Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, elderly patients, saxagliptin, randomised, double-blind
Brief summary
This study will evaluate the efficacy and tolerability of saxagliptin compared to glimepiride in elderly patients with type 2 diabetes mellitus who have inadequate glycaemic control on metformin monotherapy.
Interventions
DRUGSaxagliptin
5 mg, oral tablet, once daily
DRUGGlimepiride
1, 2, 3, 4 or 6 mg, oral encapsulated tablet, once daily
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures * Established clinical diagnosis of type 2 diabetes. Treatment with a stable metformin monotherapy, for at least 8 weeks prior to Visit 1 * HbA1c ≥7.0% and ≤9.0%
Exclusion criteria
* Type 1 diabetes, history of diabetic ketoacidosis or hyperosmolar non-ketonic coma. Current use of any injectable or oral antihyperglycemic agent excluding metformin. * Renal impairment as defined by a creatinine clearance \<60 mL/min * Individuals who, in the opinion of the investigator, in which participation in this study may pose a significant risk to the patient and could render the patient unable to successfully complete the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | From week 0 to week 52. | Defined as obtained on or before the 8th day after the last dosing day, as determined by central laboratory. Safety analysis set. Confirmed hypoglycaemia defined as: any event defined as either a symptomatic event with blood glucose level \<3 mmol/L (\<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement \<3 mmol/L (\<54 mg/dL). Major (or severe) hypoglycaemia defined as: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level \<3 mmol/L (\<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 52 in HbA1c. | From week 0 to week 52. | Measured as the difference between the last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), and the last pre-randomisation HbA1c value, as determined by central laboratory. Full analysis set. |
| Proportion of Patients Achieving a Therapeutic Glycaemic Response at Week 52 Defined as HbA1c <7.0% | From week 0 to week 52 | Proportion of patients with their last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), as determined by central laboratory, below the specified limits. Full analysis set. |
| Proportion of Patients Having Experienced at Least One Hypoglycaemic Event (Confirmed or Severe) Over the 52-week Double-blind Treatment Period. | From week 0 to week 52. | Hypoglyceamic event defined as, Confirmed hypoglycaemia: any event defined as either a symptomatic event with blood glucose level \<3 mmol/L (\<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement \<3 mmol/L (\<54 mg/dL). Major (or severe) hypoglycaemia: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level \<3 mmol/L (\<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration. Safety analysis set. |
| Change From Baseline to Week 52 in Insulin | From week 0 to week 52 | Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date) and the last pre-randomisation fasting plasma insulin value, as determined by central laboratory. Full analysis set. |
| Change From Baseline to Week 52 in β-cell Function (as Measured by Homeostasis Model Assessment-β [HOMA-β] | From week 0 to week 52 | β-cell function as estimated by the homeostasis model assessment (HOMA) model. Value is derived from FPG and fasting insulin; fasting insulin values below 2.074 μU/mL or above 57.595 μU/mL and FPG values below 3 mmol/L or above 25 mmol/L are excluded (as restricted by the calculation method used). Full analysis set. |
| Change From Baseline to Week 52 in Fasting Plasma Glucose (FPG) | From week 0 to week 52 | Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date)and the last pre-randomisation fasting plasma glucose value, as determined by central laboratory. Full analysis set. |
Countries
Austria, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Mexico, Norway, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
In total, 152 study centres in 13 countries recruited patients in this study. The first patient was enrolled in the study on 20 October 2009, and the last patient completed the study on 14 June 2012. 957 subjects were enrolled. 753 were deemed eligible for lead-in and 720 were randomized.
Pre-assignment details
A 2-week single-blind (to patient only) placebo lead-in period occurred from Week -2 to Week 0. Patients were from this period on,counselled on dietary and lifestyle modifications according to usual clinical routine. They were given a glucometer to check their plasma glucose at home at least every second day.
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin 5 mg Saxagliptin 5 mg, oral tablet, once daily | 360 |
| Glimepiride 1 - 6 mg Glimepiride 1, 2, 3, 4 or 6 mg, oral encapsulated tablet, once daily | 360 |
| Total | 720 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 7 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Incorrect enrolment | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 3 | 7 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Safety reason | 1 | 1 |
| Overall Study | Study specific discontinuation criteria | 33 | 34 |
| Overall Study | Withdrawal by Subject | 17 | 19 |
Baseline characteristics
| Characteristic | Saxagliptin 5 mg | Glimepiride 1 - 6 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 360 Participants | 360 Participants | 720 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 72.5 years STANDARD_DEVIATION 5.72 | 72.7 years STANDARD_DEVIATION 5.44 | 72.6 years STANDARD_DEVIATION 5.58 |
| Region of Enrollment Austria | 30 participants | 15 participants | 45 participants |
| Region of Enrollment Denmark | 16 participants | 17 participants | 33 participants |
| Region of Enrollment Finland | 24 participants | 19 participants | 43 participants |
| Region of Enrollment France | 11 participants | 13 participants | 24 participants |
| Region of Enrollment Germany | 44 participants | 55 participants | 99 participants |
| Region of Enrollment Greece | 21 participants | 18 participants | 39 participants |
| Region of Enrollment Hungary | 9 participants | 9 participants | 18 participants |
| Region of Enrollment Italy | 12 participants | 12 participants | 24 participants |
| Region of Enrollment Mexico | 10 participants | 7 participants | 17 participants |
| Region of Enrollment Norway | 47 participants | 59 participants | 106 participants |
| Region of Enrollment Spain | 31 participants | 25 participants | 56 participants |
| Region of Enrollment Sweden | 66 participants | 62 participants | 128 participants |
| Region of Enrollment United Kingdom | 39 participants | 49 participants | 88 participants |
| Sex: Female, Male Female | 143 Participants | 132 Participants | 275 Participants |
| Sex: Female, Male Male | 217 Participants | 228 Participants | 445 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 130 / 359 | 129 / 359 |
| serious Total, serious adverse events | 41 / 359 | 32 / 359 |
Outcome results
Primary
Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia.
Defined as obtained on or before the 8th day after the last dosing day, as determined by central laboratory. Safety analysis set. Confirmed hypoglycaemia defined as: any event defined as either a symptomatic event with blood glucose level \<3 mmol/L (\<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement \<3 mmol/L (\<54 mg/dL). Major (or severe) hypoglycaemia defined as: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level \<3 mmol/L (\<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Time frame: From week 0 to week 52.
Population: Safety analysis set (a subset of the randomised analysis set including patients who took at least one investigational product dose).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Saxagliptin 5 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | All patients | 37.9 percentage of participants |
| Saxagliptin 5 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | patients aged <75 years (n=217, n=216) | 39.2 percentage of participants |
| Saxagliptin 5 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | patients aged ≥75 years (n=142, n=143) | 35.9 percentage of participants |
| Glimepiride 1 - 6 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | All patients | 38.2 percentage of participants |
| Glimepiride 1 - 6 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | patients aged <75 years (n=217, n=216) | 33.3 percentage of participants |
| Glimepiride 1 - 6 mg | Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia. | patients aged ≥75 years (n=142, n=143) | 45.5 percentage of participants |
Secondary
Change From Baseline to Week 52 in Fasting Plasma Glucose (FPG)
Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date)and the last pre-randomisation fasting plasma glucose value, as determined by central laboratory. Full analysis set.
Time frame: From week 0 to week 52
Population: The number of subjects with non-missing baseline and Week 52 (LOCF) values in the full analysis set (defined as the subset of patients in the randomized analysis set who took at least one randomised IP dose and have non-missing baseline and post-baseline efficacy data for at least one variable).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Saxagliptin 5 mg | Change From Baseline to Week 52 in Fasting Plasma Glucose (FPG) | -0.73 mmol/L |
| Glimepiride 1 - 6 mg | Change From Baseline to Week 52 in Fasting Plasma Glucose (FPG) | -1.29 mmol/L |
Secondary
Change From Baseline to Week 52 in HbA1c.
Measured as the difference between the last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), and the last pre-randomisation HbA1c value, as determined by central laboratory. Full analysis set.
Time frame: From week 0 to week 52.
Population: The number of subjects with non-missing baseline and Week 52 (LOCF) values in the full analysis set (defined as the subset of patients in the randomized analysis set who took at least one randomised IP dose and have non-missing baseline and post-baseline efficacy data for at least one variable).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Saxagliptin 5 mg | Change From Baseline to Week 52 in HbA1c. | -0.44 % of glycosylated hemoglobin |
| Glimepiride 1 - 6 mg | Change From Baseline to Week 52 in HbA1c. | -0.64 % of glycosylated hemoglobin |
Secondary
Change From Baseline to Week 52 in Insulin
Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date) and the last pre-randomisation fasting plasma insulin value, as determined by central laboratory. Full analysis set.
Time frame: From week 0 to week 52
Population: The number of subjects with non-missing baseline and Week 52 (LOCF) values in the full analysis set (defined as the subset of patients in the randomized analysis set who took at least one randomised IP dose and have non-missing baseline and post-baseline efficacy data for at least one variable).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Saxagliptin 5 mg | Change From Baseline to Week 52 in Insulin | -2.0 µU/mL |
| Glimepiride 1 - 6 mg | Change From Baseline to Week 52 in Insulin | -0.6 µU/mL |
Secondary
Change From Baseline to Week 52 in β-cell Function (as Measured by Homeostasis Model Assessment-β [HOMA-β]
β-cell function as estimated by the homeostasis model assessment (HOMA) model. Value is derived from FPG and fasting insulin; fasting insulin values below 2.074 μU/mL or above 57.595 μU/mL and FPG values below 3 mmol/L or above 25 mmol/L are excluded (as restricted by the calculation method used). Full analysis set.
Time frame: From week 0 to week 52
Population: The number of subjects with non-missing baseline and Week 52 (LOCF) values in the full analysis set (defined as the subset of patients in the randomized analysis set who took at least one randomised IP dose and have non-missing baseline and post-baseline efficacy data for at least one variable).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Saxagliptin 5 mg | Change From Baseline to Week 52 in β-cell Function (as Measured by Homeostasis Model Assessment-β [HOMA-β] | 3.83 percentage of change from baseline |
| Glimepiride 1 - 6 mg | Change From Baseline to Week 52 in β-cell Function (as Measured by Homeostasis Model Assessment-β [HOMA-β] | 16.22 percentage of change from baseline |
Secondary
Proportion of Patients Achieving a Therapeutic Glycaemic Response at Week 52 Defined as HbA1c <7.0%
Proportion of patients with their last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), as determined by central laboratory, below the specified limits. Full analysis set.
Time frame: From week 0 to week 52
Population: The number of subjects with non-missing baseline and Week 52 (LOCF) values in the full analysis set (defined as the subset of patients in the randomized analysis set who took at least one randomised IP dose and have non-missing baseline and post-baseline efficacy data for at least one variable).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 5 mg | Proportion of Patients Achieving a Therapeutic Glycaemic Response at Week 52 Defined as HbA1c <7.0% | 44.7 percentage of responders |
| Glimepiride 1 - 6 mg | Proportion of Patients Achieving a Therapeutic Glycaemic Response at Week 52 Defined as HbA1c <7.0% | 54.7 percentage of responders |
Secondary
Proportion of Patients Having Experienced at Least One Hypoglycaemic Event (Confirmed or Severe) Over the 52-week Double-blind Treatment Period.
Hypoglyceamic event defined as, Confirmed hypoglycaemia: any event defined as either a symptomatic event with blood glucose level \<3 mmol/L (\<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement \<3 mmol/L (\<54 mg/dL). Major (or severe) hypoglycaemia: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level \<3 mmol/L (\<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration. Safety analysis set.
Time frame: From week 0 to week 52.
Population: Safety analysis set (a subset of the randomised analysis set including patients who took at least one investigational product dose).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 5 mg | Proportion of Patients Having Experienced at Least One Hypoglycaemic Event (Confirmed or Severe) Over the 52-week Double-blind Treatment Period. | 1.1 percentage of patients |
| Glimepiride 1 - 6 mg | Proportion of Patients Having Experienced at Least One Hypoglycaemic Event (Confirmed or Severe) Over the 52-week Double-blind Treatment Period. | 15.3 percentage of patients |