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    Summary
    EudraCT Number:2018-003789-15
    Sponsor's Protocol Code Number:9.2
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-01-08
    Trial 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 number2018-003789-15
    A.3Full title of the trial
    Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands
    Digoxine behandeling voor patiënten met chronisch hartfalen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands
    Digoxine behandeling voor patiënten met chronisch hartfalen
    A.3.2Name or abbreviated title of the trial where available
    DECISION
    A.4.1Sponsor's protocol code number9.2
    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 SponsorDepartment of Cardiology, Hartcentrum, University Medical Center Groningen
    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 supportZonMW/Hartstichting
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDisphar International BV
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportTeva Nederland BV
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportTiofarma BV
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDepartment of Cardiology
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of Cardiology, Thoraxcenter, University Medical Center Groningen
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713 GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310503612355
    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 DIGOXIN TEVA, 100 µg, tablets
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA Pharmaceuticals Polska
    D.2.1.2Country which granted the Marketing AuthorisationPoland
    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 nameDIGOXIN TEVA, 100 µg, tablets
    D.3.4Pharmaceutical form 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 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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    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 placeboTablet
    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
    Heart failure
    Hartfalen
    E.1.1.1Medical condition in easily understood language
    Heart failure
    Hartfalen
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    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
    To study whether low-level digoxin reduces the composite primary endpoint of (repeated) HF hospitalizations and cardiovascular mortality, compared to placebo, in chronic HF.
    Onderzoeken of laag-gedoseerd digoxine, in vergelijking met placebo, het gecombineerde eindpunt van (herhaaldelijke) hartfalen opnames en cardiovasculaire mortaliteit verlaagd in hartfalen patiënten
    E.2.2Secondary objectives of the trial
    -To assess whether low-level digoxin reduces all-cause mortality
    -To assess whether low-level digoxin reduces cardiovascular death
    -To assess whether low-level digoxin reduces (repeated) HF hospitalizations
    -To assess whether low-level digoxin treatment is cost-effective
    -To assess whether low-level digoxin reduces all-cause hospitalizations
    -To assess whether low-level digoxin reduces unscheduled cardiovascular hospital visits
    -To assess whether low-level digoxin reduces days alive out of hospital of patients
    -To assess whether low-level digoxin improves QoL
    -To assess side effects (including SUSARs) associated with study medication
    -To study the effect of low-level digoxin on heart rate in both AF and sinus rhythm
    -To assess whether low-level digoxin reduces initiation of (recurrence of) AF in patients with sinus rhythm at baseline
    -To assess whether low-level digoxin increases conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF at baseline
    -Onderzoeken of laaggedoseerd digoxine dood tgv alle oorzaken vermindert
    -Onderzoeken of laaggedoseerd digoxine dood tgv cardiovasculaire oorzaken vermindert
    -Onderzoeken of laaggedoseerd digoxine (herhaaldelijke) hartfalen opnames vermindert
    -Onderzoeken of laaggedoseerd digoxine kosten-effectief is
    -Onderzoeken of laaggedoseerd digoxine opnames tgv alle oorzaken vermindert
    -Onderzoeken of laaggedoseerd digoxine ongeplande CV ziekenhuisbezoeken vermindert
    -Onderzoeken of laaggedoseerd digoxine levende dagen uit het ziekenhuis in patienten vermindert
    -Onderzoeken of laaggedoseerd digoxine KvL verbetert
    -De bijeffecten (incl. SUSARs) van de studiemedicatie onderzoeken
    -Het effect van laaggedoseerd digoxine op hartslag in AF en sinusritme onderzoeken
    -Onderzoeken of digoxine de initiatie van (terugkeren van) AF in patiënten in sinusritme op baseline vermindert
    -Onderzoeken of digoxine de conversie naar sinusritme en het behouden daarvan in patiënten in AF op baseline vergroot
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    DECISION offers an excellent opportunity to conduct a sub-study in which additional mechanistic questions can be explored. Serum and plasma samples will be used to explore proteomics, hits will be validated with Elisa’s.

    In view of the principal aims of the study biochemical parameters do not need to be part of the entire study. Participation is therefore optional for both sites and participants. An additional serum (10mL) and plasma sample (10mL) will be drawn at the inclusion visit, the 1 month and te 6 month onsite visit. At these visits patients will already be onsite to determine serum digoxin concentrations. Participants in the selected sites can give additional consent for this sub-study.

    Samples will be processed and temporarily stored at sites. Samples will be collected by the UMCG and stored until the end of the study so that analyses can be done on all samples at the same time.

    Titel: DECISION-Biomarkers
    DECISION biedt een uitstekende mogelijkheid om additionele substudies te doen waarin aanvullende mechanistische vragen naar de effecten van digoxine kunnen worden beantwoord. Door een extra serum- en plasmamonster af te nemen bij het inclusiebezoek, het 1 maand on site bezoek en het 6 maanden on site bezoek, kunnen er achteraf waardevolle metingen gedaan worden.

    Gezien de hoofddoelstelling van de studie onafhankelijk van biomarkers bereikt kan worden, hoeven biochemische parameters geen deel uit te maken van de gehele studie. Deelname is dus optioneel voor zowel locaties als deelnemers. Deze additionele afnames vallen samen met de bezoeken wanneer patiënten al ter plaatse zijn om de serum digoxine concentraties te bepalen. Indien patiënten toestemming geven zal er op deze 3 visites 20mL extra bloed worden afgenomen.

    Deelnemers aan de geselecteerde sites krijgen de mogelijkheid om aanvullende toestemming te geven voor dit deelonderzoek.
    Titel: DECISION-Biomarkers

    E.3Principal inclusion criteria
    1. Age ≥18 years
    2. Outpatients with chronic HF, NYHA II - ambulatory IV
    3. LVEF≤50%
    4. Serum NT-proBNP concentrations:
    Previous HF hospitalization ≤ 1 year before randomisation ≥400pg/mL if sinus rhythm; ≥800pg/mL if AF
    Previous HF hospitalization > 1 year before randomisation or in the absence of (recent) HF hospitalizations ≥ 600pg/mL if sinus rhythm; ≥1000 pg/mL if AF
    BNP concentrations:
    Previous HF hospitalization ≤ 1 year before randomisation ≥100pg/mL if sinus rhythm; ≥200pg/mL if AF
    Previous HF hospitalization > 1 year before randomisation or in absence of (recent) HF hospitalization ≥150pg/mL if sinus rhythm; ≥250pg/mL if AF.


    6. ≥14 days stable on guideline-recommended therapy (doses and number of therapies as tolerated by each patient)
    1. Leeftijd ≥18 jaar
    2. Poliklinische patiënten met chronisch hartfalen, NYHA II-IV
    3. LVEF≤50%
    4. Serum NT-proBNP concentrations:
    Eerdere HF hospitalizatie ≤ 1 year voor randomiseren ≥400pg/mL if sinus rhythm; ≥800pg/mL if AF
    EerdereHF hospitalizatie > 1 year voor randomiseren of in afwezigheid van(recente) HF hospitalizatie ≥ 600pg/mL if sinus rhythm; ≥1000 pg/mL if AF
    BNP concentrations:
    Eerdere HF hospitalizatie ≤ 1 year voor randomiseren ≥100pg/mL if sinus rhythm; ≥200pg/mL if AF
    EerdereHF hospitalizatie > 1 year voor randomiseren of in de afwezigheid van (recente) HF hospitalizatie ≥150pg/mL if sinus rhythm; ≥250pg/mL if AF.
    6. ≥14 dagen stabiel op therapie aanbevolen volgens de richtlijnen (doseringen en aantal therapieën zoals getolereerd wordt door elke patiënt)
    E.4Principal exclusion criteria
    1. Heart rate ≤60bpm (if sinus rhythm); heart rate ≤70bpm (if AF)
    2. History of HF hospitalization ≤7days
    3. History of myocardial infarction, myocarditis, percutaneous intervention, RCT, pacemaker/ICD implantation, cardiac surgery or stroke ≤30 days
    4. Estimated glomerular filtration rate (eGFR), ≤30ml/min/1.73m2
    5. The presence of a mechanical assist device
    6. Use of inotropic drugs (dopamine, dobutamine, (nor)adrenaline, and milrinon)
    7. Scheduled for mechanical assist device or heart transplantation
    8. Other non-cardiac conditions with limited life expectancy
    9. Amyloid, hypertrophic obstructive or constrictive cardiomyopathy
    10. Accessory atrio-ventricular pathway (e.g. Wolf-Parkinson-White syndrome)
    11. (Intermittent) complete heart block or second-degree AV block type Mobitz without pacemaker
    12. Severe (grade III/III) aortic valve disease
    13. Complex congenital heart disease
    14. Proven hypersensitivity to digoxin
    15. Concomitant medication that interact with digoxin
    16. Use of digoxin ≤6 months prior to inclusion
    17.Participation in another clinical trial (registry studies not included)
    18. Women who are pregnant, breastfeeding or may be considering pregnancy during the study period
    1. Hartritme ≤60 slagen/min in sinusritme, of ≤70slagen/min in AF
    2. Voorgeschiedenis van hartfalen opname ≤7 dagen
    3. Voorgeschiedenis van myocardinfarct, myocarditis, percutane interventie, cardiale chirurgie of beroerte ≤30 dagen
    4. eGFR ≤30 ml/min/1.73m2
    5. Aanwezigheid van een mechanisch hulp device.
    6. Gebruik van inotropica (dopamine, dobutamine, (nor)adrenaline, and milrinon
    7. Gepland voor mechanisch hulp device of harttransplantatie.
    8. Andere niet-cardiale aandoeningen met een verminderde levensverwachting
    9. Amyloïdose, hypertrofische-, obstructieve-, of constrictieve cardiomyopathie
    10. Extra atrio-ventriculaire verbinding (bijv. WPW-syndroom)
    11. (Wisselend) 3e graads of 2e graads AV-block type Mobitz zonder pacemaker
    12. Ernstig (graad III/III) aortakleplijden
    13. Complexe congenitale hartziekten
    14. Bewezen overgevoeligheid voor digoxine
    15. Gebruik van medicatie die interacties hebben met digoxine
    16. Gebruik van digoxine ≤6 maanden voor inclusie
    17. Deelname aan andere klinische studies (registratie studies uitgesloten)
    18. Zwangere vrouwen, vrouwen die borstvoeding geven, of vrouwen die overwegen zwanger te worden tijdens de studieperiode
    E.5 End points
    E.5.1Primary end point(s)
    The composite of repeated HF hospitalizations and cardiovascular death.
    Het gecombineerde eindpunt van herhaalde hartfalen opnames en cardiovasculaire dood
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be evaluated at the end of the study
    Het primaire eindpunt zal worden geëvalueerd op het einde van de studie
    E.5.2Secondary end point(s)
    1. All-cause mortality
    2. Cardiovascular death
    3. (Repeated) HF hospitalization
    4. Cost-effectiveness.
    5. All-cause hospitalizations
    6. Unscheduled cardiovascular hospital visits
    7. Days alive out of hospital
    8. Quality of Life
    9. Heart rate in both AF and sinus rhythm
    10. To assess side effects (including SUSARs) associated with study medication
    11. Initiation of (recurrence of) AF in patients with sinus rhythm at baseline
    12. Conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF at baseline.
    1. Dood ten gevolge van alle oorzaken
    2. Cardiovasculaire dood
    3. (Herhaaldelijke) hartfalen opnames
    4. Kosten-effectiviteit
    5. Hospitalisaties ten gevolge van alle oorzaken
    6. Ongeplande cardiovasculaire ziekenhuisbezoeken
    7. Dagen levend uit het ziekenhuis
    8. Kwaliteit van leven
    9. Hartslag in zowel AF als sinusritme
    10. De bijeffecten (incl. SUSARs) geassocieerd met de studiemedicatie onderzoeken
    11. Initiatie van (terugkeren van) AF in patiënten met sinusritme op baseline
    12. Conversie naar sinusritme en behouden van sinusritme in patiënten met AF op baseline.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoints will be evaluated at the end of the study
    De secundaire eindpunten zullen op het einde van de studie worden geëvalueerd
    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 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 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 concerned38
    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
    LVLP
    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: 982
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 982
    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 state982
    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 Decision2019-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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