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    Summary
    EudraCT Number:2020-001247-12
    Sponsor's Protocol Code Number:20-001
    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:2020-09-30
    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 number2020-001247-12
    A.3Full title of the trial
    An Open Label, Phase IV, Mechanistic, Study to Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 Diabetes Mellitus Patients with Impaired Renal Function
    Een open-label, fase IV, mechanistisch onderzoek ter beoordeling van het natriuretisch effect van 2 weken behandeling met Dapagliflozine bij patiënten met diabetes mellitus type 2 en een verminderde nierfunctie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    2-week Dapagliflozin therapy effect on sodium elimination in patients with type 2 diabetes mellitus and renal disease
    A.3.2Name or abbreviated title of the trial where available
    DAPASALT
    A.4.1Sponsor's protocol code number20-001
    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 SponsorUniversity 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 supportUniversity Medical Center Groningen
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointDr. Hiddo Heerspink
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code30001
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+3150361 7859
    B.5.6E-mailh.j.lambers.heerspink@umcg.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 holderAstra Zeneca AB
    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.3.4Pharmaceutical 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 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 (T2DM) with impaired renal function
    E.1.1.1Medical condition in easily understood language
    Type 2 diabetes mellitus with renal disease
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10012607
    E.1.2Term Diabetes mellitus inadequate control
    E.1.2System Organ Class 10027433 - Metabolism and nutrition 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 change in 24-hr sodium excretion during dapagliflozin treatment between Baseline (average of Days −3 to −1) and average of Days 2 to 4 within each study group in patients with type 2 diabetes mellitus (T2DM) with impaired renal function.
    E.2.2Secondary objectives of the trial
    The secondary objectives to be evaluated:
    • change in 24-hr sodium excretion during dapagliflozin treatment from Baseline to end of treatment, and during follow-up
    • change in 24-hr glucose excretion
    • change in mean 24-hr systolic blood pressure
    • change in plasma volume
    • change in extracellular volume
    • pharmacokinetics of dapagliflozin
    • the change in 24-hr urine albumin: creatinine ratio (UACR)

    The safety objectives to be evaluated:
    • safety and tolerability of dapagliflozin in patients with type 2 diabetes and renal impairment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients will be entered into this study only if they meet all of the following criteria:
    1. Provision of signed and dated, written informed consent prior to any study-specific procedures.
    2. Female and/or male aged between 18 years and ≤ 80 years.
    3. A diagnosis of T2DM with HbA1c ≥6.5% (≥48 mmol/mol) and ≤12%
    (<97 mmol/mol), if using insulin or sulfonylurea (for those patients not taking insulin or sulfonylurea there is no lower limit for HbA1c). T2DM patients on insulin or sulfonylurea who do not meet the HbA1c requirement can have their medication readjusted per Investigator’s judgement and rescreened after 3 months on new dose; and eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2
    4. Patient specific optimal antihypertensive dose of an ACEi or ARB (as per Investigator’s judgement) for at least 6 weeks prior to Visit 4 (Day 1).
    5. A stable insulin dosing (intermediate, long‐acting, premixed insulin, basal bolus insulin) for the last 12 weeks prior to Visit 4 (Day 1) as judged by the Investigator. Metformin, sulphonylurea, DPP4 inhibitors, GLP1 receptor agonists or any combinations of these agents with or without insulin would be accepted but is not mandatory. If used, stable dose of metformin, sulphonylurea, DPP4 inhibitors or GLP1 receptor agonists or their combination as anti-diabetic therapy for the last 12 weeks prior to start of treatment with dapagliflozin is required (as per Investigator's judgement).
    6. Suitable veins for cannulation or repeated venepuncture
    7. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of study drug to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.
    Patients must fulfil the following criteria in order to continue participation in the study:
    8. Patient specific optimal antihypertensive dose of an ACEi or ARB (as per Investigator’s judgement) for at least 6 weeks prior to Visit 4 (Day 1) (as per Investigator’s judgement).
    9. A stable insulin dosing (intermediate, long‐acting, premixed insulin, basal bolus insulin) for the last 12 weeks prior to Visit 4 (Day 1) (as per Investigator’s judgement. Metformin, sulphonylurea, DPP4 inhibitors, GLP1 agonists or any combinations of these agents with or without insulin would be accepted but is not mandatory. If used, stable dose of metformin, sulphonylurea, or DPP4 inhibitors or GLP1 agonists or their combination as anti-diabetic therapy for the last 12 weeks prior to start of treatment with dapagliflozin is required (as per Investigator's judgement).
    E.4Principal exclusion criteria
    Patients will not be entered into this study if they meet any of the following criteria:
    Study-related:
    1. Previous enrolment in the present study or participation in another clinical study with
    an investigational product during the last 30 days prior to Screening Visit (Visit 1).
    2. Involvement in the planning and conduct of the study (applies to both UMCG staff and staff at third party vendor or at the investigational sites).
    3. Hypersensitivity to dapagliflozin, indocyanine green, sodium iodide, or iodine, or patients who have poorly tolerated indocyanine green in the past.
    4. Pregnancy or breastfeeding.
    General health-related:
    5. Known clinically significant disease or disorder; or clinically relevant abnormal
    findings in physical examination, clinical chemistry, haematology, and urinalysis; or
    unstable or rapidly progressing renal disease; other dietary restrictions that would make it difficult for the subject to follow the protocol required diet plan or any other condition or minor medical complaint, which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results, or the patient’s ability to participate in the study and comply with study
    procedures, restrictions and requirements.
    6. Diagnosis of T1DM.
    7. Hyperthyroidism or autonomic thyroid adenomas.
    8. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following
    (Visit 1):
    - Systolic blood pressure above 180 mmHg.
    - Diastolic blood pressure above 110 mmHg.
    9. Any of the following cardiovascular/vascular diseases within 3 months prior to
    signing the consent at Visit 1, as assessed by the Investigator: myocardial infarction,
    cardiac surgery or revascularization (coronary artery bypass graft [CABG]/
    percutaneous transluminal coronary angioplasty [PTCA]), unstable angina, unstable
    heart failure, heart failure New York Heart Association Class IV, transient ischemic
    attack or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia.
    10. Patients with severe hepatic impairment (Child-Pugh C).
    11. Ongoing weight-loss diet (hypocaloric diet) or use of weight-loss agents, unless the
    diet or treatment has been stopped at least 3 months before Screening Visit, ensuring patients having a stable body weight with no verified body weight variability of >3 kg during the 3 months before Screening Visit.
    Renal failure-related:
    12. Symptoms/complaints suggestive of established neurogenic bladder and/or
    incomplete bladder emptying.
    13. History of bladder cancer.
    14. Non-diabetic kidney disease.
    15. UACR >2200 mg/g at the Screening Visit based on spot urine sample (quantitative assessment).
    Concomitant Medication and/or study treatment-related:
    16. Current/chronic use of the following medication: thiazolidinediones, oral glucocorticoids (if dose is stable for at least 4 weeks this is allowed), non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (as per Investigator's judgement).
    17. Receiving immunosuppressive or other immunotherapy for primary or secondary
    renal disease within 6 months prior to Screening Visit (Visit 1).
    18. Treatment within the last 2 weeks prior to Screening Visit (Visit 1) with mineralocorticoid antagonists (allowed if dose is stable; loop or thiazide diuretics are allowed as long as they are used in stable dose for at least 4 weeks prior to screening).
    19. A metformin dose which is outside the specified dose range for renal impairment
    according to local guidelines and/or Investigator’s judgement.
    20. Medicinal products and substances that can reduce or increase absorption of
    indocyanine green: anticonvulsants, bisulphite compounds, haloperidol, heroin, meperidine, metamizol, methadone, morphium, nitrofurantoin, opium alkaloids, phenobarbital, phenylbutazone (reduced absorption), and cyclopropane, probenecid,
    rifamycin (increased absorption).
    E.5 End points
    E.5.1Primary end point(s)
    Average change in 24-hr sodium excretion from average Baseline to average values at Day 2 to 4 within each study group.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 2 to 4
    E.5.2Secondary end point(s)
    The secondary endpoints to be evaluated during or following dapagliflozin treatment within each study group are:
    • Average change in 24-hr sodium excretion from average Baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17).
    • Average change in 24-hr glucose excretion from average Baseline values to average values at Day 2 to 4; from average Baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17).
    • Change in mean 24-hr systolic blood pressure from Baseline to Day 4; from Baseline to end of treatment (Day 13); and from end of treatment (Day 13) to end of follow-up (Day 18).
    • Change in plasma volume from Baseline to Day 4; from Baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18).
    • Change in extracellular volume from Baseline to Day 4; from Baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18).
    • Dapagliflozin pharmacokinetics on Days 4 and 14.
    • Average change in mean 24-hr UACR from average Baseline to Day 4; and from average Baseline values to average end of treatment values (Day 12 to 14).

    Safety Endpoints:
    • AEs starting from first dose throughout the study including the follow-up period.
    • SAEs starting from Visit 1 throughout the study including the follow-up period.
    • Laboratory variables.
    • Vital signs.
    • Physical examination.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From end of treatment (Day 14) to end of follow-up (Day 18)
    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 Yes
    E.6.5Efficacy Yes
    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) 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 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.8.3 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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    Netherlands
    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 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 years1
    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: 2
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 17
    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.
    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 Decision2020-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-30
    P. End of Trial
    P.End of Trial StatusOngoing
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