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    Summary
    EudraCT Number:2012-002275-33
    Sponsor's Protocol Code Number:0805-2012-1
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-01-15
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2012-002275-33
    A.3Full title of the trial
    Renal and cardiac effects of terlipressin and dobutamin in cirrhosis and ascites. A randomised study.
    Renale og kardielle effekter af terlipressin og dobutamin ved cirrose og ascites. Et randomiseret studie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of the heart and kidney function during terlipressin and dobutamin treatment in patients with chronic liver disease (cirrhosis) and fluid retention (ascites)
    En undersøgelse af hjertets og nyrernes funktion og betydning hos patienter med skrumpelever og væskeophobning (ascites) under behandling med terlipressin og dobutamin.
    A.3.2Name or abbreviated title of the trial where available
    Dobustress
    A.4.1Sponsor's protocol code number0805-2012-1
    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 SponsorDept. of Gastroenterology, Universityhospital Odense
    B.1.3.4Country
    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 supportDept. Gastroenterology, Universityhospital Odense
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDept. Gastroenterology, Universityhospital Odense
    B.5.2Functional name of contact pointAleksander Krag
    B.5.3 Address:
    B.5.3.1Street AddressSdr. Boulevard 29, entrance 1
    B.5.3.2Town/ cityOdense
    B.5.3.3Post code5000
    B.5.4Telephone number004529647719
    B.5.6E-mailAleksander.krag@health.sdu.dk
    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 Glypressin (terlipressin)
    D.2.1.1.2Name of the Marketing Authorisation holderFerring
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 nameterlipressin
    D.3.4Pharmaceutical form Concentrate and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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.IMP: 2
    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 Dobutrex (dobutamin)
    D.2.1.1.2Name of the Marketing Authorisation holderPharmaCoDane
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 namedobutamin
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous bolus use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Liver cirrhosis
    skrumpelever
    E.1.1.1Medical condition in easily understood language
    Liver cirrhosis is a chronic disease with progressive loss of liver function and generalized circulatory changes leading to development of comoplications including renal failure.
    Skrumpelever er en kronisk sygdom med progredierende tab af lever funktion og generelle kredsløbsændringer, som medfører udvikling af komplikationer inklusiv nyresvigt.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    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
    Many patients with cirrhosis will die of renal failure - the hepatorenal syndrome, which has a median survival of less than 1 month. Hepatorenal syndrome is treated with terlipressin, which increases blood pressure and improves renal function. However, terlipressin also causes a decline in cardiac function, which is unfortunate, since the renal function relies on a sufficient cardiac output. This may explain why only half of the patients respond to this treatment.
    We aim to investigate if renal function in patients with cirrhosis and ascites can be improved by combining terlipressin with dobutamin - a drug that increases cardiac function. Dobutamin increases cardiac output primarily by increasing heart rate.
    En stor del af patienter med skrumpelever vil dø af nyresvigt – det hepatorenale syndrom, hvor middeloverlevelsen er under 1 måned. Dette nyresvigt behandler man med stoffet terlipressin, som øger blodtrykket og bedrer nyrernes funktion. Terlipressin kan imidlertid også svække hjertets pumpeevne, hvilket er uheldigt, da nyrernes funktion er afhængig af hjertets pumpevne – dets minutvolumen. Dette er måske forklaringen på at kun knap halvdelen af patienterne responderer på denne behandling.
    Vi ønsker derfor at undersøge, om man ved at øge hjertets pumpeevne med stoffet dobutamin i kombination med terlipressin kan bedre nyrefunktionen hos patienter med skrumpelever og ascites. Dobutamin er et stof, der øger hjertets minutvolmen, primært ved at hæve pulsen.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -The diagnosis of cirrhosis either verified by biopsy or based on established clinical, biochemical and ultrasonographic criteria
    -Age 18-75 years
    -ultrasonic vericated ascites within 3 months prior to inclusion
    • Patienter med levercirrose. Diagnosen stilles, fortrinsvis ved leverbiopsi og resultat af trykmåling ved levervenekaterisation eller ved oplagt klinisk mistanke som følge af cirrosestigmata eller endoskopisk påviste esofagusvaricer og/eller portal hypertensiv gastropati og biokemiske og ultrasoniske tegn på levercirrose.
    • Alder mellem 18 år og 75 år.
    • Ultrasonisk verificeret ascites indenfor 3 måneder.
    E.4Principal exclusion criteria
    - Denied consent
    - Patients under 18 or over 75 years of age
    - Acute medical conditions such as ongoing infection, acute heart or lung disease, other conflicting diseases.
    - Patients with known Heart, lung or kidney disease (ex. ischemic heart disease, heart failure, arrythmias, COLD, cronic kidney disease which is not hepatorenal syndrome, insulin dependent diabetes)
    - Cerebral or psychiatric disease resulting in patients unable to qualified consent.
    - Cancer including HCC
    - Malignant arterial hypertension > 220/120 mmHg
    - Hepatic encephalopathy > grade 2
    - Serum-creatinin > 200 µmol/L
    - Pregnancy (Urine-HCG negative within 7 days prior to inclusion in the trial) or breast feeding.
    - Alcohol withdrawal symptoms such as tremor, increasing heart rate, increasing temperature.
    - Treatment with vasoactive substances with cannot be paused 6 days prior to the trial and during the trial
    - Allergy towards dobutamine or terlipressin
    - Pheochromocytoma
    . ideopatic hypertrofic subaortic stenosis
    • Manglende samtykke
    • Patienter under 18 år og over 75 år.
    • Akutte medicinske tilstande som pågående infektion, akutte hjerte eller lunge sygdomme og andre akutte interkurrente sygdomme som kræver akut indlæggelse.
    • Patienter med kendt anamnestisk eller klinisk mistanke om primære hjerte, lunge eller nyre sygdomme (f.eks. IHD (iskæmisk hjerte sygdom), CHF (hjertesvigt), supra og ventrikulære arytmier, KOL (kronisk obstruktiv lungesygdom), kronisk nyresygdom som ikke er hepatorenalt syndrom samt insulinkrævende diabetes.
    • Cerebral eller psykisk sygdom der gør patienten uegnet til kvalificeret informeret samtykke.
    • Coma hepaticum > grad 2.
    • Kendte cancer sygdomme herunder HCC.
    • Patienter, hvor medicin som påvirker kredsløbet (diuretika, betablokker) ikke kan seponeres i de 7 dage forsøget varer.
    • Behandling med vasoaktive stoffer 7 dage inden forsøgets start.
    • Se-kreatinin > 200 μmol/l målt tidligst 7 dage før inklusion i forsøget.
    • Svær arteriel hypertension > 240/120 mmHg målt gentagne gange non-invasivt.
    • Allergi overfor terlipressin eller øvrige indholdsstoffer i Glypressin®
    • Allergi overfor dobutamin eller øvrige indholdsstoffer i Dobutrex®
    • Graviditet eller amning. Negativ graviditetstest er nødvendig for inklusion, og ved > 1 uge fra inklusion til undersøgelsesdato gentages urin-HCG på første forsøgsdag (antikonception ikke indiceret, idet medicinen kun gives under indlæggelsen, samt har meget kort halveringstid)
    • Abstinenssymptomer i form af pulsstigning, tremor og temperaturstigning.
    • Diagnostiseret fæokromocytom.
    • Ideopatisk hypertrofisk subaortisk stenose.
    E.5 End points
    E.5.1Primary end point(s)
    Primary end points:
    Glomerular filtration rate (GFR), and effective renal blood flow (ERPF)
    Primære endpoints er glomerulær filtrations rate (GFR), og effektive renale blodgennemstrømning (ERPF).
    E.5.1.1Timepoint(s) of evaluation of this end point
    End points are evaluated 3 times during the trial:
    1) Baseline (0-60 min)
    2) Period 1 (60-150 min): patients receive either dobutamine, terlipressin or placebo (natriumchloride)
    3) Period 2 (150-240 min): Patients receiving dobutamine in period 1 receive terlipressin, patients receiving terlipressin in period 1 receive dobutamin. The placebo group continue with natriumchloride
    End points evalueres 3 gange under forsøget:
    1) Baseline (0-60 min)
    2) Periode 1 (60-150 min): patienter gives enten dobutamin, terlipressin eller placebo (natriumklorid)
    3) Periode 2 (150-240 min): patienter som fik dobutamin i periode 1 gives terlipressin, patienter som fik terlipressin i periode 1 gives dobutamin. Placebogruppen fortsætter med natriumklorid.
    E.5.2Secondary end point(s)
    Secondary end points are:
    clearance of water, sodium, and lithium (CH2O, CNa, CLi), osmolar clearance, concentrations of hormones (renin, noradrenaline, aldosterone, proANP, proBNP), and cardiac variables (cardiac output, cardiac index, heart rate, mean arterial pressure).
    The study is of pathophysiological nature with one day of investigations, therefore we do not use classical end points such as treatment failure or death. The study is not confirmatory, hence several end points are applied.
    Sekundære endpoints er clearance af natrium og vand, (CNa, CH2O) samt clearance af lithium, osmolær clearance, hormonkoncentrationer (renin, noradrenalin og aldosteron, proANP, proBNP), samt hjerteparametre (minutvolumen, cardiac index, hjertefrekvens og middelarterieblodtryk).
    Studiet udføres som et patofysiologisk endagsstudie og opererer derfor ikke med klassiske endpoints som død, treatment failure og lignende. Dette er ikke et konfirmatorisk studie, hvorfor der opereres med flere endpoints.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End points are evaluated 3 times during the trial:
    1) Baseline (0-60 min)
    2) Period 1 (60-150 min): patients receive either dobutamine, terlipressin or placebo (natriumchloride)
    3) Period 2 (150-240 min): Patients receiving dobutamine in period 1 receive terlipressin, patients receiving terlipressin in period 1 receive dobutamin. The placebo group continue with natriumchloride
    End points evalueres 3 gange under forsøget:
    1) Baseline (0-60 min)
    2) Periode 1 (60-150 min): patienter gives enten dobutamin, terlipressin eller placebo (natriumklorid)
    3) Periode 2 (150-240 min): patienter som fik dobutamin i periode 1 gives terlipressin, patienter som fik terlipressin i periode 1 gives dobutamin. Placebogruppen fortsætter med natriumklorid.
    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 Yes
    E.6.13.1Other scope of the trial description
    To investigate the physiological changes in these patients after administration of either dobutamine/terlipressin, terlipressin/dobutamine or placebo (natriumchloride)
    At afdække det fysiologiske respons hos cirrose patienter med ascites efter indgift af enten dobutamin/terlipressin, terlipressin/dobutamin eller placebo (natriumklorid)
    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 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
    Efter at sidste patient har gennemført protokollen
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    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: 25
    F.1.3Elderly (>=65 years) No
    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 state25
    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)
    After the patient has ended participation in the trial they continue with their normal treatment.
    Efter endt deltagelse i forsøget genoptager patienterne deres vanlige behandling
    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 Decision2014-01-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-05-24
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