Pilot Study to Explore the Efficacy of DAPAglifozin as add-on to Closed-loop Control in Patients With Type 1 Diabetes
Pilot Study to Explore the Efficacy of DAPAglifozin as add-on to Closed-loop Control in Patients With Type 1 Diabetes
Dapagliflozin has a unique mechanism of action that does not directly affect either insulin
 resistance or insulin secretion, but rather improves glycemia by reduction of glucose
 re-absorption from proximal renal tubules. Dapagliflozin is expected to reduce mean daily
 glucose, improve glycemic control and reduce overall insulin requirements. Improved glycemic
 control with reduced variability may also lead to reduced frequency of hypoglycemia.

 In youth with T1D, Dapagliflozin led to a significant reduction of insulin needed to achieve
 target glucose irrespective of preexisting HbA1c levels.

 In this pilot study data will be collected to investigate the effect on glucose of two doses
 of 10mg (each) dapagliflozin within range for the ensuing 24 hours during the DreaMed
 automated insulin delivery in patients with type 1 diabetes dosing with dapagliflozin in an
 in-patient setting combined with an automated sensor based CE marked insulin delivery system
 to data if dapagliflozin is a suitable add-on therapy. This will provide optimal monitoring
 of subject safety and assessment of the effects of dapagliflozin in a structured setting.

 If this inpatient study shows evidence that Dapagliflozin is a suitable add on therapy and
 leads to an increase of time within the target glucose range when using a sensor based
 insulin pump therapy (closed-loop) further outpatient studies are planned to be conducted.
The purpose of this pilot study is to collect clinical data of two doses of 10mg (each)
 dapagliflozin as add-on to night and day closed-loop control using the DreaMed automated
 insulin delivery on the time [%] within glucose range 70-180 mg/dl (3.9-10mmol/l) for the
 ensuing 24 hours with two oral mixed-meals.

 The study aimed to patients who have different degrees of inadequate glycemic control despite
 insulin use.

 A maximum of 45 patients will be screened until 30 Type 1 Diabetes mellitus patient (15
 adults, 15 adolescents) will completed the study.

 The trial will consist of six visits: a screening visit (Visit 1), two dosing visits (Visit 2
 and Visit 4), two phone visits (Visit 3 and Visit 5) and a follow-up visit (Visit 6).
 Furthermore, an information visit will take place prior to the screening visit in order to
 obtain patient's informed consent. Screening will take place 2-21 days prior to Visit 2 and
 the follow-up visit will take place 5-21 days after the end of Visit 4. The dosing visits
 will be separated by a wash-out period (5-30 days between the end of Visit 2 and begin of
 Visit 4) during which the subjects will resume their normal insulin treatment. Each phone
 visit (Visit 3 and Visit 5) will take place 3-5 days after the end of dosing Visits 2 and 4.
 The planned total duration of the trial is 18-78 days per subject (rescheduled visits
 excluded). Each subject will be randomised to a treatment sequence consisting of two
 treatment periods in which the subjects will receive 2 times 10mg dapagliflozin and placebo
 on two separate dosing visits.

 Subjects metabolic control will be achieved by using the DreaMed system (closed loop). The
 procedure will be used in order to aim and maintain blood glucose levels between 70 and 180
 mg/dl thereby.

 Two standardized mixed-meals will be given 12 hours and 18 hours after dosing. Blood glucose
 measurements will be performed every 30min for 120min after the mixed-meal.

 Blood samples for determination of dapagliflozin concentration in serum will be taken 14times
 in 24hours as well as ß-Hydroxybutyrate and every urine sample will be collected for 24 hours
 after first dosing for the determination of 24hour urinary glucose and creatinine for
 efficacy measurement.

 In addition a full blood gas analysis will be drawn if an elevated β-hydroxybutyrate of >1.0
 mmol/L will be detected.

 24 hours after first dosing with dapagliflozin/ placebo of each dosing visit the subjects
 will resume their usual insulin treatment and can leave the hospital.

 After conclusion of the trial the documented insulin doses over time will be summed up for
 calculation of the total insulin dose and the insulin dose per kg body weight per 24 hours.
Inclusion Criteria:

 1. Male or female aged 12-21 years (both inclusive)

 2. Type 1 diabetes mellitus (as diagnosed clinically) ≥ 12 months

 3. No DKA 12 weeks prior to the study

 4. On CSII (insulin pump therapy) since at least 3 months

 5. Average daily dose of Insulin between 0.6 - 2.0 U/kg

 6. Body mass index 18 to 35 kg/m2 or the 10th to 99th centile for BMI according to age
 and gender with a minimum weight of 50kg

 7. A1c range 6,5% - 11% (inclusive)

 Exclusion Criteria:

 1. History of drug or alcohol abuse within the last five years prior to screening

 2. Anamnestic history of hypersensitivity to the study drugs (or any component of the
 study drug) or to drugs with similar chemical structures

 3. History of severe or multiple allergies

 4. Treatment with any other investigational drug within 3 months prior to screening

 5. Progressive fatal disease

 6. 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

 7. Pregnant or lactating women

 8. 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

 9. Lack of compliance or other similar reason that, according to investigator, precludes
 satisfactory participation in the study

 Target Disease Exclusions

 10. History of Type 2 diabetes, maturity onset diabetes of young (MODY), pancreatic
 surgery or chronic pancreatitis

 11. Any use of oral hypoglycemic agents within 12 months prior to the screening visit

 12. History of diabetes ketoacidosis (DKA) within 12 weeks prior to prior to the screening
 visit

 13. History of diabetes insipidus

 14. History of hospital admission for glycemic control (either hyperglycemia or
 hypoglycemia) within 3 months prior to prior to the screening visit

 15. 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.

 16. Hypoglycemic unawareness

 17. History of Addison's disease or chronic adrenal insufficiency

 Physical and Laboratory Test Findings

 18. Aspartate aminotransferase (AST) > 2x Upper limit of normal (ULN)

 19. Alanine aminotransferase (ALT) > 2x ULN

 20. Serum total bilirubin > 2x ULN

 21. 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)].

 22. Hemoglobin ≤ 11.0 g/dl (110 g/l) for boys / men; hemoglobin ≤10.0 g/dl (100 g/L) for
 girls / women.

 23. Creatine kinase (CK) > 3x ULN

 24. Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody.

 25. 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

 26. Allergies or contraindication to the contents of dapagliflozin tablets or insulin

 27. Renal, Hepatic, Hematological/Oncological Diseases/Conditions

 28. History of unstable or rapidly progressing renal disease

 29. Conditions of congenital renal glucosuria

 30. Renal allograft

 31. Significant hepatic disease, including but not limited to, chronic active hepatitis
 and/or severe hepatic insufficiency

 32. Documented history of hepatotoxicity with any medication

 33. Documented history of severe hepatobiliary disease

 34. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or

 35. thalassemia minor; or chronic or recurrent hemolysis

 36. Donation of blood or blood products to a blood bank, blood transfusion, or

 37. participation in a clinical study requiring withdrawal of > 400 mL of blood during the
 6 weeks prior to the enrolment visit

 38. Known immunocompromised status, including but not limited to, individuals who have

 39. undergone organ transplantation or who are positive for the human immunodeficiency
 virus

 40. 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

 41. Prisoners or subjects who are involuntarily incarcerated

 42. Subjects who are compulsorily detained for treatment of either a psychiatric or
 physical (eg, infectious disease) illness

 43. 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.

 44. Any unstable endocrine, psychiatric, rheumatic disorders as judged by the
 Investigator.

 45. 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.

 46. 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.

 47. Subject is currently abusing alcohol or other drugs or has done so within the last 6
 months.

 48. Subject is a participating investigator, study coordinator, employee of an
 investigator or immediate family member of any of the aforementioned.

 49. Administration of any other investigational drug within 30 days of planned enrolment
 to this study.

 50. 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

 51. 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:

 52. Non-fasting, ie, consumption of food or beverages other than water, later than at
 23:00 hours the evening before dosing.

 53. Clinically significant illness with onset within 4 weeks prior to dosing

 54. Presence of clinically significant acute gastrointestinal symptoms (eg nausea,
 vomiting, heartburn or diarrhoea), as judged by the investigator

 55. Consumption of alcohol within 24 hours prior to dosing

 56. Episode of severe hypoglycemia occurring within the last 24 hours prior to dosing

 57. Any medical condition that, in the opinion of the Investigator, could interfere with
 insulin pharmacokinetics and/or glucose metabolism.

 58. 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.

 59. Non-adherence to pre-dosing insulin regimen consisting of CSII

 60. 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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