Type 2 Diabetes
Conditions
Brief summary
Study will evaluate if a combination of saxagliptin and dapagliflozin added concurrently to metformin in combination with diet and exercise is superior to sitagliptin added to metformin in combination with diet and exercise in reducing mean HbA1c over a treatment period of 26 weeks.
Interventions
DRUGSaxagliptin
administered orally once daily
DRUGDapagliflozin
administered orally once daily
DRUGSitagliptin
administered orally once daily
administered orally once daily
administered orally once daily
DRUGPlacebo matching with Sitagliptin
administered orally once daily
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: * Patients with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control, defined as a central laboratory glycosylated hemoglobin (HbA1c) ≥8.0% and ≤ 10.5 % obtained at the screening visit * Subjects should have been taking the same daily dose of metformin ≥ 1500 mg for at least 8 weeks prior to the enrollment visit and with no intake of other antihyperglycemic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening * BMI \> 20.0 kg/m2 at the enrollment visit * Males and Females, age ≥18 years old at time of screening visit * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug * Women must not be breastfeeding
Exclusion criteria
* Clinically diagnosed with Type I diabetes, known diagnosis of Maturity Onset Diabetes of Young (MODY), secondary diabetes mellitus or diabetes insipidus * History of diabetic ketoacidosis * Any of the following cardiovascular (CV)/Vascular Diseases within 3 months of the enrollment visit * Myocardial infarction * Cardiac surgery or revascularization (coronary artery bypass surgery Coronary Artery Bypass Graft \[(CABG)\]/percutaneous transluminal coronary angioplasty percutaneous transluminal coronary angioplasty \[(PTCA)\]) * Unstable angina * Unstable congestive heart failure (CHF) * Transient ischemic attack (TIA) or significant cerebrovascular disease * Unstable or previously undiagnosed arrhythmia * Congestive heart failure, defined as New York Heart Association (NYHA) Class III and IV, unstable or acute congestive heart failure and/or known left ventricular ejection fraction of ≤ 40% * Renal Disease * Hepatic Diseases * Hematological and Oncological Disease/Conditions * Hemoglobin ≤ 11.0 g/dL (110 g/L) for men; hemoglobin ≤ 10.0 g/dL (100 g/L) for women * Abnormal Free T4
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Change in HbA1c | Baseline (randomization) to Week 26 |
Secondary
| Measure | Time frame |
|---|---|
| Percent of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0% | week 26 |
| Mean Change in Total Body Weight | Baseline (randomization) to Week 26 |
| Mean Change in Fasting Plasma Glucose (FPG) | Baseline (randomization) to Week 26 |
Countries
Hungary, Mexico, Poland, Romania, South Africa, United States
Participant flow
Recruitment details
461 Patients were Randomized into the study, 411 patients completed the 26 weeks part. Out of them 402 patients continued into the additional 26 week part. Out of them 378 patients completed the 52 weeks period (26+26 weeks).
Participants by arm
| Arm | Count |
|---|---|
| SAXA + DAPA + MET Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy | 232 |
| SITA + MET Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy | 229 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 26 Week (Short Term) | Adverse Event | 1 | 9 |
| 26 Week (Short Term) | Discontinuation by the subject | 2 | 2 |
| 26 Week (Short Term) | Lost to Follow-up | 3 | 1 |
| 26 Week (Short Term) | Other | 1 | 1 |
| 26 Week (Short Term) | Subject no longer meets study criteria | 5 | 8 |
| 26 Week (Short Term) | Withrawal of the consent by the subject | 7 | 10 |
| 52 Week (Long Term) | Adverse Event | 3 | 1 |
| 52 Week (Long Term) | Lost to Follow-up | 2 | 2 |
| 52 Week (Long Term) | Non-Compliance | 2 | 3 |
| 52 Week (Long Term) | Subject no longer meets study criteria | 0 | 1 |
| 52 Week (Long Term) | Withrawal of the consent by the subject | 4 | 6 |
Baseline characteristics
| Characteristic | SAXA + DAPA + MET | SITA + MET | Total |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 8.87 | 55.8 years STANDARD_DEVIATION 9.55 | 55.9 years STANDARD_DEVIATION 9.21 |
| Region of Enrollment Central America | 46 participants | 42 participants | 88 participants |
| Region of Enrollment Europe | 72 participants | 74 participants | 146 participants |
| Region of Enrollment North America | 114 participants | 113 participants | 227 participants |
| Sex: Female, Male Female | 132 Participants | 119 Participants | 251 Participants |
| Sex: Female, Male Male | 100 Participants | 110 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 232 | 0 / 229 |
| other Total, other adverse events | 112 / 232 | 123 / 229 |
| serious Total, serious adverse events | 9 / 232 | 13 / 229 |
Outcome results
Primary
Mean Change in HbA1c
Time frame: Baseline (randomization) to Week 26
Population: The Randomized Subjects data set consists of all randomized subjects who received at least~1 dose of double-blind study drug during the double-blind treatment period. Data in this data set were analyzed based on randomized treatment group, even if the treatment they received was different
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Dapagliflozin + Metformin Group | Mean Change in HbA1c | -1.41 percentage (%) | Standard Error 0.0696 |
| SITA + MET | Mean Change in HbA1c | -1.07 percentage (%) | Standard Error 0.0719 |
p-value: 0.0008Mixed Models Analysis
Secondary
Mean Change in Fasting Plasma Glucose (FPG)
Time frame: Baseline (randomization) to Week 26
Population: randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Dapagliflozin + Metformin Group | Mean Change in Fasting Plasma Glucose (FPG) | -31.9 mg/dl | Standard Error 2.538 |
| SITA + MET | Mean Change in Fasting Plasma Glucose (FPG) | -11.0 mg/dl | Standard Error 2.668 |
p-value: 0.0001Mixed Models Analysis
Secondary
Mean Change in Total Body Weight
Time frame: Baseline (randomization) to Week 26
Population: randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Dapagliflozin + Metformin Group | Mean Change in Total Body Weight | -1.86 kg | Standard Error 0.201 |
| SITA + MET | Mean Change in Total Body Weight | -0.51 kg | Standard Error 0.2078 |
p-value: 0.0001Mixed Models Analysis
Secondary
Percent of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%
Time frame: week 26
Population: randomized subjects
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Saxagliptin + Dapagliflozin + Metformin Group | Percent of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0% | 37.3 Percentage of subjects | 3.15 |
| SITA + MET | Percent of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0% | 25.1 Percentage of subjects | 2.871 |
p-value: 0.0034Regression, Logistic