The PK and PD of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DM

A Clinical Pharmacology and Long Term Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With Type 1 Diabetes Who Have Inadequate Glycemic Control

This randomized, single-blind, 3 arm, parallel group, placebo controlled PK/PD study will enrol 30 Japanese male and female patients with T1DM and age 18 to 65 years, with inadequate glycemic control on insulin defined as HbA1c ≥ 7.0% and ≤ 10.0% at screening visit. lacebo-controlled design. Patients will be randomized in a 1:1:1 ratio into one of the 3 single-blinded treatment arms; dapagliflozin 5 mg, dapagliflozin 10 mg or placebo. CSII user are excluded.

Inclusion Criteria:

• Signed Written Informed Consent Subjects or their legally responsible representatives must be willing and able to give signed and dated written informed consent.
• Target Population Diagnosis of T1DM. In addition, the following criteria also needs to be met; Central laboratory test of C-peptide < 0.7 ng/mL Subject re-enrolment: This study does not permit the re-enrolment of a subject who has discontinued the study as a screen failure
• Insulin use for at least 12 months prior to the enrolment per subject report or medical records and Method of insulin administration (MDI) must have been unchanged for at least 3 months prior to the enrolment per subject report or medical records. Subjects must be taking a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the enrolment. CSII users are excluded. MDI insulin administration subject must be on ≥ 3x injections per day.
• Gender and reproductive Status Japanese men and women.
• HbA1c eligibility criteria include: Screening Visit: Central laboratory HbA1c ≥ 7.0 % and ≤ 10.0 % (One repeat HbA1c test for subjects in screening if their initial test result was an HbA1c ± 0.2% of the cut off values)
• BMI ≥ 20.0 kg/m², ≤ 35.0 kg/m² at visit 1
• Ages 18 to 65 years, inclusive - ≥ 18 years old and < 20 years old must have assent forms signed and dated by their parents or guardians

Exclusion Criteria:

• Target Disease Exceptions History of T2DM In cases where the subject has a history of T2DM and has a documented history of being auto-antibody positive for GAD65, tyrosine phosphatase IA-2/IA-2β, or Zinc Transporter 8 (ZnT8), or fasting c-peptide value below the lower limit of detection performed by local or central laborator, the subject will be eligible for screening
• Maturity onset diabetes of young (MODY), Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could result in decreased β-cell capacity (eg, pancreatogenous diabetes)
• Any antihyperglycemic agent use, other than thiazolidinediones, or insulin, within 1 month prior to the screening visit. Use of thiazolidinediones within 6 months prior to the screening visit.
• History of DKA requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the enrolment
• History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 1 month prior to the enrolment
• Malignancy within 5 years of the enrolment (with the exception of treated basal cell or treated squamous cell carcinoma)
• History of bladder cancer
• History of radiation therapy to the lower abdomen or pelvis at any time Unstable pre-proliferative and proliferative retinopathy (untreated or under treatment).
• Physical and Laboratory Test Findings Aspartate aminotransferase (AST) > 3x upper limit of normal (ULN) Alanine aminotransferase (ALT) > 3x ULN Serum total bilirubin (TB) > 2.0 mg/dL (34.2 μmol/L).
• Estimated GFR (eGFR) by the Japanese Society of Nephrology formula ≤ 60 mL/min/1.73m2. Hemoglobin ≤ 11.0 g/dL (110 g/L) for men; hemoglobin ≤ 10.0 g/dL (100 g/L) for women.
• Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody
• Abnormal Free T4