The PK and PD of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DM
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Intervention: Dapagliflozin 5mg; Dapagliflozin 10mg; Placebo tablet
Intervention description: Dapagliflozin, a blood glucose lowering drug. Oral dose; Dapagliflozin, a blood glucose lowering drug. Oral dose; Placebo tablet. Oral dose
Intervention MeSH terms: Dapagliflozin
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Japanese patients with type 1 diabetes with inadequate glycemic control on insulin

Summary:

      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.
    

Eligibility criteria:

        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