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History of drug or alcohol abuse within the last five years prior to screening
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Anamnestic history of hypersensitivity to the study drugs (or any component of the study drug) or to drugs with similar chemical structures
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History of severe or multiple allergies
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Treatment with any other investigational drug within 3 months prior to screening
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Progressive fatal disease
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History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.1 mg/dl in women and > 1.5 mg/dl in men), neurological, psychiatric and/or hematological disease as judged by the investigator
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Pregnant or lactating women
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Sexually active women of childbearing potential not consistently and correctly practicing birth control by implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomized partner
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Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study
Target Disease Exclusions
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History of Type 2 diabetes, maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis
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Any use of oral hypoglycemic agents within 12 months prior to the screening visit
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History of diabetes ketoacidosis (DKA) within 12 weeks prior to prior to the screening visit
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History of diabetes insipidus
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History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 3 months prior to prior to the screening visit
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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.
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Hypoglycemic unawareness
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History of Addison's disease or chronic adrenal insufficiency
Physical and Laboratory Test Findings
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Aspartate aminotransferase (AST) > 2x Upper limit of normal (ULN)
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Alanine aminotransferase (ALT) > 2x ULN
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Serum total bilirubin > 2x ULN
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Estimated GFR (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula ≤ 60 ml/min/1.73m2. The renal function, eGFR will be estimated by the abbreviated MDRD, using laboratory measurements of serum creatinine collected at screening [eGFR (ml/min/1.73m2) = 175 x (standardized Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if Black)].
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Hemoglobin ≤ 11.0 g/dl (110 g/l) for boys / men; hemoglobin ≤10.0 g/dl (100 g/L) for girls / women.
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Creatine kinase (CK) > 3x ULN
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Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody.
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Abnormal Free T4 Note: abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded. A one-time retest may be allowed, as determined by the Investigator, after a minimum of 6 weeks following the adjustment of thyroid hormone replacement therapy in subject who have had a prior diagnosis of a thyroid disorder and who are currently receiving thyroid replacement therapy. Such cases should be discussed with the Investigator prior to retesting. The subject must have all screening procedures and laboratory assessments performed as part of this re-test, and all of these must meet enrolment eligibility criteria. The subject's number will, however, remain the same as initially assigned.
Allergies and Adverse Drug Reaction
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Allergies or contraindication to the contents of dapagliflozin tablets or insulin
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Renal, Hepatic, Hematological/Oncological Diseases/Conditions
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History of unstable or rapidly progressing renal disease
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Conditions of congenital renal glucosuria
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Renal allograft
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Significant hepatic disease, including but not limited to, chronic active hepatitis and/or severe hepatic insufficiency
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Documented history of hepatotoxicity with any medication
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Documented history of severe hepatobiliary disease
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History of hemoglobinopathy, with the exception of sickle cell trait (SA) or
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thalassemia minor; or chronic or recurrent hemolysis
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Donation of blood or blood products to a blood bank, blood transfusion, or
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participation in a clinical study requiring withdrawal of > 400 mL of blood during the 6 weeks prior to the enrolment visit
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Known immunocompromised status, including but not limited to, individuals who have
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undergone organ transplantation or who are positive for the human immunodeficiency virus
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Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma of the skin) Other Exclusion Criteria
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Prisoners or subjects who are involuntarily incarcerated
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Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
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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.
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Any unstable endocrine, psychiatric, rheumatic disorders as judged by the Investigator.
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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.
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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.
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Subject is currently abusing alcohol or other drugs or has done so within the last 6 months.
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Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned.
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Administration of any other investigational drug within 30 days of planned enrolment to this study.
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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.
Dosing day exclusion criteria
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Subjects who meet one or more of the dosing day exclusion criteria will be excluded from the dosing visit or withdrawn from the trial as specified below:
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Non-fasting, ie, consumption of food or beverages other than water, later than at 23:00 hours the evening before dosing.
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Clinically significant illness with onset within 4 weeks prior to dosing
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Presence of clinically significant acute gastrointestinal symptoms (eg nausea, vomiting, heartburn or diarrhoea), as judged by the investigator
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Consumption of alcohol within 24 hours prior to dosing
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Episode of severe hypoglycemia occurring within the last 24 hours prior to dosing
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Any medical condition that, in the opinion of the Investigator, could interfere with insulin pharmacokinetics and/or glucose metabolism.
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Use of the following: systemic (oral or i.v.) corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-selective beta-blockers, growth hormone, non-routine vitamins or herbal products. Furthermore, thyroid hormones are not allowed unless the subject has used stable medication during the past 3 months.
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Non-adherence to pre-dosing insulin regimen consisting of CSII
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Subjects who meet one or more of dosing day exclusion criteria will be excluded from the dosing visit. In case a subject is excluded from the dosing visit, the dosing visit can be rescheduled 1-7 days later. Each of the dosing visits can only be rescheduled once.
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