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    Summary
    EudraCT Number:2015-003818-24
    Sponsor's Protocol Code Number:DC2015RED01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-11-10
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-003818-24
    A.3Full title of the trial
    A phase 4, monocenter, randomized, double-blind, comparator-controlled, parallel-group, mechanistic intervention trial to assess the effect of 12-week treatment with the sodium-glucose linked transporters (SGLT)-2 inhibitor dapagliflozin versus the sulfonylurea (SU) derivative gliclazide on renal physiology and biomarkers in metformin-treated patients with type 2 diabetes mellitus (T2DM)
    Een fase 4, monocenter, gerandomiseerde, dubbelblinde mechanistische interventie trial om het effect van 12 weken behandeling met de 'sodium-glucose linked transporters' (SGLT)-2 remmer dapagliflozine versus sulfonylurea (SU) derivaat gliclazide op renale fysiologie en biomarkers te onderzoeken in parallele groepen van metformine behandelde type 2 diabetes mellitus patiënten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The renal effects of the new glucose lowering drug dapagliflozin with another glucose lowering drug gliclazide in type 2 diabetes mellitus patients
    Een onderzoek om het effect van het nieuwe glucose verlagende middel dapagliflozine te vergelijken met een ander glucose verlagend middel gliclazide op nierfunctie bij type 2 diabetes mellitus patiënten
    A.3.2Name or abbreviated title of the trial where available
    RED: Renoprotective Effects of Dapagliflozin in Type 2 Diabetes
    RED: Renoprotectieve Effecten van Dapagliflozine in Type 2 Diabetes
    A.4.1Sponsor's protocol code numberDC2015RED01
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1173-7074
    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 SponsorVU University Medical Center
    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 supportAstraZeneca Nederland BV
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportVU University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University Medical Center
    B.5.2Functional name of contact pointDaniel van Raalte
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081 HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31(0)204440534
    B.5.6E-maild.vanraalte@vumc.nl
    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 bv
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameDapagliflozin
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 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 Diamicron 30
    D.2.1.1.2Name of the Marketing Authorisation holderServier Farma Nederland bv
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameDiamicron 30
    D.3.4Pharmaceutical form Coated 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 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
    Type 2 Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    Type 2 Diabetes
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    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 investigate the effects of 12-week treatment with the SGLT-2 inhibitor dapagliflozin (10 mg QD) versus the SU gliclazide (30 mg QD) on renal hemodynamics in metformin-treated T2DM patients
    E.2.2Secondary objectives of the trial
    To investigate the effects of 12-week treatment with the SGLT-2 inhibitor dapagliflozin (10 mg QD) versus the SU gliclazide (30 mg QD) on:

    Secondary objectives:
    -Renal Tubular Function
    -Renal damage
    -Blood Pressure and heart rate
    -Body anthropometrics and Body fat content
    -Glycemic variables, Lipid spectrum, Inflammation, Biochemistry and Hematology
    -Microvascular function
    -Arterial stiffness (PWA)
    -Systemic hemodynamics
    -CANS function

    Exploratory objectives:
    -Biomarkers and gut microbiome
    -DNA
    -Insulin sensitivity
    -Beta-cell function
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    • Caucasian*
    • Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
    • Age: 35 - 75 years
    • BMI: >25 kg/m2
    • HbA1c: 6.5 – 9.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 mmol/mol International Federation of Clinical Chemistry (IFCC)
    • Treatment with a stable dose of oral antihyperglycemic agents for at least 3 months prior to inclusion
    • Metformin monotherapy
    • Combination of metformin and low dose SU derivative**
    • Hypertension should be controlled, i.e. ≤140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months.
    • Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
    • Written informed consent

    * In order to increase homogeneity
    ** In order to accelerate inclusion, patients using combined metformin/SU derivative will be considered. In these patients, a 12 week wash-out period of the SU derivative will be observed, only when combined use has led to a HbA1c <8% at screening. Subsequently, patients will be eligible to enter the study, now using metformin monotherapy, provided that HbA1c still meets inclusion criteria.
    E.4Principal exclusion criteria
    Exclusion criteria
    • History of unstable or rapidly progressing renal disease
    • Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
    • Current/chronic use of the following medication: TZD, SU derivative, GLP-1RA, DPP-4I, SGLT-2 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
    • Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
    • Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
    • History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
    • Current urinary tract infection and active nephritis
    • Recent (<6 months) history of cardiovascular disease, including:
    o Acute coronary syndrome
    o Chronic heart failure (New York Heart Association grade II-IV)
    o Stroke or transient ischemic neurologic disorder
    • Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
    • Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
    • (Unstable) thyroid disease; defined as fT4 outside of laboratory reference values or change in treatment within 3 months prior to screening visit
    • History of or actual malignancy (except basal cell carcinoma)
    • History of or actual severe mental disease
    • Substance abuse (alcohol: defined as >4 units/day)
    • Allergy to any of the agents used in the study
    • Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
    • Inability to understand the study protocol or give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    • GFR (measured by the inulin-clearance technique)
    • Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid (PAH) clearance technique)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline and after 12 weeks of treatment
    E.5.2Secondary end point(s)
    • Renal tubular function, measured as:
    -24-h urine sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, urea and glucose
    • Renal damage, measured by urine biomarkers as:
    -UAE (Glomerular)
    -Neutrophil gelatinase-associated lipocalin (NGAL) and Kidney injury molecule-1 (KIM‐1) (Tubular)
    • Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) (measured by oscillometric blood pressure device)
    • Heart rate (measured by oscillometric blood pressure device)
    • Body anthropometrics: waist circumference, height, body weight and body mass index (BMI) (using the formula: weight (in kg) / height2 (in m)), measured by a tape measure and calibrated weighing scale respectively
    • Body fat content, measured by bio-impedance analysis (BIA)
    • Marker of inflammation: high sensitivity C-reactive protein (hs-CRP)
    • Glycemic variables: Glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG)
    • Lipid spectrum (triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and free fatty acids (FFA))
    • Microvascular function, measured by capillary videomicroscopy and Laser Doppler techniques
    • Arterial stiffness (Pulse Wave Analysis), measured by applanation tonometry
    • Systemic hemodynamic variables (SBP, DBP, MAP, heart rate (HR), stroke volume (SV), cardiac output (CO)/-index (CI), and total systemic vascular resistance (TPR)) derived from non-invasive beat-to-beat finger blood pressure measurements
    • Cardiac autonomic nervous system (CANS) function, as derived from electrocardiographic (ECG) and non-invasive beat-to-beat finger blood pressure measurements (NexFin®) measured as:
    -Heart rate variability (HRV); Cardiovascular autonomic reflex tests (CARTs)

    Exploratory end points:
    • Complementary markers of renal function/damage (plasma cystatin C, fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), soluble Klotho, urinary transforming growth factor-β1 (TGF-β1), collagen type IV, nephrin, podocin, microparticles, uric acid, 8-hydroxy-2' -deoxyguanosine (8-OHdG), Calcitriol, Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α)
    • Additional markers of inflammation (interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1)
    • (Cardiovascular)-biomarkers (N-terminal pro-B-Type Natriuretic Peptide (NT-proBNP), Brain Natriuretic Peptide (BNP), Atrial Natriuretic Peptide (ANP), urinary angiotensinogen, plasma renin activity (PRA), angiotensin II, aldosterone, catecholamines, insulin, C-peptide, soluble receptor for advanced glycation end products (sRAGE)
    • Deoxyribonucleic acid (DNA) (to study the influence of genetic factors on the parameters measured and the response to SGLT-2 inhibitor)
    • Gut microbiome composition
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline and after 12 weeks of treatment
    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 Yes
    E.6.13.1Other scope of the trial description
    To asses the effect of dapagliflozin on renal hemodynamics beyond glucose control
    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 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 Yes
    E.8.2.3.1Comparator description
    dapagliflozin + encapsulated gliclazide placebo OR dapagliflozin placebo + encapsulated gliclazide
    E.8.2.4Number of treatment arms in the trial2
    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 No
    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
    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
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 44
    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)
    No different treatment is expected after completion of the study. Participants will return to their own physician.
    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 Decision2015-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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