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    Summary
    EudraCT Number:2020-004832-48
    Sponsor's Protocol Code Number:GN19CA407
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-11-10
    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 ConcernedUK - MHRA
    A.2EudraCT number2020-004832-48
    A.3Full title of the trial
    DAPA-RESIST - Sodium glucose cotransporter-2 inhibitor DAPAgliflozin versus thiazide diuretic in patients with heart failure and diuretic RESISTance: a multi-centre, open-label, randomised controlled clinical trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Sodium glucose cotransporter-2 inhibitor dapagliflozin versus thiazide diuretic in patients with heart failure and diuretic resistance
    A.3.2Name or abbreviated title of the trial where available
    DAPA-RESIST
    A.4.1Sponsor's protocol code numberGN19CA407
    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 SponsorNHS Greater Glasgow and Clyde
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNHS Greater Glasgow and Clyde
    B.5.2Functional name of contact pointMaureen Travers
    B.5.3 Address:
    B.5.3.1Street AddressResearch & Innovation, Ward 11, Dykebar Hospital, Grahamston Road
    B.5.3.2Town/ cityPaisley
    B.5.3.3Post codeG3 8SW
    B.5.4Telephone number01413144012
    B.5.6E-mailMaureen.Travers@ggc.scot.nhs.uk
    B.Sponsor: 2
    B.1.1Name of SponsorUniversity of Glasgow
    B.1.3.4CountryUnited Kingdom
    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 supportAstraZeneca PLC
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Glasgow
    B.5.2Functional name of contact pointKatriona Brooksbank
    B.5.3 Address:
    B.5.3.1Street AddressBHF Glasgow Cardiovascular Research Centre
    B.5.3.2Town/ city126 University Place
    B.5.3.3Post codeG12 8TA
    B.5.6E-mailKatriona.Brooksbank@glasgow.ac.uk
    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 Forxiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameForxiga
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNDapagliflozin propanediol monohydrate
    D.3.9.1CAS number 461432-26-8
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameDapagliflozin
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 Zaroxolyn
    D.2.1.1.2Name of the Marketing Authorisation holderTeofarma S.r.l
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameZaroxolyn
    D.3.4Pharmaceutical form Tablet
    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 INNMetolazone
    D.3.9.1CAS number 17560-51-9
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diuretic resistant heart failure
    E.1.1.1Medical condition in easily understood language
    Heart failure that has not responded to loop diuretic therapy
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10010684
    E.1.2Term Congestive heart failure
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066159
    E.1.2Term Decompensated heart failure
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10019279
    E.1.2Term Heart failure
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10053073
    E.1.2Term Diuretic therapy
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the diuretic effect of dapagliflozin compared to metolazone, as assessed by mean change in weight, in hospitalised heart failure patients with diuretic resistance, type 2 diabetes or prediabetes and renal impairment.
    E.2.2Secondary objectives of the trial
    To assess the effect of dapagliflozin compared to metolazone on congestion (as assessed by lung ultrasound), loop diuretic efficiency (defined as weight loss in kilograms divided by furosemide equivalents in milligrams), laboratory tests (heart and kidney), heart failure symptoms, length of hospital stay, hospital readmissions and mortality.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male or female ≥18 years of age

    • Informed consent

    • Primary reason for admission to hospital is worsening HF meeting the European Society of Cardiology (ESC) definition

    • Diuretic Resistance as defined as lack of weight loss (decrease <1kg) or absence of a negative fluid balance (decrease <1 litre) despite treatment with high dose IV loop diuretic (equivalent of ≥160 mg IV furosemide) over the preceding 24 hours

    • Type 2 diabetes or pre-diabetes (prediabetes defined as HbA1c 39-47 mmol/mol)

    • eGFR <60 ml/min/1.73m2 at the time of randomisation

    • Ongoing clinical evidence of congestion: pitting peripheral oedema and/or ascites and/or elevated jugular venous pressure, and/or radiographic or ultrasonic evidence of pulmonary congestion

    • Expected hospital length of stay >3 days
    E.4Principal exclusion criteria
    • Inability to give informed consent e.g. due to significant cognitive impairment

    • Intravascular volume depletion based on investigator’s clinical assessment

    • eGFR <20 mL/min/1.73 m2

    • Alternative explanation for worsening renal function such as obstructive nephropathy, contrast induced nephropathy, or acute tubular necrosis

    • Enrolment in another randomized clinical trial involving medical or device-based interventions (co-enrolment in observational studies is permitted)

    • Women of child-bearing potential

    • History of allergy to SGLT2i or thiazide or thiazide-like diuretics or any of the excipients

    • Hypertrophic obstructive cardiomyopathy (HOCM) or severe stenotic valvular disease

    • SGLT2i, thiazide or thiazide-like diuretics administration in the previous 48 hours prior to randomisation

    • Active genital tract infections

    • Anyone who, in the investigators’ opinion, is not suitable to participate in the trial for other reasons
    E.5 End points
    E.5.1Primary end point(s)
    Diuretic effect, as assessed by mean change in weight, from randomisation to 48, 72 and 96 hours.
    E.5.1.1Timepoint(s) of evaluation of this end point
    48, 72 and 96 hours
    E.5.2Secondary end point(s)
    • Change in congestion, assessed using lung ultrasound, from randomisation to 48, 72 and 96 hours
    • Loop diuretic efficiency assessed at 48, 72 and 96 hours. Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams.
    E.5.2.1Timepoint(s) of evaluation of this end point
    48, 72 and 96 hours
    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) 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 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) Yes
    E.8.2.2Placebo No
    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 concerned5
    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
    End of trial is defined as the point at which the trial database is locked.

    Trial closedown begins if:
    • Planned sample size achieved, and the last patient has completed their final study visit
    • Insufficient funding to support further recruitment, and no prospect of additional support being obtained
    • New information makes it inappropriate to continue to randomise patients to either arm of the trial
    • Recruitment is so poor that completion of trial cannot reasonably be anticipated
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state120
    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)
    At the end of the trial, participants will be returned to usual care as defined by local and national guidelines at that time. Depending on local arrangements and at the discretion of their routine care team, participants may be able to continue on their allocated treatment beyond the end of the study treatment period but will no longer receive study medicine supplies.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-17
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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