Type 2 Diabetes Mellitus
Conditions
Brief summary
This research study of subjects with inadequately controlled type 2 diabetes mellitus (T2DM) will compare the glycemic control (measured by HbA1c) in subjects co-administered saxagliptin and dapagliflozin, in addition to metformin with or without sulfonylurea, to subjects receiving insulin glargine, in addition to metformin with or without sulfonylurea, over a treatment period of 52 weeks.
Detailed description
CV181-369; A 24 Week International, Open-Label Trial With a 28 Week Extension to Evaluate the Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Insulin Glargine in Subjects With Type 2 Diabetes on Metformin With or Without Sulfonylurea Therapy
Interventions
DRUGSaxagliptin, Onglyza
Tablets, Oral, 5mg , Once daily, 24 weeks
DRUGDapagliflozin, Farxiga
Tablets, Oral, 10mg , Once daily, 24 weeks
DRUGGlargine insulin
100 Units/ml solution for injection in a prefilled SoloStar pen
DRUGMetformin
Tablets, Oral, ≥ 1500mg/≤ 2500mg, Once daily, 24 weeks
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * At least 18 years of age at screening * HbA1c ≥ 8% and ≤ 12% at screening * Fasting plasma glucose (FPG) ≤ 270 mg/dL (15mmol/L) * Stable dose metformin ≥ 1500 mg per day with or without a stable dose of sulfonylurea (defined as at least 50% maximal dose per local label) for at least 8 weeks * estimated glomerular filtration rate (eGFR) < 60 ml/ml/1.73m2 * Body Mass Index ≤ 45.0 kg/m2
Exclusion criteria
* Clinical diagnosis of Type 1 diabetes * History of ketoacidosis * Renal, hepatic or pancreatic disease * Impairment of renal function (defined as creatinine clearance \[CrCl\] \< 60 mL/min * Cardiovascular or vascular diseases identified within 3 months of participationImpairment of renal function (defined as creatinine clearance \[CrCl\] \< 60 mL/min
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in HbA1c at Week 24 | Baseline and Week 24 | To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 0.3%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Total Body Weight at Week 24 | Baseline and Week 24 | To compare the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment |
| Percentage of Subjects With Confirmed Hypoglycaemia at Week 24 | Baseline and Week 24 | Hypoglycemia defined as plasma glucose ≤70 mg/dL (3.9 mmol/L) |
| Percentage of Subjects Achieving a Therapeutic Glycemic Response, Without Hypoglycaemia, at Week 24 | Baseline and Week 24 | To compare the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c \<7.0%, without any reported hypoglycemia, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. |
| Percentage of Subjects Achieving a Therapeutic Glycemic Response at Week 24 | Baseline and Week 24 | To examine whether the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c \<7.0%, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 10%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. |
| Change From Baseline in the Mean Value of 24-hour Glucose at Week 2 | Baseline and Week 2 | Change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior to titrated insulin glargine plus metformin with or without SU after 2 weeks of open-label treatment. |
Countries
Czechia, Denmark, Hungary, Mexico, Poland, Romania, South Africa, Spain, Sweden, United States
Participant flow
Recruitment details
This study was conducted at 112 centers in 11 countries from 20 Oct 2015 to 10 Nov 2017. There were 2 data cut-offs for this study: 8 May 2017 for analyses of the short-term study period (after 24 weeks of open-label treatment) and 10 Nov 2017 for analyses of the short-term plus long-term study period (after 52 weeks of open-label treatment).
Pre-assignment details
The study duration was up to 56 weeks, consisting of a 2-week screening period, 2-week lead-in period, 24-week short-term treatment period, and 28-week long-term treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin + Saxagliptin + Metformin Subjects received dapagliflozin 10 mg and saxagliptin 5 mg, administered orally QD in the morning for the 52-week treatment period (24-week short-term period and 28-week long term period).
Subjects continued to receive their stable dose of metformin with or without SU throughout the study. | 324 |
| Titrated Insulin + Metformin Subjects were to administer insulin glargine subcutaneously QD at the same time every day for the 52-week treatment period (24-week short-term period and 28-week long term period), following investigator instructions and training. All subjects started with an initial dose of 0.2 units/kg body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. The investigator had the discretion to modify insulin dose based on his/her assessment between Week 8 and Week 12 with the goal to reach an acceptable and stable insulin dose by Week 12.
Subjects continued to receive their stable dose of metformin with or without SU throughout the study. | 319 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not enter long-term study | 18 | 25 |
| Overall Study | Did not receive randomized treatment | 0 | 7 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Reason not reported | 10 | 4 |
Baseline characteristics
| Characteristic | Titrated Insulin + Metformin | Total | Dapagliflozin + Saxagliptin + Metformin |
|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 9.63 | 55.5 Years STANDARD_DEVIATION 9.57 | 55.7 Years STANDARD_DEVIATION 9.52 |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 6 Participants | 18 Participants | 12 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 24 Participants | 12 Participants |
| Race/Ethnicity, Customized Black Or African American | 35 Participants | 63 Participants | 28 Participants |
| Race/Ethnicity, Customized Native Hawaiian Or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 20 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 254 Participants | 517 Participants | 263 Participants |
| Sex: Female, Male Female | 148 Participants | 296 Participants | 148 Participants |
| Sex: Female, Male Male | 171 Participants | 347 Participants | 176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 324 | 0 / 319 |
| other Total, other adverse events | 55 / 324 | 73 / 319 |
| serious Total, serious adverse events | 20 / 324 | 13 / 319 |
Outcome results
Primary
Mean Change From Baseline in HbA1c at Week 24
To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 0.3%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment.
Time frame: Baseline and Week 24
Population: The randomized subjects data set consisted of all randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Mean Change From Baseline in HbA1c at Week 24 | -1.67 % HbA1c |
| Titrated Insulin + Metformin | Mean Change From Baseline in HbA1c at Week 24 | -1.54 % HbA1c |
p-value: 0.11895% CI: [-0.3, 0.03]Mixed Models Analysis
Secondary
Change From Baseline in the Mean Value of 24-hour Glucose at Week 2
Change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior to titrated insulin glargine plus metformin with or without SU after 2 weeks of open-label treatment.
Time frame: Baseline and Week 2
Population: The randomized subject data set consisted of all randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Change From Baseline in the Mean Value of 24-hour Glucose at Week 2 | -48.53 mg/deciliter (dL) |
| Titrated Insulin + Metformin | Change From Baseline in the Mean Value of 24-hour Glucose at Week 2 | -28.54 mg/deciliter (dL) |
p-value: <0.000195% CI: [-26.98, -13]Mixed Models Analysis
Secondary
Mean Change From Baseline in Total Body Weight at Week 24
To compare the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment
Time frame: Baseline and Week 24
Population: The number of participants is the number of subjects in the randomized subject data set with non-missing baseline assessments and at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Mean Change From Baseline in Total Body Weight at Week 24 | -1.50 kg |
| Titrated Insulin + Metformin | Mean Change From Baseline in Total Body Weight at Week 24 | 2.14 kg |
p-value: <0.00195% CI: [-4.2, -3.09]Mixed Models Analysis
Secondary
Percentage of Subjects Achieving a Therapeutic Glycemic Response at Week 24
To examine whether the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c \<7.0%, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 10%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment.
Time frame: Baseline and Week 24
Population: The randomized subject data set consisted of all randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Percentage of Subjects Achieving a Therapeutic Glycemic Response at Week 24 | 33.2 Adjusted % Participants |
| Titrated Insulin + Metformin | Percentage of Subjects Achieving a Therapeutic Glycemic Response at Week 24 | 33.5 Adjusted % Participants |
95% CI: [-7.42, 6.54]
Secondary
Percentage of Subjects Achieving a Therapeutic Glycemic Response, Without Hypoglycaemia, at Week 24
To compare the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c \<7.0%, without any reported hypoglycemia, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment.
Time frame: Baseline and Week 24
Population: The randomized subject data set consisted of all randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Without Hypoglycaemia, at Week 24 | 20.9 Adjusted % Participants |
| Titrated Insulin + Metformin | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Without Hypoglycaemia, at Week 24 | 13.1 Adjusted % Participants |
p-value: 0.00895% CI: [1.16, 2.67]Regression, Logistic
Secondary
Percentage of Subjects With Confirmed Hypoglycaemia at Week 24
Hypoglycemia defined as plasma glucose ≤70 mg/dL (3.9 mmol/L)
Time frame: Baseline and Week 24
Population: The randomized subject data set consisted of all randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Percentage of Subjects With Confirmed Hypoglycaemia at Week 24 | 21.3 Adjusted % Participants |
| Titrated Insulin + Metformin | Percentage of Subjects With Confirmed Hypoglycaemia at Week 24 | 38.4 Adjusted % Participants |
p-value: <0.00195% CI: [0.3, 0.62]Regression, Logistic