Type 2 Diabetes
Conditions
Keywords
Type 2 diabetes, metformin treated, inadequate control, metformin treatment alone
Brief summary
This study is being carried out to see if dapagliflozin - administered in a daily dose of 2.5 mg given twice a day or 5 mg twice a day or 10mg once daily - in addition to metformin, is beneficial in diabetes treatment, and if so, how it compares to treatment with metformin alone.
Interventions
DRUGdapagliflozin
2.5 mg tablet, taken orally, twice daily
DRUGmetformin
\>/= 1500 mg total daily dose, tablets taken orally, twice daily
DRUGplacebo
placebo
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 77 Years
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures * Diagnosis of T2DM * Current antihyperglycaemic treatment with metformin immediate release formulation monotherapy \>/= 1500 mg/day at a stable dose for at least 10 weeks prior to enrolment. Other treatment with OADs within the 10 weeks prior to enrolment is not permitted. * HbA1c ≥ 6.7% and ≤10.5%, based on central laboratory values from Screening Visit, and Enrolment Visit 1.
Exclusion criteria
* Diagnosis of Type 1 diabetes mellitus, known diagnosis of Maturity Onset Diabetes of the Young (MODY) or secondary causes of diabetes mellitus * History of diabetic ketoacidosis * Symptoms of poorly controlled diabetes including, but not limited to, marked polyuria, polydipsia, and/or greater than 10% weight loss during the 3 months prior to enrolment * FPG \>270 mg/dL (\>15.0 mmol/L) * BMI \>45 kg/m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 16 | To compare the change from baseline in HbA1c achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Percent Change in Body Weight | Baseline to Week 16 | To compare the percent change from baseline in body weight achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID, and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. |
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | Baseline to Week 1 | To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 1 week of double-blind treatment. |
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | Baseline to Week 16 | To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. |
| Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | Baseline to Week 16 | To compare the adjusted proportions controlling for baseline HbA1c \[acc. to Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu\] of participants with HbA1c \<7.0% achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment, in patients who had HbA1c ≥7.0% at baseline. |
Countries
Germany, Hungary, Romania, Slovakia, South Africa, Switzerland, Ukraine
Participant flow
Recruitment details
First participant enrolled: 5 November 2010. Last participant last visit for the 16-week period: 25 August 2011. 520 participants were enrolled, and 400 were randomized in 53 study centers in Europe and South Africa. Subjects with T2DM who showed inadequate glycemic control on metformin therapy alone.
Pre-assignment details
During a placebo lead-in period, participants were counselled on dietary and life-style modifications. Subjects eligible for the study were stratified according to their baseline HbA1c.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, \>=1500mg total daily dose | 100 |
| Dapagliflozin 5mg BID Plus Metformin Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, \>=1500mg total daily dose | 99 |
| Dapagliflozin 10mg OD Plus Metformin Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, \>=1500mg total daily dose | 99 |
| Placebo Plus Metformin Placebo plus Metformin, oral, twice daily, \>=1500mg total daily dose | 101 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 0 |
| Overall Study | Incorrect enrollment | 0 | 1 | 1 | 0 |
| Overall Study | Lab value | 1 | 0 | 1 | 0 |
| Overall Study | Poor/Non-Compliance | 0 | 0 | 1 | 0 |
| Overall Study | Subject no longer meets study criteria | 5 | 2 | 4 | 8 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Dapagliflozin 2.5mg BID Plus Metformin | Dapagliflozin 5mg BID Plus Metformin | Dapagliflozin 10mg OD Plus Metformin | Placebo Plus Metformin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.3 Years STANDARD_DEVIATION 9.01 | 55.3 Years STANDARD_DEVIATION 9.34 | 58.5 Years STANDARD_DEVIATION 9.78 | 58.5 Years STANDARD_DEVIATION 9.4 | 57.7 Years STANDARD_DEVIATION 9.45 |
| Body weight | 92.49 kg STANDARD_DEVIATION 18.632 | 93.62 kg STANDARD_DEVIATION 16.641 | 90.58 kg STANDARD_DEVIATION 15.929 | 88.82 kg STANDARD_DEVIATION 15.327 | 91.37 kg STANDARD_DEVIATION 16.716 |
| Fasting Plasma Glucose (FPG) | 153.3 mg/dL STANDARD_DEVIATION 33.27 | 155.3 mg/dL STANDARD_DEVIATION 31.92 | 155.3 mg/dL STANDARD_DEVIATION 36.26 | 157.8 mg/dL STANDARD_DEVIATION 35.93 | 155.4 mg/dL STANDARD_DEVIATION 34.3 |
| HbA1c | 7.77 Percent [%] STANDARD_DEVIATION 0.747 | 7.78 Percent [%] STANDARD_DEVIATION 0.762 | 7.71 Percent [%] STANDARD_DEVIATION 0.709 | 7.94 Percent [%] STANDARD_DEVIATION 0.848 | 7.80 Percent [%] STANDARD_DEVIATION 0.77 |
| Sex: Female, Male Female | 63 Participants | 53 Participants | 50 Participants | 54 Participants | 220 Participants |
| Sex: Female, Male Male | 37 Participants | 46 Participants | 49 Participants | 47 Participants | 179 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 100 | 0 / 100 | 6 / 99 | 9 / 101 |
| serious Total, serious adverse events | 4 / 100 | 1 / 100 | 2 / 99 | 0 / 101 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
To compare the change from baseline in HbA1c achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.52 Percent | Standard Error 0.0594 |
| Dapagliflozin 5mg BID Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.65 Percent | Standard Error 0.06 |
| Dapagliflozin 10mg OD Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.59 Percent | Standard Error 0.0598 |
| Placebo Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.30 Percent | Standard Error 0.0593 |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05 using Hochberg's method to control the overall Type I error across hypotheses in the two Dapagliflozin BID groups, two-sided)p-value: 0.010695% CI: [-0.38, -0.05]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05 using Hochberg's method to control the overall Type I error across hypotheses in the two Dapagliflozin BID groups, two-sided)p-value: <0.000195% CI: [-0.52, -0.18]ANCOVA
Secondary
Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1
To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 1 week of double-blind treatment.
Time frame: Baseline to Week 1
Population: Full Analysis Set, participants with non-missing baseline and Week 1 values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | -13.7 mg/dL | Standard Error 2.657 |
| Dapagliflozin 5mg BID Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | -14.7 mg/dL | Standard Error 2.672 |
| Dapagliflozin 10mg OD Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | -15.5 mg/dL | Standard Error 2.634 |
| Placebo Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | 2.0 mg/dL | Standard Error 2.584 |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: <0.000195% CI: [-21.7, -9.7]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: <0.000195% CI: [-22.7, -10.7]ANCOVA
Secondary
Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16
To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -20.8 mg/dL | Standard Error 2.738 |
| Dapagliflozin 5mg BID Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -25.6 mg/dL | Standard Error 2.759 |
| Dapagliflozin 10mg OD Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -20.4 mg/dL | Standard Error 2.72 |
| Placebo Plus Metformin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -10.4 mg/dL | Standard Error 2.669 |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: 0.00195% CI: [-16.5, -4.2]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: <0.000195% CI: [-21.4, -9.1]ANCOVA
Secondary
Adjusted Percent Change in Body Weight
To compare the percent change from baseline in body weight achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID, and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin | Adjusted Percent Change in Body Weight | -2.84 Percent | Standard Error 0.3099 |
| Dapagliflozin 5mg BID Plus Metformin | Adjusted Percent Change in Body Weight | -3.20 Percent | Standard Error 0.3125 |
| Dapagliflozin 10mg OD Plus Metformin | Adjusted Percent Change in Body Weight | -2.76 Percent | Standard Error 0.3086 |
| Placebo Plus Metformin | Adjusted Percent Change in Body Weight | -1.04 Percent | Standard Error 0.3105 |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: <0.000195% CI: [-2.53, -1.1]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)p-value: <0.000195% CI: [-2.89, -1.46]ANCOVA
Secondary
Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline.
To compare the adjusted proportions controlling for baseline HbA1c \[acc. to Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu\] of participants with HbA1c \<7.0% achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment, in patients who had HbA1c ≥7.0% at baseline.
Time frame: Baseline to Week 16
Population: Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg BID Plus Metformin | Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | 33.6 Percentage of participants |
| Dapagliflozin 5mg BID Plus Metformin | Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | 38.2 Percentage of participants |
| Dapagliflozin 10mg OD Plus Metformin | Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | 28.1 Percentage of participants |
| Placebo Plus Metformin | Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | 21.4 Percentage of participants |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.045595% CI: [0.2, 24.1]Regression, Logistic
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.006295% CI: [4.8, 28.9]Regression, Logistic