Type 2 Diabetes
Conditions
Brief summary
The purpose of this clinical research study is to learn if BMS-512148, added to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone), can help reduce the blood sugar levels compared to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone) alone, in subjects with type 2 diabetes. The safety of this treatment will also be studied.
Interventions
DRUGDapagliflozin
Tablets, Oral, once daily, up to 12 weeks
DRUGPlacebo
Tablets, Oral, 0 mg, once daily, up to 12 weeks
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Males and females, 18 to 75 years old, with type 2 diabetes with inadequate glycemic control * Subjects receiving insulin and metformin and/or a thiazolidinedione * Body Mass Index \<=45.0 kg/m2 * Serum creatinine \<1.5 mg/dL for men or \<1.4 mg/dL for women * No overt proteinuria (in subjects with a microalbumin/creatinine ratio ≥300 mg/g, the 24-hour urinary excretion of total protein must be \<3 g/24 hrs)
Exclusion criteria
* History of type 1 diabetes * AST and/or ALT \>2.5 times the upper limit of normal * Creatinine kinase ≥3 times the upper limit of normal * Symptoms of severely uncontrolled diabetes * History of hypoglycemic unawareness * Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | From Baseline to Week 12 | HbA1c was measured as percent of hemoglobin by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 6, 8, 10, and 12 in the double-blind period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | From Baseline to Week 12 | Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 6, 8, 10, and 12 in the double-blind period. |
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | From Baseline to Week 12 | Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. |
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | From Baseline to Week 12 | Therapeutic glycemic response is defined as HbA1c \<=6.5%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. |
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | From Baseline to Week 12 | Therapeutic glycemic response is defined as HbA1c decrease from baseline \>= 0.5% at Week 12. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. |
| Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2 | From Baseline to Week 12 | Baseline TDDI was reduced by 50% prior to treatment, except 2 subjects. TDDI could be up-titrated according to prespecified criteria at Weeks 4, 6, 8, 10 and 12 in the double-blind period. |
Countries
Canada, United States
Participant flow
Recruitment details
Of 163 participants enrolled, Of these 163 participants, 71 were randomized and received treatment. Of these 71 participants, 60 completed double-blind treatment period
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 20 mg Tablets, oral, once daily for 12 weeks | 24 |
| Placebo Tablets, oral, once daily for 12 weeks | 23 |
| Dapagliflozin 10 mg Tablets, oral, once daily for 12 weeks | 24 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cohort 2 | Adverse Event | 1 | 1 | 1 |
| Cohort 2 | Lack of Efficacy | 0 | 2 | 1 |
| Cohort 2 | Lost to Follow-up | 0 | 1 | 0 |
| Cohort 2 | non-compliance, not met criteria, etc | 1 | 1 | 0 |
| Cohort 2 | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Dapagliflozin 20 mg | Placebo | Dapagliflozin 10 mg |
|---|---|---|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 8.92 | 56.1 Years STANDARD_DEVIATION 10.63 | 58.4 Years STANDARD_DEVIATION 6.49 | 55.7 Years STANDARD_DEVIATION 9.2 |
| Age, Customized 65 years or older | 12 Participants | 4 Participants | 4 Participants | 4 Participants |
| Age, Customized Younger than 65 years | 59 Participants | 20 Participants | 19 Participants | 20 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Back/African American | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 67 Participants | 23 Participants | 22 Participants | 22 Participants |
| Sex/Gender, Customized Female | 29 Participants | 11 Participants | 7 Participants | 11 Participants |
| Sex/Gender, Customized Male | 42 Participants | 13 Participants | 16 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 24 | 12 / 23 | 12 / 24 |
| serious Total, serious adverse events | 1 / 24 | 1 / 23 | 0 / 24 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
HbA1c was measured as percent of hemoglobin by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 6, 8, 10, and 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 0.09 % of hemoglobin | Standard Error 0.1406 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | -0.61 % of hemoglobin | Standard Error 0.1276 |
| Dapagliflozin 20 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | -0.69 % of hemoglobin | Standard Error 0.1278 |
95% CI: [-1.08, -0.32]
95% CI: [-1.16, -0.4]
Secondary
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 6, 8, 10, and 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing FPG values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 17.80 mg/dL | Standard Error 8.1941 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 2.36 mg/dL | Standard Error 7.9992 |
| Dapagliflozin 20 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | -9.64 mg/dL | Standard Error 7.9908 |
95% CI: [-38.37, 7.48]
95% CI: [-50.33, -4.55]
Secondary
Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2
Baseline TDDI was reduced by 50% prior to treatment, except 2 subjects. TDDI could be up-titrated according to prespecified criteria at Weeks 4, 6, 8, 10 and 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing TDDI values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2 | 1.69 units/day | Standard Error 2.7659 |
| Dapagliflozin 10 mg | Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2 | -1.35 units/day | Standard Error 2.6489 |
| Dapagliflozin 20 mg | Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2 | -0.83 units/day | Standard Error 2.6484 |
95% CI: [-10.69, 4.6]
95% CI: [-10.17, 5.12]
Secondary
Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
Therapeutic glycemic response is defined as HbA1c \<=6.5%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 0 Participants | 5.3 |
| Dapagliflozin 10 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 1 Participants | 13 |
| Dapagliflozin 20 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 0 Participants | 4.3 |
Secondary
Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 1 Participants | 5.3 |
| Dapagliflozin 10 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 3 Participants | 13 |
| Dapagliflozin 20 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 1 Participants | 4.3 |
Secondary
Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
Therapeutic glycemic response is defined as HbA1c decrease from baseline \>= 0.5% at Week 12. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time frame: From Baseline to Week 12
Population: Chort 2 all randomized participants who received study medication and had nonmissing values at baseline and Week 12 (LOCF). Note: participants in cohort 1 provided data to establish an acceptable safety and tolerability profile when dapagliflozin 20 mg was added to open-label oral antidiabetic agent plus insulin.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 3 Participants | 5.3 |
| Dapagliflozin 10 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 15 Participants | 13 |
| Dapagliflozin 20 mg | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | 15 Participants | 4.3 |