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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin 5 mg
* Drug: Dapagliflozin 10mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dapagliflozin 5mg + insulin<br>dapagliflozin tablet 5mg + adjustable insulin | Drug: Dapagliflozin 5 mg<br>* Dapagliflozin, a blood glucose lowering drug. Oral dose<br>|
| Experimental: dapagliflozin 10mg + insulin<br>dapagliflozin tablet 10mg + adjustable insulin | Drug: Dapagliflozin 10mg<br>* Dapagliflozin, a blood glucose lowering drug. Oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Adverse Event Summary | 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. | From baseline to 52 weeks | 
| Hypoglycemia | 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. | From baseline to 52 weeks | 
| Diabetic Ketoacidosis (DKA) | 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. | From baseline to 52 weeks | 
| Vital Signs (Heart Rate) | 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. | From baseline to 52 weeks | 
| ECGs | 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. | From baseline to 52 weeks | 
| Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality) | 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. | From baseline to 52 weeks | 
| Vital Signs (Blood Pressure) | 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. | From baseline to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Change From Baseline in HbA1c | 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. | From baseline to 24/52 weeks | 
| Adjusted Percent Change From Baseline in Total Daily Insulin Dose | 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. | From baseline to 24/52 weeks | 
| Adjusted Percent Change From Baseline in Body Weight | 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. | From baseline to 24/52 weeks | 
| Adjusted Change From Baseline in Glycoalbumin | 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. | From baseline to 24/52 weeks | 
| Adjusted Change From Baseline in Average Daily Glucose Measured by 6-point SMBG | 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. | From baseline to 24/52 weeks | 
| Adjusted Change From Baseline in Post-prandial Glucose Measured by 6-point SMBG | 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. | From baseline to 24/52 weeks | 
| Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent Without Severe Hypoglycemia | 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 | From baseline to 24/52 weeks | 
| Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent | 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 | From baseline to 24/52 weeks | 
| Proportion of Subjects Achieving HbA1c < 7.0 Percent | 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 | From baseline to 24/52 weeks | 
| Adjusted Change From Baseline in SBP in Subjects With Baseline SBP/DBP >= 140/90 mmHg | 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 | From baseline to 24/52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Japanese patients with type 1 diabetes with inadequate glycemic control on insulin