Diabetes
Conditions
Brief summary
This clincial trial is evaluating if the co-administration of saxagliptin and dapagliflozin, in addition to metformin, results in better glycemic control, as measured by HbA1c, over a treatment period of 52 weeks, compared to the addition of glimepiride to metformin in subjects with Type 2 Diabetes Mellitus who have inadequate glycemic control on Metformin Alone. We will compare the change from baseline in HbA1c achieved with saxagliptin, in co-administration with dapagliflozin, added to current background therapy with metformin compared to glimepiride added to current background therapy with metformin ≥1500 mg at Week 52.
Interventions
DRUGSaxagliptin
DRUGDapagliflozin
DRUGGlimepiride
OTHERPlacebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
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: * Subjects must be willing and able to give signed and dated written informed consent * Patients with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control * Subjects should have been taking the same daily dose of metformin ≥ 1500 mg * Fasting Plasma Glucose ≤ 270 mg/dL (≤15 mmol/L) * Males and females, aged ≥18 years old at time of screening visit * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test * WOCBP and males must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug
Exclusion criteria
* Clinical diagnosis of type I diabetes * History of diabetic ketoacidosis * Cardiovascular/vascular diseases within 3 months of the enrollment * Renal disease * Hepatic diseases * History of, or currently, acute or chronic pancreatitis * Hematological and oncological disease/conditions * Patients who have contraindications to therapy being studied * Patients on weight loss program(s) * Replacement or chronic systemic corticosteroid therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52 | Baseline and Week 52 | To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52 | At Week 52 | Therapeutic glycemic response was defined as HbA1c \<7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c. |
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 | Baseline and Week 52 | To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. |
| Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period | Up to Week 52 | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short -term treatment period. |
| Change From Baseline in Total Body Weight at Week 52 | Baseline and Week 52 | To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. |
| Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156 | At Week 156 | Therapeutic glycemic response was defined as HbA1c \<7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c. |
| Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | Up to Week 156 | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. Time to treatment intensification curves were generated using Kaplan-Meier estimates and compared using a Cox proportional hazards model. |
| Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | Up to Week 156 | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week treatment period. |
Countries
Czechia, Germany, Hungary, Mexico, Poland, Romania, Russia, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 444 subjects were randomized in this international, multi-center study which was conducted at 88 centers in 10 countries between 14 Aug 2015 and 18 September 2019.
Pre-assignment details
The study duration was up to 160 weeks, consisting of a 2-week screening period, 2-week lead-in period, 52-week short-term treatment period, and 104-week long-term treatment period (156-week treatment period). One subject did not start the short-term treatment period and so only 443 subjects received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day | 227 |
| Titrated Glimepiride Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day. | 216 |
| Total | 443 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Treatment Period | Adverse Event | 0 | 5 |
| Long-term Treatment Period | Death | 0 | 1 |
| Long-term Treatment Period | Lack of Efficacy | 1 | 1 |
| Long-term Treatment Period | Lost to Follow-up | 6 | 4 |
| Long-term Treatment Period | Non-compliance with Study Drug | 1 | 1 |
| Long-term Treatment Period | Other | 4 | 4 |
| Long-term Treatment Period | Subject Decision | 2 | 4 |
| Long-term Treatment Period | Withdrawal by Subject | 8 | 2 |
| Short-term Treatment Period | Adverse Event | 1 | 1 |
| Short-term Treatment Period | Death | 0 | 2 |
| Short-term Treatment Period | Lost to Follow-up | 6 | 6 |
| Short-term Treatment Period | Non-compliance with Study Drug | 0 | 2 |
| Short-term Treatment Period | Subject moved out of state | 0 | 1 |
| Short-term Treatment Period | Subject Request To Discontinue Treatment | 1 | 1 |
| Short-term Treatment Period | Withdrawal by Subject | 9 | 9 |
| Short-term Treatment Period | Worsening of liver function | 0 | 1 |
Baseline characteristics
| Characteristic | Titrated Glimepiride | Total | Dapagliflozin 10mg and Saxagliptin 5mg |
|---|---|---|---|
| Age, Continuous | 56.1 Years STANDARD_DEVIATION 9.23 | 56.1 Years STANDARD_DEVIATION 9.68 | 56.1 Years STANDARD_DEVIATION 10.11 |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 10 Participants | 21 Participants | 11 Participants |
| Race/Ethnicity, Customized Black Or African American | 5 Participants | 9 Participants | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian Or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 10 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 196 Participants | 402 Participants | 206 Participants |
| Sex: Female, Male Female | 115 Participants | 225 Participants | 110 Participants |
| Sex: Female, Male Male | 101 Participants | 218 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 227 | 3 / 216 |
| other Total, other adverse events | 99 / 227 | 106 / 216 |
| serious Total, serious adverse events | 29 / 227 | 24 / 216 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52
To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time frame: Baseline and Week 52
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52 | -1.35 % HbA1c |
| Titrated Glimepiride | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52 | -0.98 % HbA1c |
p-value: <0.00195% CI: [-0.57, -0.18]Mixed Models Analysis
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) at Week 52
To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time frame: Baseline and Week 52
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 | -2.6 mmHg |
| Titrated Glimepiride | Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 | 1.0 mmHg |
p-value: 0.00795% CI: [-6.3, -1]Mixed Models Analysis
Secondary
Change From Baseline in Total Body Weight at Week 52
To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time frame: Baseline and Week 52
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Change From Baseline in Total Body Weight at Week 52 | -3.11 kilogram (kg) |
| Titrated Glimepiride | Change From Baseline in Total Body Weight at Week 52 | 0.95 kilogram (kg) |
p-value: <0.00195% CI: [-4.84, -3.28]Mixed Models Analysis
Secondary
Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156
Therapeutic glycemic response was defined as HbA1c \<7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
Time frame: At Week 156
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156 | 21.4 Percentage of Subjects |
| Titrated Glimepiride | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156 | 11.7 Percentage of Subjects |
p-value: 0.00695% CI: [1.23, 3.42]Regression, Logistic
Secondary
Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52
Therapeutic glycemic response was defined as HbA1c \<7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
Time frame: At Week 52
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52 | 44.3 Percentage of subjects |
| Titrated Glimepiride | Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52 | 34.3 Percentage of subjects |
p-value: 0.04495% CI: [1.01, 2.29]Regression, Logistic
Secondary
Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period.
Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week treatment period.
Time frame: Up to Week 156
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | 37.0 Percentage of Subjects |
| Titrated Glimepiride | Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | 55.6 Percentage of Subjects |
Comparison: Time to treatment intensification was analyzed using a Cox proportional hazards model.p-value: <0.00195% CI: [0.39, 0.68]Regression, Cox Proportional Hazards
Secondary
Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period
Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short -term treatment period.
Time frame: Up to Week 52
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period | 1.3 Percentage of Subjects |
| Titrated Glimepiride | Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period | 8.8 Percentage of Subjects |
Comparison: Time to treatment intensification was analyzed using a Cox proportional hazards model.p-value: 0.00295% CI: [0.04, 0.5]Regression, Cox Proportional Hazards
Secondary
Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period.
Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. Time to treatment intensification curves were generated using Kaplan-Meier estimates and compared using a Cox proportional hazards model.
Time frame: Up to Week 156
Population: The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapagliflozin 10mg and Saxagliptin 5mg | Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | NA Weeks |
| Titrated Glimepiride | Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | 92.3 Weeks |
p-value: <0.00195% CI: [0.39, 0.68]Regression, Cox Proportional Hazards