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    Summary
    EudraCT Number:2014-004599-49
    Sponsor's Protocol Code Number:MB102-230
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-04
    Trial results View 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 number2014-004599-49
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects with Type 1 Diabetes Mellitus - Study Two
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Double-Blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects with Type 1 Diabetes Mellitus, Parallel Group
    A.4.1Sponsor's protocol code numberMB102-230
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1163-0908
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post code19850-5437
    B.5.3.4CountryUnited States
    B.5.4Telephone number001800236993
    B.5.6E-mailinformation.center@astrazeneca.com
    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 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.3.9.2Current sponsor codeBMS-512148
    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 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.IMP: 2
    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 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.3.9.2Current sponsor codeBMS-512148
    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 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
    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
    Type 1 Diabetes Mellitus
    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 18.0
    E.1.2Level PT
    E.1.2Classification code 10067584
    E.1.2Term Type 1 diabetes mellitus
    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
    The primary objective of this study is to compare the change from baseline in HbA1c between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment.

    E.2.2Secondary objectives of the trial
    -Compare % change in total daily insulin dose with DAPA 5or10 mg + insulin vs placebo + insulin after 24w
    -% change in BW with DAPA 5or10 mg + insulin vs placebo + insulin after 24w
    -The change in value of 24h glucose from CGM with dapagliflozin 5or10 mg + insulin vs placebo + insulin after 24w
    -The change in MAGE of 24-hour glucose from CGM with DAPA 5or10 mg plus insulin vs placebo + insulin after 24w
    -The change in the percent of 24h glucose from CGM that falls within the target range of >70 mg/dL and ≤180 mg/dL with DAPA 5or10 mg + insulin vs placebo plus insulin after 24w
    -Compare DAPA 5or10 mg + insulin vs placebo + insulin for the proportion of achieving an HbA1c reductionfrom baseline to W24 visit ≥ 0.5% without severehypoglycemia
    -Proportion of hypoglycemia and the frequency and severity of the hypoglycemia with DAPA 5or10 mg + insulin vs placebo + insulin
    -Safety&tolerability by assessment of AE, vital signs, DKA, physical and lab findings
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent
    - Diagnosis of T1DM. In addition, a central laboratory C-peptide < 0.7 ng/mL (0.23 nmol/L) is required
    - Ages 18 to 75 years, inclusive
    - Insulin use for at least 12 months prior to screening per subject reported or medical records and:
    o Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 months prior to screening per subject reported or medical records. Subjects must be taking a total insulin dose of ≥0.3 U/kg/day for at least 3 months prior to screening
    o If using MDI, the subject must be taking ≥ 3 injections per day
    - HbA1c eligibility criteria include:
    o Screening Visit: Central laboratory HbA1c ≥ 7.7% and ≤ 11.0%
    Note: a one-time repeat HbA1C is allowed for subjects in screening if their initial result is within ± 0.2% of the cut off values
    o Week -1 Visit: Central laboratory HbA1c ≥7.5 % and ≤ 10.7%
    Note: a one-time repeat HbA1C is allowed for subjects in lead-in if their test result is within ± 0.2% of the cut off values
    - BMI ≥ 18.5 kg/m2
    - Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product
    - WOCBP must agree to follow instructions for method(s) of contraception as outlined in the study
    - Women must not be breastfeeding
    E.4Principal exclusion criteria
    o History of T2DM
    Note: subjects with a previous misdiagnosis of T2DM in their medical history must have one of the following in order to be eligible for this trial:
    -Positive autoantibodies for GAD65, phosphatase IA-2/IA2β, or ZnT8
    -Fasting c-peptide value below the lower limit of detection performed by the Lab
    o History of maturity onset diabetes of young
    o Pancreatic surgery, chronic or other pancreatic disorders that could result in decreased β-cell capacity
    o Previous use of DAPA and/or any other SGLT-2 inhibitors
    o Use of insulin-sensitizing agents, such as metformin and/or thiazolidinediones, within 2 months prior to the screening
    o Use of any GLP-1 receptor agonist within the following timeframe prior to the screening:
    i) 1 month for once or twice daily administration
    ii) 2 months for once weekly administration
    o Any non-insulin, antihyperglycemic agent use within 1 month prior to the Screening
    o History of DKA requiring medical intervention within 1 month prior to the screening
    o History of hospital admission for glycemic control within 1 month prior to the Screening
    o Frequent episodes of severe hypoglycemia as defined by more than one episode requiring medical assistance, emergency care, and/or glucagon therapy administered by a third-party individual within 1 month prior to the screening
    o Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to screening
    o History of Addison’s disease or chronic adrenal insufficiency
    o History of diabetes insipidus
    o Any of the following cardiovascular/vascular diseases within 6 months of the screening:
    - Myocardial infarction
    - Cardiac surgery or revascularization
    - Unstable angina
    - Unstable congestive heart failure
    - CHF New York Heart Association Class III or IV
    -TIA or significant cerebrovascular disease
    - Unstable or previously undiagnosed arrhythmia
    o Renal Disease:
    - History of unstable or rapidly progressing renal disease
    - Conditions of congenital renal glucosuria
    - Renal allograft
    o Hepatic Diseases:
    - Significant hepatic disease
    o Hematological and Oncological Disease/Conditions:
    - History of hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor; or chronic or recurrent hemolysis
    - Known immunocompromised status, individuals who have undergone organ transplantation or who are positive for the HIV
    - 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 8 weeks prior to the screening visit
    - Malignancy within 5 years of the screening visit
    - History of bladder cancer
    - History of radiation Th to the lower abdomen or pelvis at any time
    Physical and Laboratory Test Findings
    o AST> 3x ULN
    o ALT > 3x ULN
    o Serum total bilirubin > 2.0 mg/dL unless exclusively caused by Gilbert’s Syndrome
    o CrCl < 60 mL/min as estimated by the Cockcroft-Gault formula, using lab measurements of serum creatinine collected at the screening visit
    o Hgb ≤ 11.0 g/dL for men; Hgb ≤ 10.0 g/dL for women
    o Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody
    o Abnormal Free T4 Note: abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal freeT4 values will be excluded. A one-time retest may be allowed after a minimum of 6w following the adjustment of thyroid hormone replacement Th who have had a prior diagnosis of a thyroid disorder and who are currently receiving thyroid replacement therapy
    Allergies and Adverse Drug Reaction
    o Allergies or contraindication to the contents of DAPA or insulin
    - Sex and Reproductive Status
    o Women who are pregnant
    Other Exclusion Criteria
    o Prisoners or subjects who are involuntarily incarcerated
    o Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
    o Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program
    o History of bariatric surgery or lap-band procedure within 12m prior to screening
    o Replacement or chronic systemic corticosteroid Th, defined as any dose of systemic corticosteroid taken for > 4 w within 3M prior to the Day 1 visit NOTE: Topical or inhaled corticosteroids are allowed
    o Any unstable endocrine, psychiatric or rheumatic disorders
    o Volume-depleted subjects
    o Subject who is found to be unlikely to comply with the protocol, or is unable to correctly self-administer subcutaneous insulin injections and/or manage their insulin pump, or has any severe concurrent medical or psychological condition that may affect the interpretation of efficacy or safety data
    o Subject is currently abusing alcohol or other drugs or has done so within the last 6 months prior to the Day 1 visit
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is the change in HbA1c from baseline to Week 24.
    For subjects whose insulin dose is up-titrated by more than 25% of insulin prior to randomization, measurements obtained after meeting the above insulin up-titration criteria will be excluded from the primary analysis. Multiple sensitivity analyses, including the sensitivity analyses using data regardless of insulin dose up-titration, will also be performed for the primary efficacy endpoint to assess the robustness of the primary efficacy results.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timepoint will be evaluated on specified visits per schedule of
    assessments, please section 5.1 in protocol
    E.5.2Secondary end point(s)
    1. Percent change from baseline to Week 24 in total daily insulin dose
    2. Percent change from baseline to Week 24 in body weight
    3. Change from baseline to Week 24 in the mean value of 24-hour glucose readings obtained from CGM
    4. Change from baseline to Week 24 in mean amplitude of glucose excursion (MAGE) of 24-hour glucose readings obtained from CGM
    5. Change from baseline to Week 24 in the percent of 24-hour glucose readings obtained from CGM that falls within the range of > 70 mg/dL and  180 mg/dL
    6. Proportion of subjects achieving an HbA1c reduction from baseline to Week 24 ≥ without severe hypoglycemia events.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The timepoint will be evaluated on specified visits per schedule of
    assessments, please see section 5.1.1 in protocol
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Argentina
    Belgium
    Canada
    Chile
    Germany
    Japan
    Netherlands
    Poland
    Russian Federation
    Sweden
    Switzerland
    United Kingdom
    United States
    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
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 1488
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 372
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 565
    F.4.2.2In the whole clinical trial 1860
    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 study, BMS/AZ will not continue to provide BMS supplied study drug to subjects/investigators unless BMS/AZ chooses to extend the study. The investigator should ensure that the subject receives appropriate standard of care to treat the condition under study.
    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 Decision2015-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-18
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