The PK and PD 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 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.

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 5mg
* Drug: Dapagliflozin 10mg
* Drug: Placebo tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dapagliflozin Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin 3-O-Glucuronide Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin 3-O-Glucuronide Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin 3-O-Glucuronide Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin 3-O-Glucuronide Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| Dapagliflozin Ratio of Metabolite to Parent AUC of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set | Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose). | Day 1-7 | 
| 24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set | The 24-hour period is defined based on the morning void, from the first morning void to the one of the next day. | Baseline (the last available assessment prior to the first dose of study medication), Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Daily Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set | Total daily insulin dose is defined as the sum of all insulin doses (basal+bolus+premixed) for each day. Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation. | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 | 
| Daily Basal Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set | Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation. | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 | 
| Daily Bolus Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set | Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation. | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 | 
| Fasting Plasma Glucose (FPG) (mg/dL) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set |  | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 | 
| Seated Systolic Blood Pressure (mmHG) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set |  | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 | 

 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