Type 2 Diabetes Mellitus
Conditions
Keywords
Japanese patients with type 2 diabetes with inadequate glycemic control on insulin
Brief summary
Japanese male and female patients with Type 2 Diabetes and aged ≥ 20 years old, with inadequate glycemic control on insulin defined as Haemoglobin A1c ≥ 7.2% and \< 11% will be enrolled into the wash-out phase or directly into the lead-in phase depending on whether the patient has been receiving an Oral antidiabetic drug (including Glucagon-Like Peptide-1 agonists and excluding Thiazolidinedions) other than a Dipeptidyl Peptidase-4 inhibitor as part of the baseline treatment. Additional treatment with a concomitant Dipeptidyl Peptidase-4 inhibitor is allowed. And around 180 eligible patients in total will be randomized into the study with a 2:1 randomization scheme (i.e.120 patients into the dapagliflozin treatment group and 60 patients into the placebo treatment group. All subjects who completed a 16 weeks double-blind treatment period will shift to a 36 weeks open extension treatment period.
Interventions
Dapagliflozin, a blood glucose lowering drug. Oral dose
DRUGPlacebo tablet
Placebo tablet. Oral dose
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures * Diagnosis of Type 2 Diabetes according the criteria specified by the Japan Diabetes Society * Japanese Men or women age ≥ 20 years at time of consenting. * Stable (unless adjustment is required based on Fasting Plasma Glucose values) dose insulin\* mono-therapy with the mean insulin \[up to two types of insulin within authorized indication in Japan\] dose of ≥ 0.2 IU/kg/day AND ≥ 15 IU/body/day over the past 8 weeks prior to enrolment. * HbA1c ≥ 7.2% and \< 11% from the blood samples collected at Visit 1 (enrolment) and Visit 3, observed from the central laboratory
Exclusion criteria
* Diagnosis of Type 1 diabetes mellitus, known diagnosis of Maturity Onset Diabetes of the Young, secondary diabetes mellitus or diabetes insipidus * History of diabetic ketoacidosis. * Thyroid-stimulating hormone and free T4 values outside normal range, observed from the central laboratory; an abnormal Thyroid-stimulating hormone value needs to be followed up with a free T4 test. Patients with abnormal free T4 values will be excluded at Visit 1 * Fasting Plasma Glucose \>240 mg/dL (twice in a row) despite the permitted dose adjustment of insulin therapy during washout period and lead-in period. * Recent cardiovascular events in a patient. * eGFR \<45 mL/min/1.73 m2 at Visit 3, observed from the central laboratory. * History of unstable or rapidly progressing renal disease. * History of unexplained microscopic or gross hematuria, or microscopic hematuria at Visit 1, confirmed by a follow-up sample at next scheduled visit, where according to the investigator a satisfactory evaluation of hematuria has not been conducted. * Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN, observed from the central laboratory at Visit 1. * Total bilirubin \>2.0 mg/dL (34.2 μmol/L), observed from the central laboratory at Visit 1. * Positive serologic evidence of current infectious liver disease including Hepatitis A viral antibody IgM, Hepatitis B surface antigen and Hepatitis C virus antibody, observed from the central laboratory. * Haemoglobin \<10 g/dL (\<100 g/L) or 6.2 mmol/L for men; haemoglobin \<9.0 g/dL (\<90 g/L) or 5.9 mmol/L for women, observed from the central laboratory at Visit 1. * History of chronic haemolytic anaemia or haemoglobinopathies (for example, sickle cell anaemia, thalassemia, sideroblastic anaemia). Mild haemolysis due to artificial heart valves or due to sickle cell trait is not an exclusion criterion except when haemoglobin levels are too low (as defined in haemoglobin criteria above). * History of malignancy within the last 5 years prior to enrolment, excluding successful treatment of basal or squamous cell skin cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 16 | Mean change in HbA1c levels from baseline to Week 16 between dapagliflozin 5 mg versus placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose | Baseline to Week 16 | Mean change in fasting plasma glucose from baseline to Week 16 between dapagliflozin 5 mg versus placebo |
| Total Body Weight | Baseline to Week 16 | Mean change in total body weight from baseline to Week 16 between dapagliflozin 5 mg versus placebo |
| Total Mean Daily Insulin Dose | Baseline to Week 16 | Mean change in calculated mean daily insulin dose from baseline to Week 16 between dapagliflozin 5 mg versus placebo |
| Proportion of Participants With Mean Daily Insulin Dose Reduction of Greater Than or Equal 10% | Baseline to Week 16 | Proportion of participants with mean daily insulin dose reduction greater than or equal 10% from baseline to week 16 (LOCF) between dapagliflozin 5 mg versus placebo |
Countries
Japan
Participant flow
Recruitment details
First participant enrolled: 06-Jun-2014; Last participant last visit of ST period: 02-Feb-2015; 266 participants were enrolled in 20 Japanese centers. 183 Japanese men or women aged \>=20 years with inadequate glycemic control (HbA1c levels of \>=7.2% to \<11.0%) with diet, exercise and on stable dose of insulin +/- DPP-4 inhibitor were treated.
Pre-assignment details
A 8-week wash-out period was applicable only for participants on ongoing anti-diabetic treatment at enrollment. A 2-week lead-in period was applicable for all participants.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor | 122 |
| Placebo Placebo plus insulin alone or in combination with DPP-4 inhibitor | 60 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Poor/Non-compliance | 1 | 0 |
| Overall Study | Subject no longer meets study criteria | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Dapagliflozin |
|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 9.82 | 57.6 years STANDARD_DEVIATION 9.86 | 58.3 years STANDARD_DEVIATION 9.83 |
| Age, Customized <=65 years | 127 participants | 43 participants | 84 participants |
| Age, Customized >=75 years | 2 participants | 1 participants | 1 participants |
| Age, Customized Between 65 and 75 years | 53 participants | 16 participants | 37 participants |
| Body Mass Index | 26.64 kg/m^2 STANDARD_DEVIATION 4.51 | 26.12 kg/m^2 STANDARD_DEVIATION 3.485 | 26.89 kg/m^2 STANDARD_DEVIATION 4.93 |
| Body Weight | 73.24 kg STANDARD_DEVIATION 14.956 | 71.89 kg STANDARD_DEVIATION 13.43 | 73.90 kg STANDARD_DEVIATION 15.663 |
| Calculated Mean Daily Insulin Dose | 38.76 IU/Day STANDARD_DEVIATION 17.625 | 40.58 IU/Day STANDARD_DEVIATION 16.764 | 37.87 IU/Day STANDARD_DEVIATION 18.033 |
| DPP-4 Inhibitor Usage No | 101 participants | 33 participants | 68 participants |
| DPP-4 Inhibitor Usage Yes | 81 participants | 27 participants | 54 participants |
| Fasting Plasma Glucose | 160.36 mg/dL STANDARD_DEVIATION 42.679 | 159.68 mg/dL STANDARD_DEVIATION 38.001 | 160.70 mg/dL STANDARD_DEVIATION 44.948 |
| HbA1c | 8.34 percent of hemoglobin glycosylated STANDARD_DEVIATION 0.849 | 8.52 percent of hemoglobin glycosylated STANDARD_DEVIATION 0.937 | 8.26 percent of hemoglobin glycosylated STANDARD_DEVIATION 0.792 |
| Region of Enrollment Japan | 182 participants | 60 participants | 122 participants |
| Sex: Female, Male Female | 53 Participants | 20 Participants | 33 Participants |
| Sex: Female, Male Male | 129 Participants | 40 Participants | 89 Participants |
| Waist Circumference | 92.9 cm STANDARD_DEVIATION 10.96 | 92.3 cm STANDARD_DEVIATION 9 | 93.2 cm STANDARD_DEVIATION 11.83 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 123 | 10 / 60 |
| serious Total, serious adverse events | 3 / 123 | 0 / 60 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
Mean change in HbA1c levels from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin | Adjusted Mean Change in HbA1c Levels | -0.55 percentage of hemoglobin glycosylated |
| Placebo | Adjusted Mean Change in HbA1c Levels | 0.05 percentage of hemoglobin glycosylated |
Comparison: H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-0.81, -0.39]Mixed Models Analysis
Secondary
Fasting Plasma Glucose
Mean change in fasting plasma glucose from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin | Fasting Plasma Glucose | -21.7 mg/dL |
| Placebo | Fasting Plasma Glucose | 1.0 mg/dL |
Comparison: H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-33.2, -12.2]Mixed Models Analysis
Secondary
Proportion of Participants With Mean Daily Insulin Dose Reduction of Greater Than or Equal 10%
Proportion of participants with mean daily insulin dose reduction greater than or equal 10% from baseline to week 16 (LOCF) between dapagliflozin 5 mg versus placebo
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) value
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin | Proportion of Participants With Mean Daily Insulin Dose Reduction of Greater Than or Equal 10% | 8.2 percentage of participants |
| Placebo | Proportion of Participants With Mean Daily Insulin Dose Reduction of Greater Than or Equal 10% | 4.9 percentage of participants |
Comparison: H0: proportion(dapa) minus proportion(placebo) = 0 versus alternative HA: proportion(dapa) minus proportion(placebo) =/= 0p-value: 0.372795% CI: [-4, 10.7]Regression, Logistic
Secondary
Total Body Weight
Mean change in total body weight from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin | Total Body Weight | -0.6 kg |
| Placebo | Total Body Weight | 0.7 kg |
Comparison: H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-1.7, -0.7]Mixed Models Analysis
Secondary
Total Mean Daily Insulin Dose
Mean change in calculated mean daily insulin dose from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin | Total Mean Daily Insulin Dose | -0.74 IU/Day |
| Placebo | Total Mean Daily Insulin Dose | -0.02 IU/Day |
Comparison: H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0p-value: 0.074395% CI: [-1.51, 0.07]Mixed Models Analysis