Inadequate Glycaemic Control, Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus Type 2,, metformin,, saxagliptin,, dapagliflozin,, glimepiride,, inadequate glycaemic control
Brief summary
This study is being carried out to see if dapagliflozin and dapagliflozin plus saxagliptin as an addition to metformin is effective and safe in treating patients with type 2 diabetes when compared to glimepiride (sulphonylurea) as an addition to metformin treatment.
Interventions
DRUGDapagliflozin
10 mg, orally Green, plain, diamond-shaped, film-coated tablet
DRUGSaxagliptin
5 mg, orally Plain, yellow, biconvex, round, film-coated tablet
DRUGGlimepiride
1, 2, or 4 mg, orally Opaque gray capsule
Does not contain active ingredient, orally Green, plain, diamond-shaped, film-coated tablet
Does not contain active ingredient, orally Plain, yellow, biconvex, round, film-coated tablet
Does not contain active ingredient, orally. Opaque gray capsule
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 74 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Is male or female and ≥18 and \<75 years old at time of informed consent. 2. Has a HbA1c of ≥7.5% and ≤10.5% based on central laboratory results from Visit 1, with individual need for therapy escalation. 3. Currently treated with a stable maximum tolarated dose (MTD) (≥1500 mg/day) of metformin therapy for at least 8 weeks prior to Enrolment visit. 4. Has a BMI of ≤45 kg/m2 at Enrolment visit. 5. Has a C-peptide laboratory value of ≥1.0 ng/mL (0.33 nmol/L; 333.3 pmol/L) based on central laboratory results from Visit 1. Main,
Exclusion criteria
1. Clinically diagnosed with Type I diabetes, known diagnosis of maturity onset diabetes of the young (MODY), or secondary diabetes mellitus or known presence of glutamate decarboxylase 65 (GAD65) antibodies. 2. Patients who, in the judgment of the Investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety and/or the interpretation of efficacy or safety data. 3. Clinically significant cardiovascular disease or procedure within 3 months prior to Enrolment or expected to require coronary revascularization procedure during the course of the study. 4. Concomitant treatment with loop diuretics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52 | Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis | Change in HbA1c from baseline (week 0) to week 52. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patients With at Least One Episode of Confirmed Hypoglycaemia | Up to Week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis | Percentage of patients reporting at least 1 episode of hypoglycaemia (symptomatic + blood glucose \<=50 mg/dL) during the double-blind treatment period |
| Change in Total Body Weight From Baseline at Week 52 | Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis | Change in body weight from baseline (week 0) to week 52 |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis | Change in FPG from baseline (week 0) to week 52 |
| Time to Rescue | Over the 52 week treatment period | The time to rescue (from first dose date after randomisation to start of rescue medication or discontinuation due to lack of glycaemic control) during the 52 week double blind treatment period |
| Number of Patients Rescued | Over the 52 week treatment period | Number (%) of patients rescued. |
Countries
Czechia, Germany, Hungary, Poland, Slovakia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 10mg Dapagliflozin 10mg + Metformin | 314 |
| Saxagliptin 5mg and Dapagliflozin 10mg Saxagliptin 5mg and Dapagliflozin 10mg + Metformin | 312 |
| Glimepiride 1mg/2mg/4mg Glimepiride 1mg/2mg/4mg + Metformin | 313 |
| Total | 939 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 1 | 2 |
| Overall Study | Developed Study Withdrawal Criteria | 4 | 1 | 2 |
| Overall Study | Failure to Meet Randomization Criteria | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 3 |
| Overall Study | Other reasons not specified | 10 | 7 | 12 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 4 | 5 |
Baseline characteristics
| Characteristic | Dapagliflozin 10mg | Saxagliptin 5mg and Dapagliflozin 10mg | Glimepiride 1mg/2mg/4mg | Total |
|---|---|---|---|---|
| Age, Continuous | 57.4 Years STANDARD_DEVIATION 9.36 | 59.2 Years STANDARD_DEVIATION 7.87 | 58.6 Years STANDARD_DEVIATION 8.38 | 58.4 Years STANDARD_DEVIATION 8.58 |
| Age, Customized <65 | 232 Participants | 226 Participants | 226 Participants | 684 Participants |
| Age, Customized >=65-<75 | 81 Participants | 86 Participants | 85 Participants | 252 Participants |
| Age, Customized >=75 | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Black Or African American | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 311 Participants | 307 Participants | 311 Participants | 929 Participants |
| Sex: Female, Male Female | 112 Participants | 122 Participants | 105 Participants | 339 Participants |
| Sex: Female, Male Male | 202 Participants | 190 Participants | 208 Participants | 600 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 313 | 0 / 312 | 0 / 312 |
| other Total, other adverse events | 29 / 313 | 31 / 312 | 37 / 312 |
| serious Total, serious adverse events | 39 / 313 | 22 / 312 | 35 / 312 |
Outcome results
Primary
Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52
Change in HbA1c from baseline (week 0) to week 52.
Time frame: Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapaglifozin 10mg | Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52 | -0.82 HbA1c % | Standard Error 0.049 |
| Saxagliptin 5mg and Dapagliflozin 10mg | Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52 | -1.2 HbA1c % | Standard Error 0.046 |
| Glimepiride 1mg/2mg/4mg | Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52 | -0.99 HbA1c % | Standard Error 0.048 |
95% CI: [0.0294, 0.2986]Mixed Models Analysis
p-value: 0.00195% CI: [-0.3443, -0.0825]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52
Change in FPG from baseline (week 0) to week 52
Time frame: Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapaglifozin 10mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | -1.62 FPG (mmol/L) | Standard Error 0.106 |
| Saxagliptin 5mg and Dapagliflozin 10mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | -2.08 FPG (mmol/L) | Standard Error 0.1 |
| Glimepiride 1mg/2mg/4mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | -1.49 FPG (mmol/L) | Standard Error 0.105 |
p-value: 0.37495% CI: [-0.43, 0.16]Mixed Models Analysis
p-value: <0.00195% CI: [-0.88, -0.31]Mixed Models Analysis
Secondary
Change in Total Body Weight From Baseline at Week 52
Change in body weight from baseline (week 0) to week 52
Time frame: Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapaglifozin 10mg | Change in Total Body Weight From Baseline at Week 52 | -3.54 Weight (kg) | Standard Error 0.231 |
| Saxagliptin 5mg and Dapagliflozin 10mg | Change in Total Body Weight From Baseline at Week 52 | -3.15 Weight (kg) | Standard Error 0.219 |
| Glimepiride 1mg/2mg/4mg | Change in Total Body Weight From Baseline at Week 52 | 1.76 Weight (kg) | Standard Error 0.224 |
p-value: <0.00195% CI: [-5.93, -4.67]Mixed Models Analysis
p-value: <0.00195% CI: [-5.52, -4.29]Mixed Models Analysis
Secondary
Number of Patients Rescued
Number (%) of patients rescued.
Time frame: Over the 52 week treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapaglifozin 10mg | Number of Patients Rescued | 18.6 Percentage of participants |
| Saxagliptin 5mg and Dapagliflozin 10mg | Number of Patients Rescued | 8.3 Percentage of participants |
| Glimepiride 1mg/2mg/4mg | Number of Patients Rescued | 21.4 Percentage of participants |
Secondary
Patients With at Least One Episode of Confirmed Hypoglycaemia
Percentage of patients reporting at least 1 episode of hypoglycaemia (symptomatic + blood glucose \<=50 mg/dL) during the double-blind treatment period
Time frame: Up to Week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapaglifozin 10mg | Patients With at Least One Episode of Confirmed Hypoglycaemia | 0 Percentage of participants |
| Saxagliptin 5mg and Dapagliflozin 10mg | Patients With at Least One Episode of Confirmed Hypoglycaemia | 0.32 Percentage of participants |
| Glimepiride 1mg/2mg/4mg | Patients With at Least One Episode of Confirmed Hypoglycaemia | 4.21 Percentage of participants |
p-value: <0.00195% CI: [-6.45, -1.97]Fisher Exact
p-value: <0.00195% CI: [-6.21, -1.56]Fisher Exact
Secondary
Time to Rescue
The time to rescue (from first dose date after randomisation to start of rescue medication or discontinuation due to lack of glycaemic control) during the 52 week double blind treatment period
Time frame: Over the 52 week treatment period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapaglifozin 10mg | Time to Rescue | NA Weeks |
| Saxagliptin 5mg and Dapagliflozin 10mg | Time to Rescue | NA Weeks |
| Glimepiride 1mg/2mg/4mg | Time to Rescue | NA Weeks |
p-value: 0.77795% CI: [0.67, 1.35]Regression, Cox
p-value: <0.00195% CI: [0.23, 0.57]Regression, Cox