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    Summary
    EudraCT Number:2014-003552-31
    Sponsor's Protocol Code Number:ESR-14-10179
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-11-03
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-003552-31
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-controlled, Single-center Phase 1 Pilot Study to Explore the Safety and Pharmacokinetics of a Single-Dose of DAPAglifozin as Add-on to Intravenous Insulin-Infusion in Adolescent and Adult Subjects with Type 1 Diabetes mellitus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Double-Blind, Placebo-controlled, Single-center Phase 1 Pilot Study to Explore the Safety and Pharmacokinetics of a Single-Dose of DAPAglifozin as Add-on to Intravenous Insulin-Infusion in Adolescent and Adult Subjects with Type 1 Diabetes mellitus
    A.3.2Name or abbreviated title of the trial where available
    DAPA-IIT1
    A.4.1Sponsor's protocol code numberESR-14-10179
    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 SponsorKinderkrankenhaus AUF DER BULT
    B.1.3.4CountryGermany
    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
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKinderkrankenhaus AUF DER BULT
    B.5.2Functional name of contact pointBärbel Aschemeier
    B.5.3 Address:
    B.5.3.1Street AddressJanusz-Korczak-Allee 12
    B.5.3.2Town/ cityHannover
    B.5.3.3Post code30173
    B.5.3.4CountryGermany
    B.5.4Telephone number+4951181153342
    B.5.6E-mailaschemeier@hka.de
    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 AuthorisationGermany
    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.3.2Product code BMS-512148
    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
    D.3.9.1CAS number 461432-26-8
    D.3.9.3Other descriptive nameDAPAGLIFLOZIN
    D.3.9.4EV Substance CodeSUB31650
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Type 1 Diabetes mellitus
    E.1.1.1Medical condition in easily understood language
    insulin-dependent autoimmune 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 degree of insulin dose reduction 24 hours after a single dose of 10mg dapagliflozin in patients with type 1 diabetes
    E.2.2Secondary objectives of the trial
    To investigate the effect on urinary glucose excretion
    To investigate if this effect is influenced by baseline glycemic control
    To investigate if dapagliflozin influences postprandial insulin need
    To investigate if dapagliflozin is associated with elevated ß-hydroxybutyrate levels
    To investigate PK after oral administration of 10mg dapagliflozin
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For inclusion in the study subjects should fulfill the following criteria:
    1. Provision of informed consent from participant and all legal representatives prior to any study specific procedures
    2. Female and/or male aged 12 to 21years (both inclusive)
    3. Subject must have type 1 diabetes (as diagnosed clinically) ≥ 12 months
    4. without completely inadequate glycemic control, defined as local laboratory A1c above 12.5% (subjects will be stratified according to glycemic control being in target (A1c 5.5 to 7.4%), slightly elevated (7.5 – 9.0%) or clearly elevated 9.1 – 12.5% ) obtained at the screening visit (Note: A one-time central laboratory re-test of the A1C is allowed)
    5. Insulin use with an average daily dose between 0.6 – 2.0 U/kg, either continuous subcutaneous insulin infusion, (CSII) or multiple doses (at least 2x/day) of insulin
    6. BMI 18.0 to 35.0 kg/m2 for adults or BMI between 10th and 99th age and gender related centile for pediatric patients
    7. Minimum weight of 50 kg
    8. Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study as judged by the investigator
    9. WOCBP must have a negative urine pregnancy test at screening as well as at Visit 2 and Visit 4.
    10. Women must not be breastfeeding
    E.4Principal exclusion criteria
    1) Target Disease Exclusions
    a) History of T2DM, maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis
    b) Any use of oral hypoglycemic agents within 12 months prior to the screening visit
    c) History of diabetes ketoacidosis (DKA) within 12 weeks prior to prior to the screening visit
    d) History of diabetes insipidus
    e) History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia)
    within 3 months prior to prior to the screening visit
    f) Frequent episodes of hypoglycemia as defined by more than one episode requiring assistance, emergency care (paramedics or emergency room care) or glucagon therapy, or more than 2 unexplained episodes of symptomatic hypoglycemia within 3 months prior to the screening visit. An unexplained event is defined as an event that cannot be explained by circumstances such as dietary (e.g. missed meal), strenuous exercise, error in insulin dosing, etc.
    g) Hypoglycemic unawareness
    h) History of Addison’s disease or chronic adrenal insufficiency

    2) Physical and Laboratory Test Findings
    a) Aspartate aminotransferase (AST) > 2X Upper limit of normal (ULN)
    b) Alanine aminotransferase (ALT) > 2X ULN
    c) Serum total bilirubin > 2X ULN
    d) Estimated GFR (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula ≤ 60 ml/min/1.73m2. e) Hemoglobin ≤ 11.0 g/dl (110 g/l) for boys / men; hemoglobin ≤10.0 g/dl (100 g/L) for girls / women.
    f) Creatine kinase (CK) > 3X ULN
    g) Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody.
    h) Abnormal Free T4
    3) Allergies and Adverse Drug Reaction
    a) Allergies or contraindication to the contents of dapagliflozin tablets or insulin

    4) Renal, Hepatic, Hemotological/Oncological Diseases/Conditions
    a) History of unstable or rapidly progressing renal disease
    b) Conditions of congenital renal glucosuria
    c) Renal allograft
    d) Significant hepatic disease, including but not limited to, chronic active hepatitis and/or severe hepatic insufficiency
    e) Documented history of hepatotoxicity with any medication
    f) Documented history of severe hepatobiliary disease
    g) History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis
    h) Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 6 weeks prior to the enrolment visit
    i) Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for the human immunodeficiency virus
    j) Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma of the skin)

    5) Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    c) Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to Day -3 visit. NOTE: Topical or inhaled corticosteroids are allowed.
    d) Any unstable endocrine, psychiatric, rheumatic disorders as judged by the Investigator.
    e) Subject is, in the judgment of the Investigator, unlikely to comply with the protocol or has any severe concurrent medical or psychological condition that may affect the interpretation of efficacy or safety data.
    f) Subject with any condition which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject.
    g) Subject is currently abusing alcohol or other drugs or has done so within the last 6 months.
    h) Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned.
    i) Administration of any other investigational drug within 30 days of planned enrolment to this study.
    j) No clinical conditions or clinically significant abnormalities, in any laboratory value(s) collected after screening and prior to randomization which, in the Investigator’s judgment, should preclude entry into the treatment period
    E.5 End points
    E.5.1Primary end point(s)
    The primary study variable of interest is as follows:
    • reduction of intravenous insulin dose with glucose kept between 160 - 220 mg/dl 24 hours after oral administration of 10mg dapagliflozin
    E.5.1.1Timepoint(s) of evaluation of this end point
    The intravenous insulin dose will be calculated as total infused insulin dose from study drug administration to 24h postdose. The primary analysis will be an ANOVA model using intravenous insulin dose as response variable and treatment, sequence and period as fixed factor and subject within sequence as random factor. The difference between dapagliflozin and placebo will be estimated, together with 2-sided 95% confidence interval.
    To get further information on the effect of baseline A1c on reduction of intravenous insulin dose a point estimate and 95% confidence intervals for the mean change in intravenous insulin dose (percent change) between dapagliflozin and placebo will be provided for each HbA1c group as supportive analysis.
    E.5.2Secondary end point(s)
    The secondary study variables of interest are described below:
    • effect of baseline A1c on insulin-dose lowering effect of 10mg dapagliflozin
    • increase of urinary glucose excretion with blood glucose kept between 160 - 220 mg/dl 24 hours after oral administration of 10mg dapagliflozin
    E.5.2.1Timepoint(s) of evaluation of this end point
    To assess the effect of baseline A1c on intravenous insulin dose an ANCOVA model will be applied using intravenous insulin dose as response variable, treatment, sequence and period as fixed factor, baseline A1c as covariate and subject within sequence as random factor. The main effect of baseline A1c will be reported as a statistical result from the model. In addition, the difference between dapagliflozin and placebo will be estimated, together with 2-sided 95% confidence interval.
    The urinary glucose excretion will be analyzed using the same model as described for the primary endpoint.
    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 Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First trial with pediatric patients
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    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 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 (anticipated for December 2015)
    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
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 15
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The study is conducted also with children aged 12 to 18 years.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    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)
    24 hours after dosing with dapagliflozin the subjects will resume their usual insulin treatment and can leave the hospital until the next visit.
    The investigator must provide information to the subjects on how to resume their usual insulin treatment. Before leaving the trial site, the subject must be informed about the symptoms of hypoglycaemia and about appropriate methods to treat hypoglycemia.
    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 Decision2014-11-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-17
    P. End of Trial
    P.End of Trial StatusOngoing
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