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    Summary
    EudraCT Number:2011-003081-32
    Sponsor's Protocol Code Number:1160.166
    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:2012-02-24
    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 number2011-003081-32
    A.3Full title of the trial
    An exploratory study to investigate the pharmacokinetics and effects of DABIgatran etexilate in patients with stable severe RENAL disease: DabiRenal
    Een studie naar de farmacokinetiek en effecten van Dabigatran etexilate in patienten met een stabiele ernstige nierziekte: DabiRenal
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Dabigatran, an anticoagulant drug in patients with impaired renal function
    Dabigatran, een bloedverdunner in patienten met een ernstig verminderde nierfunctie
    A.3.2Name or abbreviated title of the trial where available
    DabiRenal
    DabiRenal
    A.4.1Sponsor's protocol code number1160.166
    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 SponsorBoehringer Ingelheim bv
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBoehringer Ingelheim bv
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number0018002430127
    B.5.5Fax number0018008217119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    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 Pradaxa 75 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameDabigatran Etexilate (pradaxa)
    D.3.2Product code BIBR 1048 MS
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDABIGATRAN ETEXILATE
    D.3.9.1CAS number 211915-06-9
    D.3.9.3Other descriptive namen.a.
    D.3.9.4EV Substance CodeSUB20521
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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
    Chronic kidney disease and coagulation
    Chronische nierinsufficientie en stolling
    E.1.1.1Medical condition in easily understood language
    Impaired renal function and coagulation
    Nierziekte en stolling
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10060318
    E.1.2Term Anticoagulation drug level
    E.1.2System Organ Class 10022891 - Investigations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10038444
    E.1.2Term Renal failure chronic
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the pharmacokinetics and dynamics of dabigatran etexilate (75 mg twice daily) in patients with severe CKD (eGFR 15 - 30 ml/min).
    Het onderzoeken van de farmacokinetiek en farmacodynamiek van dabigatran etexilate (75 mg tweemaal daags) bij patienten met ernstige CKD (eGFR 15-30 ml/min).
    E.2.2Secondary objectives of the trial
    not applicable
    niet van toepassing
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age: 18 years and older
    • Provision of informed consent
    • Impaired renal function defined as a stable Cockroft-Gault and/or creatinine clearance
    between 15-30 ml/min over the last 3 months before study participation
    • The single use of either aspirin or vitamin K-antagonists
    • Patiënten van 18 jaar of ouder
    • Patiënten die welwillend en in staat zijn om Informed consent af te geven
    • Verminderde nierfunctie met een eGFR tussen 15 en 30 ml/min geschat
    middels de Cockroft-Gault formule of op basis van een 24 uurs urine in de 3 maanden
    voorafgaand aan de studie
    • Het gebruik van of aspirine of vitamine K-antagonisten
    E.4Principal exclusion criteria
    -Unstable renal function defined as an increase or a decrease in serum creatinine > 20% in the last three months, measured during normal clinical practice.
    -Renal impairment (estimated CrCl calculated by Cockcroft-Gault equation) <15mL/min at screening
    -Patients treated with two or more platelet aggregation inhibitors, like for instance but not limited to ticagrelor, clopidogrel, prasugrel and dipyridamol
    -Use of or indication for therapeutic (low molecular weight) heparin, fibrinolytic therapy and/or glycoprotein IIb/IIIa inhibitors
    -Patients with prosthetic heart valves
    -Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention)
    -Platelet count <100 x 10e9/L) at screening or during the last 30 days before screening.
    -Uncontrolled hypertension (systolic blood pressure (SBP) >180mm Hg and/or diastolic blood pressure (DBP) >100mm Hg)
    -Diabetes mellitus with active retinopathy
    -Pre-menopausal (last menstruation ≤1 year prior to screening) who:
    *Are pregnant or breast feeding or
    *Are not surgically sterile or
    *Are of child bearing potential and not using an acceptable method of birth control, or do not plan to continue using an acceptable method of birth control throughout the trial (highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, i.e. oral anti conceptive drugs or intrauterine devices)
    -Any history of haemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, AV malformation or aneurysm
    -History of intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding unless the causative factor has been permanently eliminated or repaired (e.g. by surgery)
    -Liver disease as indicated by at least one of the following:
    Prior and persistent alanine aminotransferase (ALT) or Aspartate transaminase (AST) or alkaline phosphatase (AP) >3 x upper limit of normal (ULN)
    and/or
    *Active hepatitis C1 (as evidenced by positive hepatitis C virus ribonucleic acid assay by sensitive polymerase chain reaction (PCR) based assay, such as Roche Monitor or Bayer TMA assay)
    *Active hepatitis B1 (HBs antigen + or anti HBc IgM+2)
    and/or
    *Active hepatitis A
    -Gastrointestinal (GI) haemorrhage within the past year, unless the cause has been permanently eliminated (e.g. by surgery) or symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days
    -Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John’s Wort or any cytotoxic/myelosuppressive therapy
    -Relevant acute infections (e.g. acute pneumonia)
    -History of allergy or hypersensitivity (including drug allergies) deemed relevant by the investigator
    -Planned diagnostic or therapeutic procedures within 30 days before, during or after the trial
    -Indication of past or present use of drugs or substance abuse
    -Past history of alcoholism with clinical sequelae
    -Abnormal routine lab test values that are outside of the range that can be expected in patients with CKD
    -Participation in another drug trial in the last 30 days before screening
    -Instabiele nierfunctie (stijging in serum creatinine > 20% in de laatste drie maanden)
    -Nierfalen (geschatte creatinine klaring berekend met Cockroft-Gault formule) <15mL/min bij screening
    -Patiënten behandeld met twee of meer trombocytenaggregatieremmers
    -Gebruik (of een indicatie voor) van laag moleculair gewicht heparine
    -Patiënten met een kunsthartklep
    -Bloedingsneiging of –ziekten
    -Hoeveelheid bloedplaatjes <100 x 10e9/L bij screening of 30 dagen voorafgaand aan screening
    -Ongecontroleerde hypertensie (systolisch > 180 mmHg en/of diastolisch > 100 mmHg)
    -Diabetes mellitus met actieve retinopathie
    -Pre-menopauzale vrouwen die: zwanger zijn of borstvoeding geven, die niet gesteriliseerd zijn óf die geen adequate anticonceptie methodes gebruiken (orale anticonceptie of intra-uteriene spiraal).
    -Voorgeschiedenis van
    -Geschiedenis van cerebrale bloeding of intracraniale trauma’s
    -Geschiedenis van intraoculaire, spinale, retroperitoneale of intra-articulaire bloedingen tenzij de oorzaak is verwijderd of hersteld (bijv chirurgisch)
    -Leverfalen (ALT, AST of AP > 3 x ULN) en/of actieve hepatitis C1, B1 en/of A
    -Gastrointestinale bloeding in het afgelopen jaar behalve als de oorzaak chirurgisch is verwijderd of een maag/darmzweer in de fagelopen 30 dagen.
    -Noodzaak voor behandeling met systemisch ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. Jan’s kruid of een cytotoxische/myelosuppressieve therapie
    -Relevante acute infecties (longontsteking)
    -Voorgeschiedenis van allergie of hypersensitiviteit (inclusief medicatie allergieën) die relevant zijn voor het onderzoek volgens de onderzoeker
    -Geplande diagnostische of therapeutische procedures binnen dertig dagen voor, tijdens of na de studie
    -Indicatie voor de aanwezigheid of voorgeschiedenis van middelen misbruik
    -Voorgeschiedenis van alcoholisme met klinische uitingen daarvan of huidig misbruik van alcohol
    -Abnormale labwaarden anders dan de waarden die men verwacht bij patienten met nierziekte
    -Deelnamen aan een andere medicatie studie 30 dagen voor de studie
    E.5 End points
    E.5.1Primary end point(s)
    pharmacokinetic data:
    *Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval

    *Area under the concentration curve of the analyte in plasma at steady state over a uniform dsoing interval
    farmacokinetiek:
    *maximaal gemeten concentratie van het analyte in plasma bij steady state bij een uniform dosing interval

    *AUC van het analyte in plasma bij steady state bij een uniform dosing interval
    E.5.1.1Timepoint(s) of evaluation of this end point
    Lab sampling will be drawn at the following points in time:
    • Predose
    • .5
    • 1
    • 2
    • 3
    • 4
    • 6
    • 8
    • 12
    • 23.5
    • 47.5
    • 71.5
    • 95.5
    • 119.5
    • 155.5
    • 167.5
    • 168.5
    • 169
    • 170
    • 171
    • 172
    • 174
    • 176
    • 179.5
    • 180
    • 192
    • 216
    • 240
    This scheme requires a patient’s admission for two days of thirteen hours (predose -1-12 hours and 167-180 hours after the first intake). From day two until day six, one sample will be drawn each day, prior to oral intake of dabigatran.
    Er wordt lab afgenomen op de volgende uren na de inname van het eerste tablet Dabigatran:
    • voor de eerste dosering
    • .5
    • 1
    • 2
    • 3
    • 4
    • 6
    • 8
    • 12
    • 23.5
    • 47.5
    • 71.5
    • 95.5
    • 119.5
    • 155.5
    • 167.5
    • 168.5
    • 169
    • 170
    • 171
    • 172
    • 174
    • 176
    • 179.5
    • 180
    • 192
    • 216
    • 240
    Tijdens de eerste en de laatste doserings dag zullen patiënten worden opgenomen (13 uur) in het ziekenhuis ter beoordeling en om frequent labmonsters af te nemen. Op alle andere doseringsdagen zullen patiënten gezien worden op een poliklinische basis om continu de patiëntenveiligheid te waarborgen en om labmonsters af te nemen.
    E.5.2Secondary end point(s)
    not applicable
    niet van toepassing
    E.5.2.1Timepoint(s) of evaluation of this end point
    not applicable
    niet van teopassing
    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 No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    study PK/PD profiles and effect on coagulation parameters by twice daily 75 mg dabigatran in CKD
    studie van PK/PD en effect op stolling door dabigatran 75 mg 2dd bij chronische nierpatienten
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 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
    At every visit an aPTT will be sampled for safety. Patients will have a dose reduction if aPTT is >80 msec. The DMC will check safety data quarterly and advice on stopping the trial if patient safety is at risk.
    Op ieder bezoek wordt een aPTT geprikt voor veiligheid. De dosis wordt aangepast bij een aPTT groter dan 80 msec. De DMC bekijkt per kwartaal de data en zal adviseren te stoppen als patienten veiligheid in het geding komt.
    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.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 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 state12
    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)
    All patients will remain into the care of the principal investigator untill coagulation assay values have returned to baseline value. Furthermore, treatment with aspirin and vitamin K-antagonists will be restarted after the last sampling has been performed, 240 hours after the first dose and when coagulation tests show that dabigatran activity has been diminished.
    Alle patiënten blijven onder medische verantwoordelijkheid van de hoofdonderzoeker tot de waardes van de stollingstesten aantonen dat het effect van Dabigatran verdwenen is en nadat de patiënt weer goed ingesteld is op aspirine of vitamine K-antoganisten. Na de laatste labafname en nadat middels APTT waardes is aangetoond dat het antistollend effect van Dabigatran verdwenen is, zal de behandeling met vitamine K-antoganisten of ascal weer hervat worden.
    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 Decision2012-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-18
    P. End of Trial
    P.End of Trial StatusCompleted
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