Type 2 Diabetes Mellitus
Conditions
Keywords
Saxagliptin, Acarbose, Type 2 Diabetes, Metformin
Brief summary
SMART Study - A 24-Week, Multicenter, Randomized, Parallel-group, Open-label, Active Controlled Phase IV Study to Assess the Efficacy, Safety and Tolerability of Saxagliptin Compared with Acarbose when in Combination with Metformin in Patients with Type 2 Diabetes Mellitus (T2D) Inadequately Controlled with Metformin Monotherapy
Interventions
DRUGSaxagliptin
The dose of saxaglitpin will be 5mg oral qd.
DRUGAcarbose
Patients who take acarbose will begin with 50mg tid for 7 days then be titrated to 100mg tid till the end of the study. A call visit (V5) will be performed at Week 1 for adverse event and reminding patients the dose titration of acrabose.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 150 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosed with type 2 diabetes mellitus 2. Men and women (non-pregnant and using a medically approved birth-control method) aged at least 18 years at screening. 3. T2D patients treated with stable metformin monotherapy for at least 8 weeks prior to screening. Metformin dose should be ≥ 1500 mg/day (or individual maximally tolerated dose), but not more than the maximum dose specified in the label 4. HbA1c ≥ 7.5% and ≤ 11.0% at screening or within 4 weeks prior to screening (by local laboratory) and HbA1c ≥ 7.0% and ≤ 11.0% at pre-randomization visit (by central laboratory) 5. FPG ≤ 13.3 mmol/L (≤ 240 mg/dL) at pre-randomization visit (by central laboratory) 6. Able and willing to provide written informed consent and to comply with the study protocol
Exclusion criteria
1. Women who are pregnant, intending to become pregnant during the study period, lactating females, or women of child-bearing potential not using highly effective, medically approved birth control methods. 2. Diagnosis or history of: 1. Type 1 diabetes mellitus, diabetes resulting from pancreatic injury or secondary forms of diabetes, eg, acromegaly or Cushing's syndrome. 2. Acute metabolic diabetic complications such as ketoacidosis or hyperosmolar coma within the past 6 months. 3. Previous treatment with any dipeptidyl peptidase-4 (DPP4) inhibitor or GLP-1 receptor agonists within the past one year. 4. History of hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to dipeptidyl peptidase-4 inhibitor (DPP4) or Acarbose. 5. Treatment with any anti-diabetic medication for more than 7 consecutive days other than metformin in the last 8 weeks prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in HbA1c at Week 24 (DAO) | From baseline to 24 week | Primary Objective: Efficacy of saxagliptin plus metformin on glycemic control compared with acarbose plus metformin in patients with T2D inadequately controlled with metformin. By Measure absolute change from baseline in HbA1c at Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion (%) of Patients Achieving a Therapeutic Glycemic Response Defined as HbA1c<7.0% | 24 weeks | Secondary Objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure proportion (%) of patients achieving a therapeutic glycemic response defined as HbA1c\<7.0% |
| Proportion (%) of Patients Achieving HbA1c<7.0% Without GI Adverse Events | Whole study duration | Secondary Objective: Assessment of any gastrointestinal adverse events of saxagliptin versus acarbose. by measure proportion (%) of patients achieving HbA1c\<7.0% without GI adverse events. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | From baseline to 24 week | Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24 |
| Proportion (%) of Patients With Any GI Adverse Events | 24 weeks | Secondary Objective: Assessment of any gastrointestinal adverse events of saxagliptin versus acarbose. by measure proportion (%) of patients with any gastrointestinal adverse events. |
| Change From Baseline in HOMA-β | From baseline to 24 week | Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function was estimated by the Homeostasis model assessment-β (HOMA-β), which was defined as fasting insulin (mU/mL) x 20 / (fasting glucose (mmol/mL) - 3.5, body weight at week 24 |
| Change From Baseline in Body Weight | From baseline to 24 week | Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24 |
| Change From Baseline in 2H Postprandial Glucose (2HPPG) | From baseline to 24 week | Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24 |
Countries
China
Participant flow
Recruitment details
A total of 689 patients were enrolled into this study from 35 sites in China. The enrolled patient number ranged from 10 to 58 among 24 centers, and 2 to 9 patients from eight centers, none was enrolled in 3 centers. The enrolment period was from 24 Sep 2014 to 29 Sep 2015.
Pre-assignment details
A total of 201 patients were enrolled but not randomized: 171 patients did not meet eligibility criteria, and 24 patients were voluntary discontinuations, two patients developed study-specific withdrawal criteria, one patient lost follow-up, and three patient failed due to other reasons
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin The dose of saxaglitpin will be 5mg oral qd. An estimated total of 480 patients (240 per treatment arm) will be randomized in a 1:1 ratio to the active treatment arm and the active comparator arm. So estimated 240 patients will be allocated to this arm. | 238 |
| Acarbose Patients who take acarbose will begin with 50mg tid for 7 days then be titrated to 100mg tid till the end of the study. A call visit (V5) will be performed at Week 1 for adverse event and reminding patients the dose titration of acrabose. An estimated total of 480 patients (240 per treatment arm) will be randomized in a 1:1 ratio to the active treatment arm and the active comparator arm. So estimated 240 patients will be allocalted to this arm. | 243 |
| Total | 481 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Other reason | 1 | 2 |
| Overall Study | protocol specified withdrawal critera | 1 | 3 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Total | Saxagliptin | Acarbose |
|---|---|---|---|
| 2hPPG | 10.7 mmol/l STANDARD_DEVIATION 2.89 | 11.17 mmol/l STANDARD_DEVIATION 2.82 | 10.25 mmol/l STANDARD_DEVIATION 2.89 |
| Age, Continuous | 55.6 Years STANDARD_DEVIATION 10.69 | 54.7 Years STANDARD_DEVIATION 10.51 | 56.5 Years STANDARD_DEVIATION 10.81 |
| Any current medication，excluding antidiabetic drugs No | 349 Participants | 179 Participants | 170 Participants |
| Any current medication，excluding antidiabetic drugs Yes | 132 Participants | 59 Participants | 73 Participants |
| Any diabetes mellitus complications No | 435 Participants | 214 Participants | 221 Participants |
| Any diabetes mellitus complications Yes | 46 Participants | 24 Participants | 22 Participants |
| Any relevant medical conditions Missing | 108 Participants | 54 Participants | 54 Participants |
| Any relevant medical conditions No | 129 Participants | 65 Participants | 64 Participants |
| Any relevant medical conditions Yes | 244 Participants | 119 Participants | 125 Participants |
| BMI | 26.3 kg/m^2 STANDARD_DEVIATION 3.48 | 26.4 kg/m^2 STANDARD_DEVIATION 3.47 | 26.3 kg/m^2 STANDARD_DEVIATION 3.49 |
| Currently taking antidiabetic medication | 481 Participants | 238 Participants | 243 Participants |
| Duration of diabetes mellitus (years) | 5.2 Years STANDARD_DEVIATION 4.58 | 5.1 Years STANDARD_DEVIATION 4.4 | 5.3 Years STANDARD_DEVIATION 4.76 |
| FPG | 8.90 mmol/l STANDARD_DEVIATION 2.04 | 9.01 mmol/l STANDARD_DEVIATION 2.14 | 8.81 mmol/l STANDARD_DEVIATION 1.95 |
| HbA1c (%) | 8.20 % STANDARD_DEVIATION 0.83 | 8.23 % STANDARD_DEVIATION 0.85 | 8.16 % STANDARD_DEVIATION 0.81 |
| HDL | 1.18 mmol/l STANDARD_DEVIATION 0.3 | 1.16 mmol/l STANDARD_DEVIATION 0.29 | 1.2 mmol/l STANDARD_DEVIATION 0.3 |
| Height | 166.1 cm STANDARD_DEVIATION 7.87 | 166.3 cm STANDARD_DEVIATION 8 | 165.9 cm STANDARD_DEVIATION 7.75 |
| LDL | 2.75 mmol/l STANDARD_DEVIATION 0.84 | 2.73 mmol/l STANDARD_DEVIATION 0.89 | 2.77 mmol/l STANDARD_DEVIATION 0.79 |
| Race/Ethnicity, Customized Asian (China Mainland) | 481 Participants | 238 Participants | 243 Participants |
| Sex: Female, Male Female | 196 Participants | 91 Participants | 105 Participants |
| Sex: Female, Male Male | 285 Participants | 147 Participants | 138 Participants |
| TC | 4.80 mmol/l STANDARD_DEVIATION 1.01 | 4.78 mmol/l STANDARD_DEVIATION 1.07 | 4.82 mmol/l STANDARD_DEVIATION 0.94 |
| Triglycerides | 1.97 mmol/l STANDARD_DEVIATION 1.26 | 1.99 mmol/l STANDARD_DEVIATION 1.12 | 1.96 mmol/l STANDARD_DEVIATION 1.38 |
| Type of diabetes mellitus Other | 0 Participants | 0 Participants | 0 Participants |
| Type of diabetes mellitus Type 2 | 481 Participants | 238 Participants | 243 Participants |
| Weight | 72.9 kg STANDARD_DEVIATION 12.43 | 73.3 kg STANDARD_DEVIATION 12.61 | 72.6 kg STANDARD_DEVIATION 12.27 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 241 | 74 / 244 |
| serious Total, serious adverse events | 5 / 241 | 2 / 244 |
Outcome results
Primary
Absolute Change From Baseline in HbA1c at Week 24 (DAO)
The primary endpoint was analyzed based on Per protocol analysis set as the supportive analysis.
Time frame: From baseline to 24 week
Population: The Per Protocol analysis set was a subset of the Full analysis set that included subjects who did not have significant protocol deviations that affect the study outcome. The exclusions from the PP analysis set was determined prior to database lock.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Absolute Change From Baseline in HbA1c at Week 24 (DAO) | -0.83 % (HbA1c) | Standard Error 0.06 |
| Acarbose | Absolute Change From Baseline in HbA1c at Week 24 (DAO) | -0.80 % (HbA1c) | Standard Error 0.07 |
Comparison: H01: μS-μA≥ 0.4% vs Ha1: μS-μA\< 0.4%. Null hypothesis will be rejected if the upper limit of 2-sided 95% CI is below 0.4%.If the null hypothesis above (H01) is rejected, the following hypothesis will be tested to further establish superiority:~H02: μS-μA≥ 0 vs Ha2: μS-μA\< 0. This null hypothesis (H02) will be rejected if the upper limit of 2-sided 95% CI is below 0.p-value: 0.780995% CI: [-0.21, 0.15]Mixed Model Repeated Measures
Primary
Absolute Change From Baseline in HbA1c at Week 24 (DAO)
Primary Objective: Efficacy of saxagliptin plus metformin on glycemic control compared with acarbose plus metformin in patients with T2D inadequately controlled with metformin. By Measure absolute change from baseline in HbA1c at Week 24
Time frame: From baseline to 24 week
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Absolute Change From Baseline in HbA1c at Week 24 (DAO) | -0.82 % (HbA1c) | Standard Error 0.06 |
| Acarbose | Absolute Change From Baseline in HbA1c at Week 24 (DAO) | -0.78 % (HbA1c) | Standard Error 0.06 |
Comparison: H01: μS-μA≥ 0.4% vs Ha1: μS-μA\< 0.4%. Null hypothesis will be rejected if the upper limit of 2-sided 95% CI is below 0.4%.If the null hypothesis above (H01) is rejected, the following hypothesis will be tested to further establish superiority:~H02: μS-μA≥ 0 vs Ha2: μS-μA\< 0. This null hypothesis (H02) will be rejected if the upper limit of 2-sided 95% CI is below 0.p-value: 0.623695% CI: [-0.22, 0.13]Mixed Model Repeated Measures
Secondary
Change From Baseline in 2H Postprandial Glucose (2HPPG)
Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24
Time frame: From baseline to 24 week
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in 2H Postprandial Glucose (2HPPG) | -0.77 mmol/l | Standard Error 0.176 |
| Acarbose | Change From Baseline in 2H Postprandial Glucose (2HPPG) | -1.07 mmol/l | Standard Error 0.174 |
p-value: 0.224895% CI: [-0.186, 0.791]ANCOVA
Secondary
Change From Baseline in Body Weight
Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24
Time frame: From baseline to 24 week
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Body Weight | -1.36 kg | Standard Error 0.18 |
| Acarbose | Change From Baseline in Body Weight | -2.05 kg | Standard Error 0.18 |
p-value: 0.007895% CI: [0.18, 1.19]Mixed Model Repeated Measures
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function, body weight at week 24
Time frame: From baseline to 24 week
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.99 mmol/l | Standard Error 0.13 |
| Acarbose | Change From Baseline in Fasting Plasma Glucose (FPG) | -1.01 mmol/l | Standard Error 0.13 |
p-value: 0.891595% CI: [-0.33, 0.38]Mixed Model Repeated Measures
Secondary
Change From Baseline in HOMA-β
Secondary objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure change from baseline in fasting plasma glucose, 2h postprandial glucose, β-cell function was estimated by the Homeostasis model assessment-β (HOMA-β), which was defined as fasting insulin (mU/mL) x 20 / (fasting glucose (mmol/mL) - 3.5, body weight at week 24
Time frame: From baseline to 24 week
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in HOMA-β | 20.56 mU/mmol | Standard Error 5.932 |
| Acarbose | Change From Baseline in HOMA-β | 13.08 mU/mmol | Standard Error 5.958 |
p-value: 0.373995% CI: [-9.039, 24.005]ANCOVA
Secondary
Proportion (%) of Patients Achieving a Therapeutic Glycemic Response Defined as HbA1c<7.0%
Secondary Objective: Effects of saxagliptin versus acarbose on the additional parameters, by measure proportion (%) of patients achieving a therapeutic glycemic response defined as HbA1c\<7.0%
Time frame: 24 weeks
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin | Proportion (%) of Patients Achieving a Therapeutic Glycemic Response Defined as HbA1c<7.0% | 38.3 percentage of participants |
| Acarbose | Proportion (%) of Patients Achieving a Therapeutic Glycemic Response Defined as HbA1c<7.0% | 41.5 percentage of participants |
p-value: 0.504495% CI: [0.74, 1.15]Cochran-Mantel-Haenszel
Secondary
Proportion (%) of Patients Achieving HbA1c<7.0% Without GI Adverse Events
Secondary Objective: Assessment of any gastrointestinal adverse events of saxagliptin versus acarbose. by measure proportion (%) of patients achieving HbA1c\<7.0% without GI adverse events.
Time frame: Whole study duration
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin | Proportion (%) of Patients Achieving HbA1c<7.0% Without GI Adverse Events | 37.0 percentage of participants |
| Acarbose | Proportion (%) of Patients Achieving HbA1c<7.0% Without GI Adverse Events | 28.8 percentage of participants |
p-value: 0.051895% CI: [0.98, 1.67]Cochran-Mantel-Haenszel
Secondary
Proportion (%) of Patients With Any GI Adverse Events
Secondary Objective: Assessment of any gastrointestinal adverse events of saxagliptin versus acarbose. by measure proportion (%) of patients with any gastrointestinal adverse events.
Time frame: 24 weeks
Population: The Full analysis set included all randomized subjects who took at least 1 randomized IP dose, and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Saxagliptin | Proportion (%) of Patients With Any GI Adverse Events | NO | 94.5 percentage of participants |
| Saxagliptin | Proportion (%) of Patients With Any GI Adverse Events | YES | 5.5 percentage of participants |
| Acarbose | Proportion (%) of Patients With Any GI Adverse Events | NO | 75.3 percentage of participants |
| Acarbose | Proportion (%) of Patients With Any GI Adverse Events | YES | 24.7 percentage of participants |
p-value: <0.000195% CI: [0.12, 0.39]Cochran-Mantel-Haenszel