Type 2 Diabetes
Conditions
Brief summary
The purpose of this study is to learn if BMS-512148 (Dapagliflozin) as part of a triple combination therapy can improve (decrease) hemoglobin A1c in patients with type 2 diabetes after 24 weeks of treatment compared to a 2 drug oral antidiabetic therapy. The safety of this treatment will also be studied.
Detailed description
Prior to randomization, all eligible subjects will receive open-label treatment with Saxagliptin 5mg and Metformin IR during the 16-week open-label treatment period.
Interventions
DRUGDapagliflozin
Tablets, Oral, 10 mg, Once daily, Up to 52 weeks
Tablets, Oral, 0 mg, Once daily, Up to 52 weeks
DRUGSaxagliptin
Tablets, Oral, 5 mg, Once daily, Up to 52 weeks
Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks
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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed Written Informed Consent 1. Subjects must be willing and able to give signed and dated written informed consent. 2. Target Population For inclusion into Stratum A: i) Subjects with T2DM with inadequate glycemic control, defined as central laboratory HbA1c ≥ 8.0 and ≤ 11.5% obtained at the screening visit (ie Week -18 visit), on stable metformin therapy alone for at least 8 weeks prior to screening visit at a dose ≥ 1500 mg per day For inclusion into Stratum B: ii) Subjects with T2DM with inadequate glycemic control, and HbA1c ≥ 7.5 and ≤ 10.5% obtained at the screening visit and on stable metformin therapy at a dose ≥ 1500 mg per day AND a DPP4 inhibitor at the maximum approved dose for at least 8 weeks prior to screening visit. b) C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) at screening visit. c) BMI ≤ 45.0 kg/m2 at the screening visit. 3. Age and Reproductive Status 1. Men and women, aged ≥ 18 years old at time of screening visit. 2. Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. 3. WOCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of investigational product. 4. Women must not be breastfeeding 5. Sexually active fertile men must use highly effective birth control if their partners are WOCBP.
Exclusion criteria
1. Target Disease Exceptions 1. History of diabetes insipidus 2. 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 three months prior to screening, or other signs and symptoms. 3. History of diabetic ketoacidosis or hyperosmolar nonketotic coma. 2. Medical History and Concurrent Diseases 1. History of bariatric surgery or lap-band procedure within 12 months prior to screening. 2. Any unstable endocrine, psychiatric or rheumatic disorders as judged by the Investigator. 3. Subject who, in the judgment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data and concomitant use of loop diuretics in countries where this is not recognized in the Dapagliflozin label. 4. Subject is currently abusing alcohol or other drugs or has done so within the last 6 months. Acute Vascular Event: 5. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg. 6. Cardiovascular Disease within 3 months of the screening visit \[ie myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, stroke or transient ischemic attack (TIA)\]. 7. Congestive heart failure as New York Association (NYHA) class IV, unstable or acute congestive heart failure. Renal Diseases: 8. Moderate or severe impairment of renal function \[defined as eGFR \< 60 mL/min/1.73m2 (estimated by MDRD) or serum creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females.\] 9. Conditions of congenital renal glucosuria Hepatic Diseases: 10. Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency, including subjects with ALT and/or AST \> 3x ULN and or Total Bilirubin \> 2.5 x ULN. Hematological and Oncological Disease/Conditions: 11. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis. 12. Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma) 13. Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for the human immunodeficiency virus. 14. Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of \> 400 mL of blood during the 6 months prior to the screening visit. Prohibited treatment and therapies: 15. Administration of any antihyperglycemic therapy, other than metformin and DPP4's, for more than 14 days (consecutive or not) during the 12 weeks prior to screening, as well as previous exposure to DPP4 or SGLT-2 inhibitor in any DPP4 or SGLT-2 inhibitor trial is an exclusion criterion. 16. Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the dapagliflozin label). 17. Administration of any other investigational drug or participation in any interventional clinical studies within 30 days of planned screening to this study. Subjects who failed to satisfy all eligibility criteria at screening and did not enter the lead-in or open-label period in CV181-168 or CV181-169 studies specifically, do not need to wait 30 days. 3. Physical and Laboratory Test Findings a) Hemoglobin ≤ 11.0 g/dL (110 g/L) for men; hemoglobin ≤ 10.0 g/dL (100 g/L) for women b) Presence of hematuria: i) For male subjects being considered for Stratum A: microscopic hematuria present at Week -18 or Week -16 AND no common cause that can be confirmed is exclusionary. Male subjects with a confirmed common cause can be entered into the open-label phase with a documented negative result for hematuria microscopic urinalysis performed by the central laboratory. ii) For male subjects being considered for Stratum B: microscopic hematuria present at Week -10 or Week -8 AND no common cause that can be confirmed is exclusionary. Male subjects with a confirmed common cause can be entered into the open-label phase with a documented negative result for hematuria microscopic urinalysis performed by the central laboratory. NOTE: Female sub}ects with hematuria can be entered into the open-label phase and be randomized, but should be investigated according to local standards and best clinical practices. (See Appendix 3) c) Other central laboratory test findings: \- Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated by free T4. Sub}ects with abnormal free T4 values will be excluded. * Positive for hepatitis B surface antigen * Positive for anti-hepatitis C virus antibody 4. Allergies and Adverse Drug Reaction a) Subjects who have contraindications to therapy as outlined in the dapagliflozin and saxagliptin Investigator Brochure, the local dapagliflozin or saxagliptin package insert or the local metformin package insert, including current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the local Onglyza (saxagliptin) label. 5. Sex and Reproductive Status a) Women who are pregnant 6. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | From Baseline to Week 24 | HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 | From Baseline to Week 24 | Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period |
| Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24 | From Baseline to Week 24 | 2-hour postprandial glucose (PPG) from a liquid meal tolerance test (2-h MTT) Subject must be fasted for at least 8 hrs prior to the MTT. |
| Adjusted Mean Change From Baseline in Body Weight at Week 24 | From baseline to Week 24 | Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weights were measured during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period. |
| Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | From baseline to week 24 | Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after rescue medication was excluded from this analysis. |
Countries
Czechia, Mexico, Poland, Puerto Rico, Romania, Russia, United Kingdom, United States
Participant flow
Recruitment details
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial with Dapagliflozin added to Saxagliptin in Combination with Metformin compared to placebo added to Saxagliptin in combination with Metformin in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin and Saxagliptin
Pre-assignment details
Arm1: Dapagliflozin (10 mg) + Saxagliptin + Metformin IR Arm 2: Placebo + Saxagliptin + Metformin IR
Participants by arm
| Arm | Count |
|---|---|
| Dapa+Saxa+Met Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks | 160 |
| Pla+Saxa+Met Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks | 160 |
| Total | 320 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Period (Weeks 24 to 52) | Adverse Event | 4 | 2 |
| Long-term Period (Weeks 24 to 52) | Lack of Efficacy | 0 | 1 |
| Long-term Period (Weeks 24 to 52) | Lost to Follow-up | 0 | 2 |
| Long-term Period (Weeks 24 to 52) | Subject no longer meets study criteria | 2 | 0 |
| Long-term Period (Weeks 24 to 52) | Withdrawal by Subject | 0 | 2 |
| Short-term Period (Day 1 to Week 24) | Adverse Event | 3 | 0 |
| Short-term Period (Day 1 to Week 24) | Lost to Follow-up | 4 | 4 |
| Short-term Period (Day 1 to Week 24) | No longer meets study criteria | 0 | 1 |
| Short-term Period (Day 1 to Week 24) | Not reported | 2 | 2 |
| Short-term Period (Day 1 to Week 24) | Other | 1 | 0 |
| Short-term Period (Day 1 to Week 24) | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Dapa+Saxa+Met | Pla+Saxa+Met | Total |
|---|---|---|---|
| Age, Continuous | 55.2 YEARS STANDARD_DEVIATION 8.61 | 55.0 YEARS STANDARD_DEVIATION 9.6 | 55.1 YEARS STANDARD_DEVIATION 9.1 |
| Age, Customized < 65 years | 137 Participants | 132 Participants | 269 Participants |
| Age, Customized >= 65 years | 23 Participants | 28 Participants | 51 Participants |
| Race/Ethnicity, Customized AMERICAN INDIAN/ALASKA NATIVE | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized ASIAN | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized BLACK/AFRICAN AMERICAN | 8 Participants | 10 Participants | 18 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN/OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized OTHER | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized WHITE | 150 Participants | 147 Participants | 297 Participants |
| Sex: Female, Male Female | 90 Participants | 84 Participants | 174 Participants |
| Sex: Female, Male Male | 70 Participants | 76 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 160 | 112 / 160 |
| serious Total, serious adverse events | 7 / 160 | 4 / 160 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24
HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.
Time frame: From Baseline to Week 24
Population: The Randomized Subjects Data Set consists of all randomized subjects who received at least one dose of double-blind study medication during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapa+Saxa+Met | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | -0.82 Percentage of glycosylated hemoglobin | Standard Error 0.0686 |
| Pla+Saxa+Met | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | -0.1 Percentage of glycosylated hemoglobin | Standard Error 0.0704 |
p-value: <0.000195% CI: [-0.91, -0.53]Longitudinal Repeated Measures Analysis
Secondary
Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24
2-hour postprandial glucose (PPG) from a liquid meal tolerance test (2-h MTT) Subject must be fasted for at least 8 hrs prior to the MTT.
Time frame: From Baseline to Week 24
Population: The Randomized Subjects Data Set consists of all randomized subjects who received at least one dose of double-blind study medication during the double-blind treatment period. Number of participants analyzed is the number of randomized subjects with non-missing baseline and Week 24 (LOCF) values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapa+Saxa+Met | Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24 | -73.5 mg/dL | Standard Error 4.055 |
| Pla+Saxa+Met | Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24 | -38.0 mg/dL | Standard Error 4.104 |
p-value: <0.000195% CI: [-46.3, -24.7]Longitudinal Repeated Measures Analysis
Secondary
Adjusted Mean Change From Baseline in Body Weight at Week 24
Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weights were measured during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.
Time frame: From baseline to Week 24
Population: The Randomized Subjects Data Set consists of all randomized subjects who received at least one dose of double-blind study medication during the double-blind treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapa+Saxa+Met | Adjusted Mean Change From Baseline in Body Weight at Week 24 | -1.91 kg | Standard Error 0.2191 |
| Pla+Saxa+Met | Adjusted Mean Change From Baseline in Body Weight at Week 24 | -0.41 kg | Standard Error 0.227 |
p-value: <0.000195% CI: [-2.12, -0.89]Longitudinal Repeated Measures Analysis
Secondary
Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24
Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period
Time frame: From Baseline to Week 24
Population: The Randomized Subjects Data Set consists of all randomized subjects who received at least one dose of double-blind study medication during the double-blind treatment period. Number of participants analyzed corresponds to the number of randomized subjects with non-missing baseline value and at least one post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapa+Saxa+Met | Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 | -32.7 mg/dL | Standard Error 2.821 |
| Pla+Saxa+Met | Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 | -5.3 mg/dL | Standard Error 2.968 |
p-value: <0.000195% CI: [-35.4, -19.6]Longitudinal Repeated Measures Analysis
Secondary
Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after rescue medication was excluded from this analysis.
Time frame: From baseline to week 24
Population: The Randomized Subjects Data Set consists of all randomized subjects who received at least one dose of double-blind study medication during the double-blind treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapa+Saxa+Met | Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 36.7 Percentage of subjects |
| Pla+Saxa+Met | Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 13.3 Percentage of subjects |
p-value: <0.000195% CI: [16.7, 34.4]Modified logistic regression