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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| dapagliflozin 5mg | Experimental | dapagliflozin tablet 5mg |
|
| dapagliflozin 10mg | Experimental | dapagliflozin tablet 10mg |
|
| Placebo | Placebo Comparator | dapagliflozin tablet 5mg placebo or 10 mg placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dapagliflozin 5mg | Drug | Dapagliflozin, a blood glucose lowering drug. Oral dose |
| |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fukuoka | Japan |
Of 62 patients who signed informed consent, 42 eligible patients randomized and completed the 7-day treatment period (Part A) of the study.
26 October 2015 to 04 June 2016, Japan, patients with type 1 diabetes mellitus.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo + Insulin | Placebo administered orally once daily in the morning. |
| FG001 | Dapagliflozin 5mg + Insulin | Dapagliflozin 5 mg administered orally once daily in the morning. |
| FG002 | Dapagliflozin 10 mg + Insulin | Dapagliflozin 10 mg administered orally once daily in the morning. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Randomized Subjects
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo + Insulin | Placebo administered orally once daily in the morning. |
| BG001 | Dapagliflozin 5mg + Insulin | Dapagliflozin 5 mg administered orally once daily in the morning. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1-7 |
|
Non-serious adverse event (AE): onset on or after the 1st day of dose up to on or prior to the last day of dose plus 4 days. Serious AE: onset on or after the 1st day of dose up to on or prior to the last day of dose plus 30 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo + Insulin | Placebo administered orally once daily in the morning. | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| THIRST | General disorders | MedDRA Version: 19.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yu Shimizuishi | AstraZeneca K.K. | 81 6 7711 4669 | Yu.Shimizuishi@astrazeneca.com |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C529054 | dapagliflozin |
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| Dapagliflozin 10mg |
| Drug |
Dapagliflozin, a blood glucose lowering drug. Oral dose |
|
| Placebo tablet | Drug | Placebo tablet. Oral dose |
|
| 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 |
| 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 |
| BG002 | Dapagliflozin 10 mg + Insulin | Dapagliflozin 10 mg administered orally once daily in the morning. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Number | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Duration of Type 1 Diabetes | Mean | Standard Deviation | years |
|
| Hemoglobin A1c (HbA1c)% | Mean | Standard Deviation | percent of hemoglobin |
|
| Fasting Plasma Glucose (FPG) | Mean | Standard Deviation | mg/dL |
|
| C-Peptide | Number | Participants |
|
| Dapagliflozin 10mg + Insulin |
Dapagliflozin 10 mg administered orally once daily in the morning. |
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Median | Full Range | hours | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Median | Full Range | hours | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Day 1-7 |
|
|
|
| Primary | 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). | Pharmacokinetic set - Part A (PK-A): The PK set consisted of all randomized subjects who had at least one dose of randomized study medication for Part A and had an evaluable plasma concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Day 1-7 |
|
|
|
| Primary | 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. | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Deviation | g/24-hour | Baseline (the last available assessment prior to the first dose of study medication), Day 7 |
|
|
|
| Secondary | 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. | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Error | percent chagne | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 |
|
|
|
| Secondary | 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. | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Error | percent change | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 |
|
|
|
| Secondary | 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. | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Error | percent change | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 |
|
|
|
| Secondary | Fasting Plasma Glucose (FPG) (mg/dL) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Deviation | mg/dL | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 |
|
|
|
| Secondary | Seated Systolic Blood Pressure (mmHG) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set | Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable. | Posted | Mean | Standard Deviation | mmHG | Baseline (the last available assessment on or prior to the first dose of study medication), Day 7 |
|
|
|
| 14 |
| 0 |
| 14 |
| 1 |
| 14 |
| EG001 | Dapagliflozin 5mg + Insulin | Dapagliflozin 5 mg administered orally once daily in the morning. | 0 | 14 | 0 | 14 | 2 | 14 |
| EG002 | Dapagliflozin 10 mg + Insulin | Dapagliflozin 10 mg administered orally once daily in the morning. | 0 | 14 | 0 | 14 | 5 | 14 |
| MALAISE | General disorders | MedDRA Version: 19.0 | Systematic Assessment |
|
| MUMPS | Infections and infestations | MedDRA Version: 19.0 | Systematic Assessment |
|
| SINUSITIS | Infections and infestations | MedDRA Version: 19.0 | Systematic Assessment |
|
| INFLUENZA | Infections and infestations | MedDRA Version: 19.0 | Systematic Assessment |
|
| URINE OUTPUT INCREASED | Investigations | MedDRA Version: 19.0 | Systematic Assessment |
|
| DECREASED APPETITE | Metabolism and nutrition disorders | MedDRA Version: 19.0 | Systematic Assessment |
|
| POLLAKIURIA | Renal and urinary disorders | MedDRA Version: 19.0 | Systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |