The Safety and Efficacy of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DM

Phase 3

Completed

Conditions: Type 1 Diabetes Mellitus

Interventions: Drug: Dapagliflozin 10mg
Drug: Dapagliflozin 5 mg

Registration Number: NCT02582814

Lead Sponsor: AstraZeneca

Brief Summary: This study will enroll eligible subjects into a long-term safety study (Part B).

Japanese male and female patients with T1DM and age 18 to 75 years, with inadequate glycemic control on insulin defined as HbA1c ≥ 7.5% and ≤ 10.5% at screening visit. As a condition of enrollment, subjects must be on a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the screening visit. The study design of Part B is a randomized, open-label, 2 arm, parallel-group design. 140 Japanese subjects in total will be randomized in a 1:1 ratio into one of the two treatment arms; dapagliflozin 5 mg or dapagliflozin 10 mg.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 151

Inclusion Criteria

Signed Written Informed Consent
Diagnosis of T1DM. In addition, the following criteria also needs to be met; Central laboratory test of C-peptide < 0.7 ng/mL
Insulin use for at least 12 months prior to the enrolment per subject report or medical records and Method of insulin administration (MDI or CSII) 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. If on MDI insulin administration subject must be on ≥ 3x injections per day.
Japanese men and women
Screening Visit: Central laboratory HbA1c ≥ 7.5% and ≤ 10.5%
BMI ≥ 20.0 kg/m² at visit 1
Age 18 to 75 years, inclusive

Exclusion Criteria

Target Disease Exceptions History of T2DM Maturity onset diabetes of young (MODY) Any anti-hyperglycemic agent use, other than α-GI or insulin, within 1 month prior to the enrolment.

Use of thiazolidinediones within 6 months prior to the enrolment History of DKA requiring medical intervention 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

Medical History and Concurrent Diseases 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
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 ≤ 45 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
dapagliflozin 10mg + insulin	Dapagliflozin 10mg	dapagliflozin tablet 10mg + adjustable insulin
dapagliflozin 5mg + insulin	Dapagliflozin 5 mg	dapagliflozin tablet 5mg + adjustable insulin

Primary Outcome Measures

Name	Time	Method
ECGs	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Hypoglycemia	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Diabetic Ketoacidosis (DKA)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Vital Signs (Blood Pressure)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Overall Adverse Event Summary	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Vital Signs (Heart Rate)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Secondary Outcome Measures

Name	Time	Method
Adjusted Change From Baseline in HbA1c	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Percent Change From Baseline in Total Daily Insulin Dose	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Percent Change From Baseline in Body Weight	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Glycoalbumin	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Average Daily Glucose Measured by 6-point SMBG	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Post-prandial Glucose Measured by 6-point SMBG	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent Without Severe Hypoglycemia	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Proportion of Subjects Achieving HbA1c < 7.0 Percent	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Adjusted Change From Baseline in SBP in Subjects With Baseline SBP/DBP >= 140/90 mmHg	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin