trial where available
    SALYCENDO-study
    SALYCENDO-studie
    A.4.1Sponsor's protocol code numberSALYCENDO
    A.5.4Other Identifiers
    Name:CMO numberNumber:2016-2550
    Name:ABRNumber:57410.091.16
    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 SponsorRadboudumc
    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 supportRadboudumc
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboudumc
    B.5.2Functional name of contact pointResearch IC, office of Guus Leijte
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein 10 (route 710)
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6500HB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310243668420
    B.5.6E-mailguus.leijte@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 Acetylsalicylzuur Cardio Teva 80 mg
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Nederland BV
    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 Dispersible tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    We will investigate the effects of acetylsalicylic acid on immunoparalysis following human endotoxemia in healthy male volunteers
    We onderzoeken het effect van acetylsalicylzuur op immuunparalyse volgend op humane endotoxemie in gezonde mannelijke vrijwilligers
    E.1.1.1Medical condition in easily understood language
    We will study the effect of aspirin on an attenuated immune system after human endotoxemia in healthy male volunteers
    We onderzoeken het effect van aspirine op een verzwakt immuunsysteem dat wordt gezien na humane endotoxemie in gezonde mannelijke vrijwilligers
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To determine whether acetylsalicylic acid treatment can reverse endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge.
    E.2.2Secondary objectives of the trial
    2. To determine whether acetylsalicylic acid prophylaxis can prevent endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge.
    3. To determine whether ASA treatment and prophylaxis modulate the absolute plasma cytokine levels upon the second endotoxin challenge.
    4. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on ex vivo responsiveness of whole blood and peripheral blood mononuclear cells to various inflammatory stimuli.
    5. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on cell surface expression of markers of immunoparalysis on circulating leukocytes, including but not limited to HLA-DR, PD-L1, PD-1, and IL-7R.
    6. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on plasma and urine levels of prostaglandin E2.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent
    - Age ≥18 and ≤35 yrs
    - Male
    - Healthy (as confirmed by medical history, examination, ECG, blood sampling)
    - Getekend informed consent
    - Leeftijd ≥18 en ≤35 jaar
    - Mannelijk geslacht
    - Gezond (bevestigd door medische geschiedenis, lichamelijk onderzoek, ECG, bloedanalyse)
    E.4Principal exclusion criteria
    • Use of any medication
    • Use of ASA within 6 weeks prior to the first endotoxemia day
    • Smoking
    • Known anaphylaxis or hypersensitivity to acetylsalicylic acid or non-investigational products
    • History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema)
    • History of hematological disease
    • Thrombocytopenia (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L)
    • History of intracranial hemorrhage
    • Quantitative bleeding assessment tool (BAT) score>3
    • History, signs or symptoms of cardiovascular disease, in particular:
    • Previous spontaneous vagal collapse
    • History of atrial or ventricular arrhythmia
    • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left 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 creatinine >120 μmol/l)
    • Liver enzyme abnormalities (above 2x the upper limit of normal)
    • Medical history of any disease associated with immune deficiency
    • CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L, hemoglobin < 8 mmol/L or clinically significant acute illness, including infections, within 4 weeks before the first endotoxemia day
    • Previous (participation in a study with) LPS administration
    • Participation in a drug trial or donation of blood 3 months prior to first endotoxemia day
    • Any vaccination within 3 months prior to the first endotoxemia day until the end of the study
    • Recent hospital admission or surgery with general anesthesia (<3 months to endotoxemia day)
    • Use of recreational drugs within 21 days prior to the first endotoxemia day
    • Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study
    • Medicatiegebruik
    • Gebruik van ASA in de 6 weken voorafgaand aan de eerste endotoxemie dag
    • Roken
    • Bekende anafylaxie of overgevoeligheid voor ASA of voor non-investigational products
    • Voorgeschiedenis van hematologische aandoeningen
    • Thrombocytopenie (<150*10^9/ml) of anemie (hemoglobin < 8.0 mmol/L)
    • Voorgeschiedenis van intracraniële bloeding
    • Kwantitatieve Bleeding Assessment Tool (BAT) score>3
    • Voorgeschiedenis, tekenen of symptomen van cardiovasculaire ziekte, in het bijzonder:
    • Verleden met spontane vagale reactie
    • Verleden met atriale of ventriculaire aritmieën
    • Cardiale geleidingsstoornis op ECG (2e graads atrioventriculair block of compleet linker bundeltakblok
    • Hypertensie (gedefinieerd als systolische RR > 160 of diastolische RR > 90)
    • Hypotensie (gedefinieerd als systolische RR < 100 of diastolische RR < 50)
    • Nierfunctiestoornissen (gedefinieerd als plasma kreatinine >120 μmol/l)
    • Leverenzymafwijkingen (meer dan 2x bovenlimiet)
    • Voorgeschiedenis van immunodeficiëntie
    • CRP > 20 mg/L, Leukocyten > 12x109/L of < 4 x109/L, hemoglobine < 8 mmol/L of klinisch significante ziekte, inclusief infecties, in de 4 weken voorafgaand aan de eerste endotoxemie
    • Eerder deelname aan een LPS-challenge
    • Deelname aan een geneesmiddelenonderzoek of bloeddonatie in de 3 maanden voorafgaand aan de eerste endotoxemie
    • Vaccinatie in de 3 maanden voorafgaan aan de eerste endotoxemie
    • Recente ziekenhuisopname of operatie met algehele anesthesie (< 3 maanden)
    • Recreatief drugsgebruik in de 21 dagen voorafgaand aan de eerste endotoxemie
    • Onvermogen tot individueel informed consent (vanwege taal of mentale reden) of onvermogen tot deelname aan studieonderdelen
    E.5 End points
    E.5.1Primary end point(s)
    The primary study endpoint, endotoxin tolerance, is the decrease in the area under the curve (AUC) of the plasma TNFα concentration between the first and second endotoxin challenge in the control group compared to the treatment group.
    E.5.1.1Timepoint(s) of evaluation of this end point
    AUC of TNFa on endotoxemia day 7 and day 14. AUC is estimated using blood sampling at timepoints (relative to LPS administration): -60; 0; 30; 60;90; 120;150; 180;210; 240; 360; 480.
    E.5.2Secondary end point(s)
    - Plasma levels of other inflammatory mediators on the first and second endotoxemia day (including but not limited to TNFα, IL-6, IL-8, IL-10, IL-1RA)
    - Ex vivo production of inflammatory mediators and reactive oxygen species (ROS) by whole blood and peripheral blood mononuclear cells (PBMCs) stimulated by LPS and several pathogens (including but not limited to S. aureus, M. tuberculosis, C. albicans)
    - Monocyte surface antigen expression (including but not limited to mHLA-DR, Programmed Death Ligand (PDL)-1, Programmed cell Death protein (PD)-1, IL-7R)
    - Plasma thromboxane B2 levels, as an expression of thromboxane A2
    - Prostaglandin E2 urine metabolites (PGE-M)
    - Kidney damage markers in urine (including but not limited to NGAL, KIM-1, L-FABP)
    - Transcriptional activity of leukocytes
    - Symptom score
    - Mean arterial pressure
    - Heart rate
    - Temperature
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation of endpoints is done on both endotoxemia day 7 and day 14. Using blood sampling at timepoints (relative to LPS administration): -60; 0; 30; 60;90; 120;150; 180;210; 240; 360; 480.
    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 Yes
    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 Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 trial3
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 30
    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 state30
    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)
    Not applicable.
    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 Decision2016-07-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-29
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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