Inadequate Glycaemic Control, Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus Type 2,, saxagliptin,, dapagliflozin,, metformin
Brief summary
The aim of this study is to evaluate safety and efficacy of therapy with saxagliptin 5mg co-administered with dapagliflozin 5mg, compared to therapy with saxagliptin 5mg or dapagliflozin 5mg in patients who are inadequately controlled on ≥1500mg/day of metformin monotherapy.
Interventions
DRUGDapagliflozin
5mg, orally, Green, plain, diamond-shaped, film-coated tablet
Does not contain active ingredient, orally, Green, plain, diamond-shaped, film-coated tablet
DRUGSaxagliptin
5mg, orally, Plain, yellow, biconvex, round, film-coated tablet
Does not contain active ingredient, orally, Plain, yellow, biconvex, round, film-coated tablet
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 130 Years
Healthy volunteers
No
Inclusion criteria
1. Patients aged ≥18 years old at time of informed consent; 2. Patients with Type 2 diabetes mellitus (T2DM) defined as HbA1C≥7.5% to ≤10.0% at screening visit; 3. Stable metformin therapy for at least 8 weeks prior to enrolment at a dose of ≥1500mg per day; 4. BMI ≤45.0kg/m2 at Enrolment visit; 5. Fasting Plasma Glucose (FPG) ≤ 270mg/dl(15.0mmol/L) at the enrolment visit; 6. For Females Only: Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study medication in such a manner that the risk of pregnancy is minimized.
Exclusion criteria
1. History of diabetes insipidus, Type 1 diabetes or Latent Autoimmune Diabetes of Adults, diabetic ketoacidosis or hyperosmolar nonketotic coma and Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to Enrolment (Visit 1), or other signs and symptoms. 2. History of pancreatitis. 3. Administration of any antihyperglycaemic therapy, other than metformin, for more than 14 days (consecutive or not) during the 8 weeks prior to enrolment 4. Any use of DPP-4 inhibitor or SGLT-2 inhibitor within 8 weeks prior to enrolment. 5. Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency and/or significant abnormal liver function, including patients with Alanine transaminase (ALT) and/or Aspartate transaminase (AST) ≥3x ULN (Upper Limit of Normal)and/or Total Bilirubin ≥2.0x ULN. History of severe hepatobiliary disease or hepatotoxicity with any medication. Positive serologic evidence of current infectious liver disease, including patients who are known to be positive for Hepatitis viral antibody ImmunoglobulinM (IgM), Hepatitis B surface antigen, and Hepatitis C virus antibody. 6. Moderate or severe impairment of renal function \[defined as Estimated Glomerular Filtration Rate (eGFR) \<60milliLitre/min/1.73 m2 (estimated by Modification in Diet and Renal Disease (MDRD)) or serum creatinine ≥1.5mg/dL in males or ≥1.4mg/dL in females\]. Conditions of congenital renal glucosuria, history of unstable or rapidly progressing renal disease. 7. History of any clinically significant disease or disorder which, in the opinion of the investigator, may put the patient at risk because of participation in the study, may influence the results, or may limit the patient's ability to participate in or complete the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Week 24 | Baseline and week 24 | To demonstrate the superiority of the change from baseline HbA1c achieved with the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks | Baseline and week 24 | To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually on proportion of participants achieving therapeutic glycaemic response after 24 weeks. Therapeutic glycaemic response was defined as an HbA1c value at Week 24 \<7.0% irrespective of whether participant received rescue medication. Risk difference for each treatment was calculated as adjusted response rate. Participants who did not had an HbA1c measurement at Week 24 were regarded as non-responders. Results were presented for the modified full analysis set. |
| Change in Fasting Plasma Glucose at 24 Weeks | Baseline and week 24 | To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5mg to either agent individually on fasting plasma glucose after 24 weeks. Results were presented for the modified full analysis set. |
| Change in Total Body Weight at 24 Weeks | Baseline and week 24 | To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to saxagliptin 5 mg on total body weight after 24 weeks. Results were presented for the modified full analysis set. |
Countries
Canada, Czechia, Germany, Mexico, Russia, United States
Participant flow
Recruitment details
The study was conducted at 119 sites in 6 countries: Canada, Czech Republic, Germany, Mexico, Russia, and United States (US). Approximately 900 participants were to be randomized. Participants with Type 2 Diabetes (T2DM) inadequately controlled on metformin alone were randomized in this study.
Pre-assignment details
All participants had screening (Visit 0) at 1 week prior to enrolment to screen the eligibility based on non-fasting sample of Glycated haemoglobin (Hb A1c); results of HbA1c determined enrolment based on inclusion/exclusion criteria. An abbreviated informed consent was signed and review of concomitant or other medications/therapies were performed.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin + Saxagliptin + Metformin Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally) | 290 |
| Dapagliflozin + Metformin Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally) | 289 |
| Saxagliptin + Metformin Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally) | 291 |
| Total | 870 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 1 -Modified Enrolled Participants Set | Adverse Event | 10 | 4 | 1 |
| 1 -Modified Enrolled Participants Set | Lack of therapeutic response | 1 | 5 | 14 |
| 1 -Modified Enrolled Participants Set | No treatment given | 0 | 1 | 1 |
| 1 -Modified Enrolled Participants Set | Other | 6 | 6 | 7 |
| 1 -Modified Enrolled Participants Set | Participant decision | 7 | 10 | 9 |
| 1 -Modified Enrolled Participants Set | Severe non-compliance to protocol | 2 | 0 | 1 |
| 1 -Modified Enrolled Participants Set | Study-specific discontinuation criteria | 11 | 13 | 20 |
| 2 - Enrolled Participants Set | Adverse Event | 10 | 4 | 1 |
| 2 - Enrolled Participants Set | Lack of therapeutic response | 1 | 5 | 14 |
| 2 - Enrolled Participants Set | No treatment given | 0 | 1 | 1 |
| 2 - Enrolled Participants Set | Other | 6 | 6 | 7 |
| 2 - Enrolled Participants Set | Participant decision | 7 | 10 | 9 |
| 2 - Enrolled Participants Set | Severe non-compliance to protocol | 2 | 0 | 1 |
| 2 - Enrolled Participants Set | Study specific discontinuation criteria | 14 | 15 | 21 |
Baseline characteristics
| Characteristic | Dapagliflozin + Saxagliptin + Metformin | Dapagliflozin + Metformin | Saxagliptin + Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 57.2 Years STANDARD_DEVIATION 10.68 | 55.9 Years STANDARD_DEVIATION 10.94 | 57.0 Years STANDARD_DEVIATION 9.94 | 56.7 Years STANDARD_DEVIATION 10.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 99 Participants | 95 Participants | 99 Participants | 293 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 191 Participants | 194 Participants | 192 Participants | 577 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 9 Participants | 6 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 17 Participants | 24 Participants | 51 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) White | 265 Participants | 257 Participants | 258 Participants | 780 Participants |
| Sex: Female, Male Female | 148 Participants | 137 Participants | 134 Participants | 419 Participants |
| Sex: Female, Male Male | 142 Participants | 152 Participants | 157 Participants | 451 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 293 | 2 / 293 | 0 / 295 |
| other Total, other adverse events | 41 / 293 | 39 / 293 | 29 / 295 |
| serious Total, serious adverse events | 7 / 293 | 8 / 293 | 7 / 295 |
Outcome results
Primary
Change From Baseline in HbA1c at Week 24
To demonstrate the superiority of the change from baseline HbA1c achieved with the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication.
Time frame: Baseline and week 24
Population: FAS: All randomized participants who took at least one dose of the study medication and had a baseline value for HbA1c. Analysis of the FAS was based on the randomized treatment. The modified FAS included all participants from FAS with the exception of participants from one site (excluded due to serious GCP violations).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Change From Baseline in HbA1c at Week 24 | -1.03 Percentage (%) | Standard Error 0.0558 |
| Dapagliflozin + Metformin | Change From Baseline in HbA1c at Week 24 | -0.63 Percentage (%) | Standard Error 0.056 |
| Saxagliptin + Metformin | Change From Baseline in HbA1c at Week 24 | -0.69 Percentage (%) | Standard Error 0.0551 |
p-value: <0.000195% CI: [-0.55, -0.24]Mixed Models Analysis
p-value: <0.000195% CI: [-0.5, -0.19]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose at 24 Weeks
To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5mg to either agent individually on fasting plasma glucose after 24 weeks. Results were presented for the modified full analysis set.
Time frame: Baseline and week 24
Population: FAS: All randomized participants who took at least one dose of the study medication and had a baseline value for HbA1c. Analysis of the FAS was based on the randomized treatment. The modified FAS included all participants from FAS with the exception of participants from one site (excluded due to serious GCP violations).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Change in Fasting Plasma Glucose at 24 Weeks | -27.53 Milligrams per deciliter (mg/dL) | Standard Error 2.1557 |
| Dapagliflozin + Metformin | Change in Fasting Plasma Glucose at 24 Weeks | -19.95 Milligrams per deciliter (mg/dL) | Standard Error 2.1738 |
| Saxagliptin + Metformin | Change in Fasting Plasma Glucose at 24 Weeks | -12.66 Milligrams per deciliter (mg/dL) | Standard Error 2.1373 |
p-value: 0.013595% CI: [-13.59, -1.57]Mixed Models Analysis
p-value: <0.000195% CI: [-20.85, -8.91]Mixed Models Analysis
Secondary
Change in Total Body Weight at 24 Weeks
To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to saxagliptin 5 mg on total body weight after 24 weeks. Results were presented for the modified full analysis set.
Time frame: Baseline and week 24
Population: FAS: All randomized participants who took at least one dose of the study medication and had a baseline value for HbA1c. Analysis of the FAS was based on the randomized treatment. The modified FAS included all participants from FAS with the exception of participants from one site (excluded due to serious GCP violations).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Change in Total Body Weight at 24 Weeks | -2.01 Kilograms (Kg) | Standard Error 0.1829 |
| Dapagliflozin + Metformin | Change in Total Body Weight at 24 Weeks | -0.41 Kilograms (Kg) | Standard Error 0.1815 |
p-value: <0.000195% CI: [-2.11, -1.09]Mixed Models Analysis
Secondary
Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks
To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually on proportion of participants achieving therapeutic glycaemic response after 24 weeks. Therapeutic glycaemic response was defined as an HbA1c value at Week 24 \<7.0% irrespective of whether participant received rescue medication. Risk difference for each treatment was calculated as adjusted response rate. Participants who did not had an HbA1c measurement at Week 24 were regarded as non-responders. Results were presented for the modified full analysis set.
Time frame: Baseline and week 24
Population: FAS: All randomized participants who took at least one dose of the study medication and had a baseline value for HbA1c. Analysis of the FAS was based on the randomized treatment. The modified FAS included all participants from FAS with the exception of participants from one site (excluded due to serious GCP violations).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Saxagliptin + Metformin | Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks | 124 Participants |
| Dapagliflozin + Metformin | Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks | 63 Participants |
| Saxagliptin + Metformin | Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks | 83 Participants |
p-value: <0.000195% CI: [12.7, 26.9]Method of Zhang, Tsiatis, and Davidian
p-value: 0.001895% CI: [4.4, 19.1]Method of Zhang, Tsiatis, and Davidian