Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Dipeptidyl-Peptidase 4 Inhibitors, Saxagliptin, Metformin, Endocrine System Diseases
Brief summary
A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin in Combination with Metformin IR as Initial Therapy Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Subjects with Type 2 Diabetes who have Inadequate Glycaemic Control
Detailed description
Allocation: Randomized Endpoint Classification: Efficacy/Safety study Intervention Model: Parallel Assignment Masking: Double Blind Primary Purpose: Treatment
Interventions
DRUGSaxagliptin 5 mg
Tablet, Oral, 5 mg, Once daily in the morning
DRUGPlacebo 5 mg for Saxagliptin
Tablet, Oral, 5 mg, Once daily in the morning
DRUGPlacebo 500 mg for metformin (with titration)
Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration.
DRUGMetformin 500 mg with titration
Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1\. Subjects with type 2 diabetes mellitus; 2. HbA1c ≥8% but ≤12%; 3.Fasting C-peptide ≥1.0 ng/ml; 4. Subject will be drug naïve; 5. Body mass index ≤40 kg/m2.
Exclusion criteria
1\. Symptoms of poorly controlled diabetes; 2. Chronic or repeated intermittent corticosteroid treatment ; 3. Calculated creatinine clearance \<60 ml/min or serum creatinine \>132.6 μmol/L (\>1.5 mg/dL) for men, \>123.8 μmol/L (\>1.4 mg/dL) for women; 4. Creatine Kinase ≥3x ULN; 5.Abnormal TSH value at screening will be further evaluated by free T4, subjects with an abnormal free T4 will be excluded; 6. History of administration of any antihyperglycaemic therapy for a total of 28 days or for more than three consecutive days or a total of seven non-consecutive days during the eight weeks prior to screening; 7. Current treatment with a strong CYP3A4/5 inhibitor; 8. Prior treatment with saxagliptin or any DPP-4 inhibitor; 9. Significant or history of cardiovascular disease, renal disease, psychiatric disorders, Immunocompromised individuals, hemoglobinopathies, liver disease, Pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | Baseline to Week 24 (prior to rescue) | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in HbA1c (%) at the end of 24 weeks of double-blinded treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | Baseline to Week 24 prior to rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in fasting plasma glucose at the end of 24 weeks of double-blinded treatment. |
| Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | Baseline to Week 24 prior to rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 180-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. |
| Glycemic Response Defined as HbA1c < 7.0% at Week 24 | Week 24 (prior to rescue) | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c \< 7.0% at the end of 24 weeks of double-blinded treatment. |
| Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | Baseline to Week 24 prior to rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 120-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. |
| Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | Baseline to Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 weeks of double-blinded treatment. |
| Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | Week 24 (prior to rescue) | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c ≤ 6.5% at the end of 24 weeks of double-blinded treatment. |
Countries
China
Participant flow
Recruitment details
The study was conducted in 25 centers between 18 December 2014 and 03 August 2016.
Pre-assignment details
The study duration was up to 27 weeks, consisting of an initial screening period lasting up to 2 weeks, a 1-week lead-in period, and a 24-week treatment period. The number of subjects who signed the ICF is 1136, the number of subjects randomized is 640.
Participants by arm
| Arm | Count |
|---|---|
| METFORMIN + PLACEBO 5MG QD | 210 |
| SAXAGLIPTIN 5MG QD + METFORMIN | 216 |
| SAXAGLIPTIN 5MG QD + PLACEBO | 214 |
| Total | 640 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 3 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Dev. of study spec. withdrawal criteria | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 |
| Overall Study | Protocol Violation | 3 | 1 | 4 |
| Overall Study | Withdrawal by Subject | 17 | 14 | 16 |
Baseline characteristics
| Characteristic | METFORMIN + PLACEBO 5MG QD | SAXAGLIPTIN 5MG QD + METFORMIN | SAXAGLIPTIN 5MG QD + PLACEBO | Total |
|---|---|---|---|---|
| Age, Continuous | 50.1 Years STANDARD_DEVIATION 11.08 | 50.4 Years STANDARD_DEVIATION 10.78 | 49.5 Years STANDARD_DEVIATION 10.93 | 50.0 Years STANDARD_DEVIATION 10.92 |
| Race/Ethnicity, Customized Asian | 210 Participants | 216 Participants | 214 Participants | 640 Participants |
| Sex: Female, Male Female | 76 Participants | 76 Participants | 62 Participants | 214 Participants |
| Sex: Female, Male Male | 134 Participants | 140 Participants | 152 Participants | 426 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 | 30 / 210 | 37 / 215 | 21 / 214 |
| serious Total, serious adverse events | 11 / 210 | 4 / 215 | 12 / 214 |
Outcome results
Primary
Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in HbA1c (%) at the end of 24 weeks of double-blinded treatment.
Time frame: Baseline to Week 24 (prior to rescue)
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | -3.007 % HbA1c | Standard Error 0.0706 |
| Saxagliptin + Placebo | Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | -2.123 % HbA1c | Standard Error 0.0701 |
| Metformin + Placebo | Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | -2.794 % HbA1c | Standard Error 0.0715 |
p-value: <0.00195% CI: [-1.08, -0.689]ANCOVA
p-value: 0.03495% CI: [-0.41, -0.016]ANCOVA
Secondary
Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 120-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment.
Time frame: Baseline to Week 24 prior to rescue
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration, and participated in a meal tolerance test.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | -7.09 mmol/L | Standard Error 0.261 |
| Saxagliptin + Placebo | Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | -4.12 mmol/L | Standard Error 0.262 |
| Metformin + Placebo | Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | -5.95 mmol/L | Standard Error 0.268 |
p-value: <0.00195% CI: [-3.7, -2.25]ANCOVA
p-value: 0.00295% CI: [-1.88, -0.41]ANCOVA
Secondary
Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 180-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment.
Time frame: Baseline to Week 24 prior to rescue
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration, and participated in a meal tolerance test.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | -1027.8 mmol*min/L | Standard Error 36.22 |
| Saxagliptin + Placebo | Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | -611.9 mmol*min/L | Standard Error 36.69 |
| Metformin + Placebo | Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | -858.5 mmol*min/L | Standard Error 37.36 |
p-value: <0.00195% CI: [-517.3, -314.6]ANCOVA
p-value: 0.00195% CI: [-271.7, -66.9]ANCOVA
Secondary
Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in fasting plasma glucose at the end of 24 weeks of double-blinded treatment.
Time frame: Baseline to Week 24 prior to rescue
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | -3.25 mmol/L | Standard Error 0.112 |
| Saxagliptin + Placebo | Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | -1.86 mmol/L | Standard Error 0.111 |
| Metformin + Placebo | Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | -2.94 mmol/L | Standard Error 0.113 |
p-value: <0.00195% CI: [-1.7, -1.08]ANCOVA
p-value: 0.04695% CI: [-0.63, 0]ANCOVA
Secondary
Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c ≤ 6.5% at the end of 24 weeks of double-blinded treatment.
Time frame: Week 24 (prior to rescue)
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin + Metformin | Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | 67.0 Percentage of patients |
| Saxagliptin + Placebo | Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | 32.1 Percentage of patients |
| Metformin + Placebo | Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | 55.4 Percentage of patients |
p-value: <0.00195% CI: [26, 43.9]Fisher Exact
p-value: 0.0295% CI: [2.3, 20.9]Fisher Exact
Secondary
Glycemic Response Defined as HbA1c < 7.0% at Week 24
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c \< 7.0% at the end of 24 weeks of double-blinded treatment.
Time frame: Week 24 (prior to rescue)
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin + Metformin | Glycemic Response Defined as HbA1c < 7.0% at Week 24 | 81.8 Percentage of patients |
| Saxagliptin + Placebo | Glycemic Response Defined as HbA1c < 7.0% at Week 24 | 44.3 Percentage of patients |
| Metformin + Placebo | Glycemic Response Defined as HbA1c < 7.0% at Week 24 | 71.1 Percentage of patients |
p-value: <0.00195% CI: [29, 46]Fisher Exact
p-value: 0.01195% CI: [2.6, 18.9]Fisher Exact
Secondary
Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase
To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 weeks of double-blinded treatment.
Time frame: Baseline to Week 24
Population: The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin + Metformin | Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | 1.4 Percentage of patients |
| Saxagliptin + Placebo | Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | 10.3 Percentage of patients |
| Metformin + Placebo | Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | 1.4 Percentage of patients |
p-value: <0.00195% CI: [-13.3, -4.5]Fisher Exact
p-value: >0.99995% CI: [-2.3, 2.3]Fisher Exact