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    Summary
    EudraCT Number:2014-004854-33
    Sponsor's Protocol Code Number:03-AnIt-14/UKM14_0066
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-11
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-004854-33
    A.3Full title of the trial
    Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill patients with acute kidney injury (RICH-Trial).
    Regionale Citrat- versus systemische Heparin-Antikoagulation für das kontinuierliche Nierenersatzverfahren bei kritisch kranken Patienten mit akuter Nierenschädigung (RICH-Trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigating different anticoagulants for renal replacement therapy
    Untersuchung von verschiedenen Blutgerinnungshemmer zur Nierenersatztherapie
    A.3.2Name or abbreviated title of the trial where available
    RICH-Trial
    A.4.1Sponsor's protocol code number03-AnIt-14/UKM14_0066
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02669589
    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 SponsorUniversity Hospital Muenster
    B.1.3.4CountryGermany
    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 supportDeutsche Forschungsgemeinschaft (DFG)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Muenster
    B.5.2Functional name of contact pointDept. of Anesthesiology
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Schweitzer-Campus 1, Building A1
    B.5.3.2Town/ cityMuenster
    B.5.3.3Post code48149
    B.5.3.4CountryGermany
    B.5.4Telephone number+4902518347255
    B.5.5Fax number+4902518344057
    B.5.6E-mailrich@anit.uni-muenster.de
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Anticoagulant and preservative solution for blood
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Critically ill patients with acute kidney injury
    Kritisch kranke Patienten mit akuter Nierenschädigung
    E.1.1.1Medical condition in easily understood language
    Critically ill patients with acute kidney injury
    Schwerst kranke Patienten mit akuter Nierenschädigung
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    Effect of regional citrate anticoagulation (RCA) for CRRT in critically ill patients on filter life span and all cause 90-day mortality compared to systemic heparin anticoagulation for CRRT
    Die Wirkung von regionaler Citrat-Antikoagulation im Vergleich zur Heparinantikoagulation während des kontinuierlichen Nierenersatzverfahrens bei kritisch kranken Patienten auf die Filterlaufzeit und das Gesamtüberleben in einer 90-tägigen Nachbeobachtungsperiode
    E.2.2Secondary objectives of the trial
    Evaluation of the clinical impact of the intervention on
    - Length of ICU and hospital stay / 1 year all cause mortality
    - Renal replacement therapy
    - Safety of the intervention
    - Cost analysis of renal replacement therapy
    Auswirkung der Intervention auf
    - Länge des Intensiv- Krankenhausaufenthalts
    - 1-Jahres-Überleben
    - Nierenersatzverfahren
    - Sicherheit der intervention
    - Kostenanalyse des Nierenersatzverfahrens
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    New Biomarkers of acute kidney injury and mediators modulating pro- and anti-inflammatory mediators will be analysed in the blood and urine collected in different centres
    Untersuchung von neuen Biomarker der akuten Nierenschädigung und von pro- und antiinflammatorischen Mediatoren in Blut und Urin
    E.3Principal inclusion criteria
    1. Critically ill patients with clinical indication for CRRT
    o Urea serum levels > 150 mg/dl or
    o Potassium serum levels > 6 mmol/l or
    o Magnesium serum levels > 4 mmol/l or
    o Blood pH ≤ 7.15 or
    o Urine production < 200 ml/12 h or anuria or
    o Organ edema in the presence of AKI resistant to diuretic treatment
    Or
    Severe acute kidney injury (KDIGO 3-classification) despite optimal resuscitation
    2. At least one of the following conditions
    o Sepsis or septic shock
    o Use of catecholamines (norepinephrine or epinephrine ≥ 0.1 µg/kg/min or norepinephrine ≥ 0.05 µg/kg/min + dobutamine or norepinephrine ≥ 0.05 µg/kg/min + vasopressin or norepinephrine ≥ 0.05µg/kg/min + epinephrine ≥0.05µg/kg/min)
    o Refractory fluid overload: worsening pulmonary edema: PaO2/FiO2 < 300 mmHg and/or fluid balance > 10% of body weight)
    3. 18-90 years old and
    4. Intention to provide full intensive care treatment for at least 3 days and
    5. Written informed consent of the patient or the legal representatives or the authorized representative or the inclusion due to an emergency situation
    1. klinische Indikation für eine Nierenersatztherapie:
    • Serum-Harnstoff > 150 mg/dl oder
    • Kalium > 6 mmol/l und/oder EKG Veränderungen oder
    • Magnesium-Werte > 4 mmol/l oder
    • Blut-pH Werte ≤ 7,15 oder
    • Urin-Ausscheidung < 200 ml/12h oder Anurie
    • Diuretika-resistente Organödeme in Anwesenheit einer AKI
    Kritisch kranke Patienten mit schwerer akuter Nierenschädigung (KDIGO Stadium 3)
    2. Mindestens eines der folgender Kriterien:
    • Sepsis oder septischer Schock und/oder
    • Hoher Katecholamingebrauch (Norepinephrin/Epinephrin > 0,1 µg/kg/min oder Norepinephrin > 0,05 µg/kg/min + Dobutamin (jede Dosis) oder Norepinephrin >0,05 µg/kg/min + Vasopressin (jede Dosis) )
    • Refraktäre Flüssigkeitsüberladung, Bildung/ Verschlechterung eines Lungenödems (PaO2/FiO2 < 300 mmHg und/oder Flüssigkeitsbilanz > 10% des Ausgangskörpergewichtes)
    3. Alter 18 – 90 Jahre
    4. Uneingeschränkte intensivmedizinische Therapie für mind. 3 Tage geplant
    5. Einverständniserklärung des Patienten, des gesetzlichen Betreuers, des Bevollmächtigten oder Einschluss aufgrund einer Notfallsituation
    E.4Principal exclusion criteria
    1. Patients with increased bleeding risk (e.g. an active bleeding from ulcers in the gastro-intestinal tract, hypertension with a diastolic blood pressure higher than 105 mm Hg, injuries of or surgical procedures on the central nervous system if a heparinization with a target aPTT 45-60 s is not allowed by the treating neurologist or neurosurgeon, severe retinopathies, bleeding into the vitreum, ophthalmic surgical procdures or injuries, active tuberculosis, infective endocarditis)
    2. Diseases or organ damage related with hemorrhagic diathesis (coagulopathy, thrombocytopenia, severe liver or pancreas disease)
    3. Dialysis-dependent chronic kidney insufficiency
    4. Need of therapeutic anticoagulation (PTT > 60s, antiXa > 0.6 IE/ml, INR > 2)
    5. Allergic reaction to one of the anticoagulantia, or ingredients, Heparin-induced thrombocytopenia
    6. AKI caused by permanent occlusion or surgical lesion of both renal arteries
    7. AKI caused by (glomerulo)nephritis, interstitial nephritis, vasculitis
    8. Do-not-resuscitate order
    9. Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura
    10. Persistent and severe lactate acidosis in the context of an acute liver failure and/or shock
    11. Kidney transplant within the last 12 months
    12. Pregnancy and nursing period
    13. Abortus imminens
    14. No hemofiltration machine free for use at the moment of inclusion
    15. Participation in another clinical intervention trial in the last 3 months
    16. Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
    17. Persons held in an institution by legal or official ordner
    1. Patienten mit erhöhtem Blutungsrisiko (z.B. aktive Blutung aus einer Ulzeration des Gastrointestinaltraktes, Hypertension mit diastolischen Blutdrücken > 105 mmHg, Verletzungen (intrakranielle Blutungen, Hirnarterienaneurysma) oder chirurgische Eingriffe des ZNS, die laut Neurologen oder Neurochirurgen keine Heparinisierung mit einer Ziel-PTT zwischen 45-60s zulassen, schwere Retinopathien, Glaskörperblutungen, oder ophthalmologische Verletzungen/ Operationen, aktive Tuberkulose, infektiöse Endokarditis)
    2. Erkrankungen oder Organverletzungen, die mit einer hämorrhagischen Diathese einhergehen (Koagulopathie, Thrombozytopenie, schwere Leber- oder Pankreaserkrankungen)
    3. Chronisch dialysepflichtige Niereninsuffizienz
    4. Notwendigkeit einer Antikoagulation (PTT > 60 s, antiXa > 0,6IE/ml, INR > 2)
    5. Allergische Reaktionen gegenüber eines der Antikoagulantien, Inhaltsstoffen, Heparin-induzierte Thrombozytopenie
    6. AKI durch Okklusion oder chirurgische Läsion der A. renalis beidseits
    7. AKI durch (Glomerulo-) Nephritis, interstitielle Nephritis, Vaskulitis
    8. Patienten mit DNR (Do-Not-Resuscitate)
    9. Hämolytisch-urämisches Syndrom, Thrombotisch-thrombozytopenische Purpura
    10. Persistierende und schwere Laktatazidose im zusammenhang mit einem akuten Leberversagen und/oder Schock
    11. Z.n. Nierentransplantation in den letzten 12 Monaten
    12. Schwangerschaft und Stillzeit
    13. Abortus imminens
    14. Fehlen freier kontinuierlicher Dialysemaschinen zum Zeitpunkt des Einschlusses
    15. Teilnahme an einer anderen Interventionsstudie in den letzten 3 Monaten
    16. Patienten, die in einem persönlichem Bezug zu den studiendurchführenden Personen stehen
    17. Personen, die auf gerichtliche oder behördliche Anordnung in einer Anstalt untergebracht sind
    E.5 End points
    E.5.1Primary end point(s)
    filter life span (hours)
    overall survival in a 90-day follow-up period (90-day all cause mortality)
    Filterlaufzeit
    Gesamtüberleben in einer 90-tägigen Nachbeobachtungsperiode (90-Tages-Mortalität)
    E.5.1.1Timepoint(s) of evaluation of this end point
    filter live span (hours)
    overall survival (days)
    Filterlaufzeit (Stunden)
    Gesamtüberleben (Tage)
    E.5.2Secondary end point(s)
    • ICU length-of-stay and hospital length-of-stay
    • Duration of renal replacement therapy
    • Bleeding complications
    • Transfusion requirement
    • Rate of infection during primary ICU stay
    • Major adverse kidney events at day 28, 60, 90 and after 1 year
    • Complications of therapy during study treatment
    • Recovery of renal function and requirement for hemodialysis after day 28, 60, 90 and 1 year
    • SOFA Scores at day 1-14, 21 and 28
    • 28-day, 60-day and 1-year all cause mortality
    • Selected laboratory parameters
    • Cost analysis of renal replacement therapy
    • Delivered and prescribed dose of CRRT
    • Adverse events
    Add-on study:
    • New Biomarkers of acute kidney injury and mediators modulating pro- and anti-inflammatory mediators will be analysed in the blood and urine collected in different centres
    • Länge des ICU-Aufenthaltes and Länge des Krankenhausaufenthalts
    • Dauer der Nierenersatztherapie
    • Blutungskomplikationen
    • Transfusionsnotwendigkeit
    • Infektionsrate während des primären Intensivaufenthalts
    • unerwünschte Ereignisse in Bezug auf die Niere an Tag 28, 60, 90 und nach einem Jahr
    • Komplikationen durch die Therapie während der Studienbehandlung
    • Erholung der Nierenfunktion und Dialysepflichtigkeit an Tag 28, 60, 90 und nach einem Jahr
    • SOFA Organ Failure Scores an den Tagen 1-14, 21 und 28
    • 28-Tage-, 60-Tage- und 1-Jahres Mortalität
    • Ausgewählte Laborparameter
    • Kostenanalyse der Nierenersatztherapie
    • Verschriebene und durchgeführte RRT Dosis
    • Unerwünschte Ereignisse

    Add-on Studie zur
    • Untersuchung von neuen Biomarker der akuten Nierenschädigung und von pro- und antiinflammatorischen Mediatoren in Blut und Urin
    E.5.2.1Timepoint(s) of evaluation of this end point
    - from study inclusion up to end of continuous renal replacement therapy
    - from study inclusion up to end of intensive care therapy or day 28
    - 60 days after study inclusion
    - 90 days after study inclusion
    - 1 year after study inclusion
    - vom Studienstart mit zum Ende des kontinui9erlichen Nierenersatzverfahrens
    - vom Studienstart bis zum Ende des Intensivtherapieaufenthalts oder Tag 28
    - 60 Tage nach Studieneinschluss
    - 90 Tage nach Studieneinschluss
    - 1 Jahr nach Studieneinschluss
    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 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 Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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
    Medizinprodukt (regionale Citrat-Antikoagulation)
    Medical device (regional citrate anticoagulation)
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned31
    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
    Last Visit of the last subject (LVLS)
    Letzter Studientermin des letzten Patienten (LVLS)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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: 580
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 870
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Criticall ill patients will be randomised. Most of them will be not capable to provide informed consent.
    Es ist davon auszugehen, dass es sich wegen der Schwere der Erkrankung bei den einzuschließenden Studienpatienten größtenteils um nicht einwilligungsfähige Patienten handelt
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1450
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1450
    F.4.2.2In the whole clinical trial 1450
    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)
    Treatment is not different to normal treatment.
    Die weitere Behandlung unterscheidet sich nicht von der Standardbehandlung der Patienten
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Kompetenznetz Sepsis (SEPNET)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-01-03
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