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    Summary
    EudraCT Number:2012-002491-14
    Sponsor's Protocol Code Number:Sepsis_IFNg
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-07-19
    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 number2012-002491-14
    A.3Full title of the trial
    The effects of interferon-gamma on sepsis-induced immunoparalysis, a randomised double-blind placebo-controlled pilot (Phase IIIb) study
    De effecten van interferon-gamma op sepsis-geïnduceerde immuunparalyse, een gerandomiseerde dubbel-blinde placebo gecontroleerde pilot (fase IIIb) studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effects of the drug interferon-gamma on suppression of the immune system in patients with sepsis
    De effecten van het geneesmiddel interferon-gamma op onderdrukking van het immuunsysteem veroorzaakt door sepsis.
    A.3.2Name or abbreviated title of the trial where available
    The effects of interferon-gamma on sepsis-induced immunoparalysis
    De effecten van interferon-gamma op sepsis-geïnduceerde immuunparalyse
    A.4.1Sponsor's protocol code numberSepsis_IFNg
    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 pointPeter Pickkers
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein 10
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6500 HB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031243615363
    B.5.5Fax number0031243541612
    B.5.6E-mailP.Pickkers@ic.umcn.nl
    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 Immukine
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim 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.3.1Product nameRecombinant human interferon-gamma
    D.3.2Product code L03A B03
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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 Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous 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 (SIRS, Sepsis, Septic shock)
    Sepsis geïnduceerde immuunparalyse
    E.1.1.1Medical condition in easily understood language
    Patients with systemic infections (sepsis) often suffer from a suppressed immune system which makes them increased vulnerable for other infections.
    Patiënten met systemische infecties (sepsis, bloedvergiftiging), hebben vaak een onderdrukt afweersysteem waardoor zij een verhoogde vatbaarheid hebben voor andere infecties
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10062357
    E.1.2Term SIRS
    E.1.2System Organ Class 10018065 - General disorders and administration site conditions
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10061218
    E.1.2Term Inflammation
    E.1.2System Organ Class 10018065 - General disorders and administration site conditions
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10061598
    E.1.2Term Immunodeficiency
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10040070
    E.1.2Term Septic shock
    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
    To evaluate the (preliminary) efficacy of IFN-γ as adjunctive treatment in combination with standard therapy for the treatment of patients presenting with septic shock, by assessment of a series of surogate immunological parameters.
    Het primaire doel van deze studie is om de effectiviteit van IFN-γ als aanvullende behandeling voor septische shock te onderzoeken door middel van een reeks surrogate immunologische parameters.
    E.2.2Secondary objectives of the trial
    A secondary aim will be to evaluate markers (including mHLA-DR expression) that are currently used to identify patients with immunoparalysis who will benefit from immunotherapy, and to monitor the patient’s immunological response to IFN-γ.
    Een tweede doel van deze studie is het evalueren van markers die momenteel gebruikt worden om patiënten met immuunparalyse te identificeren die baat zouden kunnen hebben van immuunstimulerende therapieën en om de immunologische respons van de patiënt op IFN-γ te monitoren.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent from patient of legal representative
    2. Age >18 years
    3. Presence of septic shock of bacterial origin (A-C required):
    A. Evidence of bacterial infection (last 96 hours), at least one: pathogenic microorganism in blood, sputum, urine, normally sterile body fluid, or on central venous catheter; Focus of infection identified (e.g. ruptured bowel, purulent drainage/sputum); or leukocytes in normally sterile body fluid
    B. Two SIRS criteria (last 24 hours): fever (>38.3 ˚C), hypothermia (<35.6 ˚C), tachycardia (>90bpm), tachypnea (>20/min), or PaCO2 <32 mmHg, or mechanical ventilation, leukocytosis (>12,000/μl), leucopenia (<4,0000/μl), or >10% immature forms.
    C. Presence of shock with need for vasopressor therapy to maintain SBP ≥ 90 mmHg.
    1. Geschreven "informed consent" van de patiënt of van de wettelijke vertegenwoordiger
    2. Leeftijd >18 jaar
    3. Aanwezigheid van septische shock van bacteriële oorsprong (A-C verplicht):
    A. Bewijs van bacteriële infectie (laatste 96 uur), ten minste een: pathogene micro-organismen in bloed, sputum, urine, gewoonlijk steriel lichaamsvloeistof of op een centrale katheter, geïdentificeerde infectiebron (bijv. darmperforatie, purulente drainage / sputum) , of leukocyten in normaal steriele lichaamsvloeistof
    B. Twee SIRS criteria (laatste 24 uur): koorts (> 38,3 ˚ C), hypothermie (<35,6 ˚ C), tachycardie (> 90bpm), tachypnoe (> 20/min), of PaCO2 <32 mmHg, of mechanische ventilatie , leukocytose (> 12000 / pl), leukopenie (<4,0000 / pl) of > 10% immature vormen.
    C. Aanwezigheid van shock met behoefte aan bloeddrukverhogende middelen om de sytolische bloeddruk ≥ 90 mm ​​Hg te houden.
    E.4Principal exclusion criteria
    1. Pregnancy or lactating
    2. Subjects with a history of allergy or intolerance to IFN-
    3. Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolon equivalent of > 5 mg per day
    4. Human immunodeficiency virus positivity
    5. Presence of an advanced directive to withhold or to withdraw life sustaining treatment
    6. Underlying disease with a prognosis for survival < 3 months, or moribund patient highly likely to die within 24 hours.
    7. Cardiopulmonary resuscitation (<72 hours) before enrolment
    8. Acute myocardial infarction or pulmonary embolisation (<72 hours)
    9. Participation in a clinical trial until 30 days prior to inclusion
    10. Subjects with a history of documented epileptic seizures
    11. Subjects with severe renal impairment (creatinine clearance less than 30 mL/min)
    12. Subjects with severe liver failure (impaired synthesis of proteins such as coagulation factors manifested by increased prothrombine time)
    13. Subjects with an absolute neutrophil count of less than 500/mm3 at study entry
    1. Zwangerschap of borstvoeding geven
    2. Personen met een voorgeschiedenis van allergie of intolerantie voor interferon-gamma
    3. Systemische auto-immuunziekte, hematologische ziekten (neoplasmata, acute leukemie), transplantatie patiënten of patiënten die corticosteroïden gebruiken (met een prednisolon equivalent van> 5 mg per dag)
    4. Humaan immunodeficiëntie virus positiviteit
    5. Aanwezigheid van wilsbeschikking waarin staat dat levensverlengende maatregelen beperkt of gestopt dienen te worden
    6. Onderliggende ziekte, met een prognose voor overleving <3 maanden, of een moribunde patiënt die zeer waarschijnlijk binnen 24 uren komt te overlijden.
    7. Cardiopulmonaire resuscitatie (<72 uur) vóór de inclusie
    8. Acuut myocardinfarct of longembolie (<72 uur)
    9. Deelname aan een klinische studie tot 30 dagen voorafgaand aan de inclusie
    10. Personen met een geschiedenis van gedocumenteerd epileptische aanvallen
    11. Personen met een ernstig verminderde nierfunctie (creatinineklaring minder dan 30 ml / min)
    12. Patiënten met ernstige leverinsufficiëntie (verminderde synthese van eiwitten, zoals stollingsfactoren tot uiting komend in een verhoogde prothrombinetijd)
    13. Personen met een absoluut aantal neutrofielen van minder dan 500/mm3 bij inclusie
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the TNF-α secretion by ex vivo LPS-stimulated leukocytes as a marker of immunosuficiency/antimicrobial response.
    Het primaire eindpunt is de TNF-α secretie door ex vivo LPS-gestimuleerde leukocyten als marker van immunosuficiency / de antimicrobiële reactie van het immuunsysteem.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at admission and at days 0, 2, 7, 14, and 28
    Bij opname en op dag 0, 2, 7, 14 en 28
    E.5.2Secondary end point(s)
    - Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation)
    - Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids per day, amount of urine produced per day, daily fluid balance)
    - Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes)
    - Length of stay at ICU and duration of hospitalization
    - Organ function:
    * Cardiovascular function: lactate level, vasopressor usage, and cardiovascular Sequential Organ Failure Assessment (SOFA) score
    * Respiratory function: oxygenation index, PaO2/FiO2 (P/F) ratio, and respiratory SOFA score
    * Renal function: creatinin level, urine ouput, renal replacement therapy usage, and renal SOFA score
    * Hematologic function: hematologic SOFA score
    * Hepatic function: Hepatic SOFA score
    - Production of cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida)
    - Markers of “immune status” (including mHLA-DR and PD-1 expression, IL-6 plasma concentration)
    - To determine the correlation between the level of immunoparalysis (indicated by the commonly used marker mHLA-DR and new markers of “immune status” found), and effectiveness of IFN-γ (indicated by TNF-α secretion by ex vivo LPS-stimulated PBMC’s).
    - Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways
    - Changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence (epigenetic modifications)
    - Gevolgen van bacteriele infectie (optreden van secundaire of opportunistische infecties, lengte van antimicrobiële behandeling).
    - Hemodynamische stabiliteit (noradrenaline infusie snelheid, hoeveelheid toegediend vocht per dag, hoeveelheid urine geproduceerd per dag, dagelijkse vochtbalans.
    - Mortaliteit (inclusief tijd tot overlijden) na 2 en 4 weken (alle oorzaken).
    - Verblijfsduur op de intensive care en opnameduur in het ziekenhuis.
    - Orgaan functie:
    * Cardiovasculaire functie: lactaat, vasopressor gebruik, de "Cardiovascular Sequential Organ Failure Assessment" (SOFA) score
    * Respiratoire functie: oxygenatie index, PaO2/FiO2 (P/F) ratio, en respiratoire SOFA score
    * Nierfunctie: kreatinine, urine ouput, niervervangende therapie, en renale SOFA score
    * Hematologische functie: hematologische SOFA score
    * Leverfunctie: hepatische SOFA score
    - Productie van cytokines door leukocyten die ex vivo gestimuleerd worden met verschillende stimuli (zoals LPS, peptidoglycaan, candida)
    - Markers van de “immuun status” van de patiënt (zoals HLA-DR en PD-1 expressie op monocyten, IL-6 plasma concentratie)
    - De correlation tussen de ernst van immuunparalyse (weergegeven door de algemeen gebruikte marker HLA-DR expressie op monocyten en nieuw gevonden “immuun status” markers ), and effectiviteit van IFN-γ (weergegeven door de TNF-α secretie van ex vivo LPS-gestimuleerde PBMC’s).
    - De transcriptionele activiteit van leukocyten obv microarrays met een focus op inflammatoire pathways.
    - Veranderingen in fenotype of gen expressie veroorzaakt door andere mechanismen dan veranderingen in de onderliggende DNA-sequentie (epigenetische modificaties).
    E.5.2.1Timepoint(s) of evaluation of this end point
    at admission and at days 0, 2, 7, 14, and 28
    Bij opname en op dag 0, 2, 7, 14 en 28
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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 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 trial2
    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
    Provided in the protocol
    Staat in het protocol
    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 months6
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Septic patients are frequently sedated and therefore in the categorie of patients adressed in this study is incapable of giving consent personally
    Septische patiënten worden vaak gesedeerd en daarom is deze categorie van patiënten die behandeld worden in deze studie niet in staat om zijn/haar toestemming persoonlijk te geven.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 20
    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 Decision2012-07-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-01-01
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