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Dapagliflozin

Phase 3

Acute Myocardial Infarction | Small molecule | Cardiovascular |AstraZeneca PLC|Last Updated: Mar 7, 2025

Target and mechanism

Molecular targetSLC5A2
Target classInhibitor
ModalitySmall molecule

Success Probability

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Market & Valuation

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Trial Design

RandomizedDouble-BlindPLACEBO_CONTROLLEDDMC
Total Trials1
Total Enrollment4,017

FDA Designations

No designations recorded

Clinical trial landscape

Dapagliflozin · 65 trials · 28 indications

Phase 3 37Phase 2 11Phase 1 17
NCT04564742Dapagliflozin Effects on Cardiometabolic Outcomes in Patients With an Acute Heart Attack.Acute Myocardial Infarction
COMPLETED4,017 Analytics
NCT03877237DETERMINE-reduced - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Reduced Ejection FractionHeart Failure With Reduced Ejection Fraction (HFrEF)
COMPLETED313 Analytics
NCT03877224DETERMINE-preserved - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection FractionHeart Failure With Preserved Ejection Fraction (HFpEF)
COMPLETED504 Analytics
NCT03619213Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure.Heart Failure With Preserved Ejection Fraction
COMPLETED6,263 Analytics
NCT03199053Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus (T2DM) Aged 10 to Below 18 Years OldDiabetes Mellitus, Type 2
COMPLETED256 Analytics
NCT03036124Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart FailureChronic Heart Failure With Reduced Ejection Fraction (HFrEF)
COMPLETED4,744 Analytics
NCT03036150A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney DiseaseChronic Kidney Disease
COMPLETED4,304 Analytics
NCT02725593Study to Evaluate Safety and Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Aged 10-24 YearsType 2 Diabetes
COMPLETED72 Analytics
NCT02681094A Multi-Center, Randomized, Double-Blind, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Saxagliptin or Dapagliflozin All Given as add-on Therapy to Metformin in Subject With Type 2 DiabetesType 2 Diabetes Mellitus
COMPLETED905 Analytics
NCT02582814The Safety and Efficacy of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DMType 1 Diabetes Mellitus
COMPLETED151 Analytics
PHASE3COMPLETED
Dapagliflozin Effects on Cardiometabolic Outcomes in Patients With an Acute Heart Attack.
Acute Myocardial InfarctionUnlock trial analytics
PHASE3COMPLETED
DETERMINE-reduced - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Reduced Ejection Fraction
Heart Failure With Reduced Ejection Fraction (HFrEF)Unlock trial analytics
PHASE3COMPLETED
DETERMINE-preserved - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection Fraction
Heart Failure With Preserved Ejection Fraction (HFpEF)Unlock trial analytics
PHASE3COMPLETED
Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure.
Heart Failure With Preserved Ejection FractionUnlock trial analytics
PHASE3COMPLETED
Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus (T2DM) Aged 10 to Below 18 Years Old
Diabetes Mellitus, Type 2Unlock trial analytics
PHASE3COMPLETED
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure
Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)Unlock trial analytics
PHASE3COMPLETED
A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease
Chronic Kidney DiseaseUnlock trial analytics
PHASE3COMPLETED
Study to Evaluate Safety and Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Aged 10-24 Years
Type 2 DiabetesUnlock trial analytics
PHASE3COMPLETED
A Multi-Center, Randomized, Double-Blind, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Saxagliptin or Dapagliflozin All Given as add-on Therapy to Metformin in Subject With Type 2 Diabetes
Type 2 Diabetes MellitusUnlock trial analytics
PHASE3COMPLETED
The Safety and Efficacy of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DM
Type 1 Diabetes MellitusUnlock trial analytics

Study Endpoints

Primary Endpoints

Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set)
29 months

Study participants received dapagliflozin 10 mg or matching placebo, given once daily in addition to SoC. Overall, the mean study duration was 12.0 months (time in study until last visit) with an accumulated 4023.9 participant-years. The maximum study duration for any participant was 29 months. "Number of Events" for NYHA corresponds to the number of participants with a non-missing value for NYHA functional class at the last visit, and that all participants with a non-missing value take part in the analysis comparing their NYHA class value with all other participants with a NYHA value, according to the win-ratio method.

Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden).
At baseline and at week 16 or death before week 16

Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) domains into a single summary score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-TSS values.

Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF)
At baseline and at week 16 or death before week 16

Change from baseline in KCCQ-PLS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-PLS incorporates the 6 physical limitation items into a single score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-PLS values.

Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity).
At baseline and at week 16 or death prior to week 16

Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have 6MWD values.

Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden)
At baseline and at week 16 or death before week 16

Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ-TSS incorporates symptom frequency (4 items) and symptom burden (3 items) domains into a single score. The score is transformed to a range of 0-100 (higher score reflects better health status). Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants alive at the week 16 visit but without KCCQ-TSS values. All the data for the endpoint, except for death, collected during COVID-19, are set as missing and imputed same way as pre-COVID-19 missing data.

Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity)
At baseline and at week 16 or death before week 16

Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have 6MWD values.

Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure.
Up to 42.1 months

Dual primary efficacy Primary endpoint analysed in all patients randomised (Full analysis set). The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.

Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation
Up to 42.1 months

Dual primary efficacy Primary endpoint analysed in all patients randomised with LVEF \< 60% at baseline. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.

Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26
Baseline and Week 26

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on multiple imputation washout (MI-WO) within each arm using the data from placebo participants with Week 26 data.

Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26
Baseline and Week 26

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.

Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death.
Up to 38.2 months

End Stage Renal Disease (ESRD) is defined as: * Sustained eGFR \<15 mL/min/1.73m2 or, * Chronic dialysis treatment or, * Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.

Adjusted Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 24
Baseline to Week 24
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.

Overall Adverse Event Summary
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Hypoglycemia
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Diabetic Ketoacidosis (DKA)
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Vital Signs (Heart Rate)
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

ECGs
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Vital Signs (Blood Pressure)
From baseline to 52 weeks

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Adjusted Mean Change From Baseline in HbA1c at Week 24
Baseline and 24 weeks

To compare the change from baseline in HbA1c between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24
Baseline, Week 24

To compare the mean change from baseline in HbA1c between dapagliflozin 10 mg and placebo, after 24 weeks of oral administration of double-blind treatment in patients with type 2 diabetes, CKD stage 3A, and moderate renal impairment (CKD 3A; eGFR 45-59 mL/min/1.73m\^2). The "number analyzed" (142 dapaglifozin, 134 placebo) represents the number with change from baseline available at Week 24.

Adjusted Mean Change in HbA1c From Baseline at Week 24
From Baseline to Week 24

Adjusted mean change from baseline in HbA1c at Week 24 (Repeated Measures Model\[RMM\]).

Adjusted Mean Change in HbA1c From Baseline to Week 24
Baseline (Day 1) and 24 weeks

The adjusted mean change in the percentage of Hemoglobin A1c (HbA1c) from baseline to Week 24 was reported for each arm.

Subjects Included in the Composite Endpoint of CV Death, MI or Ischemic Stroke
up to 5.2 years

Safety and co-primary efficacy

Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure.
up to 5.2 years

Co-primary efficacy

Adjusted Mean Change From Baseline in HbA1c Levels
Baseline to week 24

To compare the change from baseline in HbA1c to week 24 between dapagliflozin 10 mg in combination with metformin and sulfonylurea and placebo in combination with metformin and sulfonylurea.

Proportion of Participants With Adverse Events
Long-term treatment up to 52 weeks

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to adverse events

Proportion of Participants With Serious Adverse Events
Long-term treatment up to 52 weeks

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to serious adverse events

Proportion of Participants With At Least One Episode of Hypoglycemia
Long-term treatment up to 52 weeks

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to occurrence of hypoglycemia

Mean Change in Hematocrit
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in hematocrit

Mean Change in Alanine Aminotransferase (ALT)
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in alanine aminotransferase

Mean Change in Aspartate Aminotransferase (AST)
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in aspartate aminotransferase

Mean Change in Blood Urea Nitrogen (BUN)
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in blood urea nitrogen

Mean Change in Magnesium
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in magnesium (1 mEq/L equivalent to 0.50 mmol/L)

Mean Change in Serum Uric Acid
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in serum uric acid

Mean Change in Seated Heart Rate
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in pulse

Mean Change in Seated Diastolic Blood Pressure
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in blood pressure

Mean Change in Seated Systolic Blood Pressure
Baseline to Week 52

To evaluate the safety and tolerability of long-term treatment up to 52 weeks with the dosing regimen of dapagliflozin, where it started with 5 mg and titrated up to 10 mg depending on participant's condition of glycemic control, in regard to the change in blood pressure

Adjusted Mean Change in HbA1c Levels
From Baseline to Week 24

To compare change from baseline in HbA1c achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.

Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure for 12 Week Double-Blind Treatment Period - Randomized Participants
Baseline to Week 12

Systolic blood pressure (SBP) was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Blood pressure (BP) values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the BP was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured.

Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) for 12 Week Double-Blind Treatment Period - Randomized Participants
Baseline to Week 12

Adjusted mean change in glycosylated hemoglobin ( HbA1c) from baseline at Week 12 was calculated. HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. HbA1c values were obtained at enrollment and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period.

Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12
From Baseline to Week 12

Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.

Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12
From Baseline to Week 12

HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.

Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])
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 4, 8, 12, 16, 20, and 24 in the double-blind period.

Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit
Baseline to Week 24

To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.

Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 (Last Observation Carried Forward) - Randomized Treated Participants
Week 24

Adjusted mean change in HbA1c from baseline at Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, ie, last observation carried forward (LOCF) was determined. 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 4, 8, 12, 16, 20, and 24 in the Double-Blind Period.

Adjusted Mean Change in Total Body Weight
Baseline to Week 24

To evaluate the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin on total body weight after 24 weeks of oral administration of double-blind treatment.

Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 Last Observation Carried Forward (LOCF) - All Randomized Participants
Baseline (Day 1), Week 24

Adjusted mean change in HbA1c from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined(LOCF). HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication (metformin) 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 values were obtained at enrollment, lead-in, and at Day 1, Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.

Adjusted Mean Change From Baseline to Week 24 in Hemoglobin A1C (HbA1c) (Last Observation Carried Forward [LOCF]): Group 1
Baseline to Week 24 (end of Short-term Period)

HbA1c was measured 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. If no Week 24 assessment was available, the last postbaseline measurement prior to Week 24 was used. For rescued participants, measurements obtained after initiation of rescue medication were not considered in calculating the primary endpoint. Evening dosing groups were summarized as exploratory endpoints.

Adjusted Mean Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) (Last Observation Carried Forward [LOCF]): Group 2
Baseline to Week 24 (end of Short-term Period)

HbA1c was measured 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. If no Week 24 assessment was available, the last postbaseline measurement prior to Week 24 was used. For rescued participants, measurements obtained after initiation of rescue medication were not considered in calculating the primary endpoint. Group 2 (patients with enrollment baseline HbA1c \>10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included.

Change From Baseline in Insulin Sensitivity at Week 12 Via Oral Glucose Tolerance Test
Baseline, 12 weeks

Insulin sensitivity was estimated by measuring circulating insulin concentrations after a 12 hour fast and after ingesting 75 g of glucose. Insulin was measured 0, 30, 60, 90 and 120 minutes after glucose ingestion. Time point 0 minutes is reported below.

Change From Baseline in Blood Pressure at Week 12
Baseline, 12 weeks

Blood pressure was measured with an automatic machine at baseline. Numbers are reported as systolic/diastolic

Change From Baseline in Perception of Satiety at Week 12
Baseline, 12 weeks

Participants answered a satiety questionnaire before liquid meal primer, immediately post liquid meal primer, 60 minutes post liquid primer, immediately post breakfast buffet, 60 minutes, 120 minutes and 180 minutes post breakfast buffet. Responses how full do you feel right now? for 60 minutes post liquid meal primer ingestion are reported below. This was determined by using a visual analog scale. The left side of the analog scale represents a null answer (e.g. How full do you feel right now)? Answer 0: Not full at all. The right side of the line represented the strongest answer in the opposite direction (e.g. How full to you feel right now)? Answer 100: Extremely full. The length of the line is 100 mm, thus the scale ranges for all answers were 0-100. All values are reported as values between 0 and 100. If the answers to the fullness questions increased, this represented a decreased desire to eat.

Change From Baseline in Perception of Hunger at Week 12
Baseline, 12 weeks

Participants answered a hunger questionnaire before liquid meal primer, immediately post liquid meal primer, 60 minutes post liquid primer, immediately post breakfast buffet, 60 minutes, 120 minutes and 180 minutes post breakfast buffet. Responses to how hungry do you feel right now? for 60 minutes post liquid meal primer ingestion are reported below. This was determined by using a visual analog scale. The left side of the analog scale represents a null answer (e.g. How hungry do you feel right now? Answer 0: Not hungry at all. The right side of the line represented the strongest answer in the opposite direction (e.g. How full to you feel right now)? Answer 100: Extremely hungry. The length of the line is 100 mm, thus the scale ranges for all answers were 0-100. All values are reported as values between 0 and 100. If the answers to the fullness questions increased, this represented an increased desire to eat.

Change From Baseline in Marker of Inflammation (High Sensitive C-reactive Protein) at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12
data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Hunger Hormone Ghrelin at Week 12
data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12
data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Maker of Oxidative Stress (Low Density Thiobarbituric Acid Reactive Substances) at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Satiety Hormone Leptin at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Change From Baseline in Satiety Hormone Insulin at Week 12
Data not collected

Will be analyzed using a commercially available biochemical assay.

Mean amplitude of glycaemic excursions (MAGE) as assessed by continuous glucose monitoring
Change from baseline to 13 weeks and 26 weeks
Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24
Baseline and Week 24

HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a mixed model repeated measures (MMRM) model.

Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24
Baseline and Week 24

UACR was analysed at baseline and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. UACR values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24.

Change From Baseline to Week 12 in % Liver Fat as Assessed by MRI (Comparison Versus Placebo)
12 weeks

To evaluate the efficacy of the combination therapy (Epanova + Dapagliflozin) when compared to placebo with respect to reduction in liver fat content (%) at the end of 12 weeks of double-blinded treatment. Treatment effect in liver fat reduction (%) was assessed using a mixed linear model with the change from baseline on logarithmic scale as response variable and the logarithm of the baseline value as covariate, treatment as fixed effect, and center as random effect. The treatment effect was then back-transformed to original scale as Geometric mean ratio and presented as percentage change from baseline.

Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7
From Baseline to Day 7

7-PGM was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the assessment on Day -1, prior to the start date and time of the first dose of the double-blind study medication. 7-PGM included the average of all available glucose values before and 2-hour (hr) after each meal (breakfast, lunch, dinner) as well as bedtime. Measurements were on Day -1, and Day 7 in the double-blind period.

Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF])
From Baseline to Week 12

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. If no Week 12 measurement was available, the last available post-baseline measurement obtained on or after Day 23 was used regardless of rescue medication. Measurements were obtained during radomization visit, and Week 12 in the double-blind period by a central laboratory.

Adjusted Mean Percent Change From Baseline in Insulin Sensitivity at Week 12 (Last Observation Carried Forward [LOCF])
From Baseline to Week 12

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. Measurements were obtained during the randomization visit and Week 12 in the double-blind period.

Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]
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 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 in the double-blind period.

Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2
From Baseline to Week 12

HbA1c was measured as percent of hemoglobin by a central laboratory. Data after insulin uptitration 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 4, 6, 8, 10, and 12 in the double-blind period.

Mean change from baseline in HbA1c compared to placebo.
at 12 weeks
PK assessment: AUC (Area under plasma concentration-time curve from time zero to infinity)
At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)

To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

PK assessment: AUC0-t (Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration)
At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)

To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

PK assessment: Cmax (Maximum observed plasma concentration)
At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)

To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

Time in Range 70-180%
24 hours

Collection of clinical data regarding the treatment of two doses of 10mg dapagliflozin as add-on to night and day closed-loop control using the DreaMed Algorithm and the time within glucose range 70-180 mg/dl (3.9-10mmol/l) \[%\]

Dapagliflozin Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin 3-O-Glucuronide Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin 3-O-Glucuronide Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin 3-O-Glucuronide Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin 3-O-Glucuronide Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Dapagliflozin Ratio of Metabolite to Parent AUC of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set
Day 1-7

Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set
Baseline (the last available assessment prior to the first dose of study medication), Day 7

The 24-hour period is defined based on the morning void, from the first morning void to the one of the next day.

Area under the curve over the time (AUC)
pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose

No statistical analysis will be performed

AUC from time zero to the time of last quantifiable analyte concentration (AUC(0-t))
pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose

No statistical analysis will be performed

Maximum concentration (Cmax)
pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose

No statistical analysis will be performed

Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanograms per milliliter (ng/mL).

Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Time of maximum observed plasma concentration (Tmax) for Dapagliflozin was derived from plasma concentrations versus time data. Medians were reported in hours (h).

Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Area under the plasma concentration-time curve from time zero extrapolated to infinite time was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng\*hr/mL).

Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanogram hours per milliliter (ng\*h/mL).

Mean Plasma Half-life (T-HALF) of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentrations versus time data. Means are reported in hours.

Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Apparent clearance after extravascular administration (CL/F) of Dapagliflozin was derived from plasma concentrations versus time data. Geometric means are reported in milliliters per minute (mL/min).

Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin
11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose

Geometric mean of apparent volume of distribution at terminal phase after extravascular administration of Dapagliflozin was derived from plasma concentration versus time data. Geometric means are reported in Liters (L)

The reduction in TmG after 7 days of oral administration of 10 mg of dapagliflozin
Before 7 days of oral administration of 10 mg of dapagliflozin
Total 24-hour Urinary Glucose Excretion as a Measure of Pharmacodynamic Effect
24 hours after dosing
To evaluate the pharmacokinetics of dapagliflozin when administered alone or in combination with voglibose in Japanese patients with type 2 diabetes by assessment of AUC and Cmax of dapagliflozin
Plasma samples will be collected through Visit 4 (up to 72 hours = 3 days after dose) for PK assessment for period 1. Plasma samples will be collected through Visit 7 (up to 72 hours = 3 days after dose) for PK assessment for period 2.
Blood samples to measure the pharmacokinetic parameters Cmax and AUC for the combination products versus each investigational product alone
48 hours post-dose
Absolute oral bioavailability
Within the 3 days after study drug administration
Exposure to the investigational drug will be measured to compare with and without the co-administration of other drugs
216 hours post-dose
Maximum plasma concentration and exposure to glimepiride and dapagliflozin when administered alone and administered together
plasma concentrations will be measures as specified timepoints for 72 hours after each administred dose
To determine the effect of metformin on the exposure of dapagliflozin and the effect of dapagliflozin on the exposure of metformin in healthy subjects after a single dose of each treatment
measures taken daily throughout the study
AEs, vital signs & physical exam
scr, Days -3, -1, 1, 2, 7, 12, 13, 14, 15, 21
Clinical labs
scr, Days -1, 2, 7, 12, 14, 15, 21
Urine safety markers
Days -1, 1, 14
Urine will be collected over a 24 h period for determination of renal glucose clearance, total protein, and measurement of total glucose excreted in urine
on Days -1, 1, 4 and 10
Blood samples for serum glucose and creatinine will be collected
on Days -1, 1, 4 and 10 at selected timepoints
Blood and urine PK samples
on Days 1, 4, 10
Iohexol PK blood & urine samples for GFR assessment
on Day -12 to -5

Secondary Endpoints

Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer).
At baseline and at end of study or death before week 16.
Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit)
Up to 42.1 months
Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation
Up to 42.1 months
Unlock Study Endpoints

Study Design & Arms

AllocationRANDOMIZED
MaskingQUADRUPLE
ModelPARALLEL
PurposeTREATMENT

Treatment Arms

ArmTypeDescription
DapagliflozinEXPERIMENTALPatients will be randomized 1:1 to either dapagliflozin or placebo
PlaceboPLACEBO_COMPARATORPlacebo matching dapagliflozin
Low dose DapagliflozinEXPERIMENTALOral route. Start with a low dose of dapagliflozin administered once daily and remain on the low dose regardless of your HbA1c at week 12.
Low dose/high dose DapagliflozinEXPERIMENTALOral route. Start with a low dose of Dapagliflozin administered once daily and up titrate to the high dose Dapagliflozin administered once daily if HbA1c \>= 7% at week 12
Low dose SaxagliptinEXPERIMENTALOral route. Start with a low dose of saxagliptin administered once daily and remain on the low dose regardless of your HbA1c at week 12
Low dose/high dose SaxagliptinEXPERIMENTALOral route. Start with a low dose of saxagliptin administered once daily and up titrate to the high dose if HbA1c \>= 7% at week 12
Placebo armPLACEBO_COMPARATOROral route. Placebo tablets administered for 52 weeks
Dapagliflozin placeboPLACEBO_COMPARATOR -
Saxagliptin+Dapagliflozin+MetforminACTIVE_COMPARATOR5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin
Dapagliflozin+Saxagliptin placebo+MetforminACTIVE_COMPARATOR5 mg Tablets, Oral, Once daily, 24 weeks for Dapagliflozin and Saxagliptin Placebo
Saxagliptin+Dapagliflozin placebo+metforminACTIVE_COMPARATOR5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin placebo
dapagliflozin 5mg + insulinEXPERIMENTALdapagliflozin tablet 5mg + adjustable insulin
dapagliflozin 10mg + insulinEXPERIMENTALdapagliflozin tablet 10mg + adjustable insulin
Dapagliflozin 5 mgEXPERIMENTALDapagliflozin 5 mg tablet orally, once daily for 52 weeks
Dapagliflozin 10 mgEXPERIMENTALDapagliflozin 10 mg tablet orally, once daily for 52 weeks
Arm A: DapagliflozinEXPERIMENTALDapagliflozin 5 mg tablet orally, once daily for 52 weeks
Arm B: DapagliflozinEXPERIMENTALDapagliflozin 10 mg tablet orally, once daily for 52 weeks
Arm C: Placebo for DapagliflozinPLACEBO_COMPARATORPlacebo tablet orally, once daily for 52 weeks
Group 1: DapagliflozinEXPERIMENTALDapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin
Group 2: Dapagliflozin PlaceboPLACEBO_COMPARATORDapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Arm1: Dapagliflozin (10 mg) + Saxagliptin + Metformin IREXPERIMENTAL -
Arm 2: Placebo + Saxagliptin + Metformin IREXPERIMENTAL -
Dapagliflozin 10 mg tabletEXPERIMENTAL -
matching placebo tabletPLACEBO_COMPARATOR -
Open label treatmentEXPERIMENTAL -
1EXPERIMENTALDapagliflozin 5 mg
2EXPERIMENTALDapagliflozin 10 mg
3PLACEBO_COMPARATOR -
4PLACEBO_COMPARATORPlacebo plus open-label metformin
Placebo matching DapagliflozinPLACEBO_COMPARATORPlacebo tablets matching dapagliflozin tablets
Dapagliflozin, 10 mgEXPERIMENTALOral tablets administered as 10 mg once daily for up to 12 weeks
Placebo-matching dapagliflozinPLACEBO_COMPARATOROral tablets administered once daily in the morning
Dapagliflozin, 2. 5 mgEXPERIMENTALOral tablets administered as 2.5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)
Dapagliflozin, 5 mgEXPERIMENTALOral tablets administered as 5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)
Group 1EXPERIMENTAL -
Group 2EXPERIMENTAL -
Group 3EXPERIMENTAL -
Dapagliflozin + Metformin XREXPERIMENTALDapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks Metformin XR: Tablets, Oral, up to 2000 mg, once daily, 24 weeks
Dapagliflozin + PlaceboEXPERIMENTALDapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks. Placebo: Metformin HCl Modified Release matching placebo tablets, once daily, 24 weeks.
Metformin XR + PlaceboACTIVE_COMPARATORMetformin XR: Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks Placebo: Dapagliflozin matching placebo tablets once daily, 24 weeks
AEXPERIMENTALDapagliflozin 10 mg plus Metformin
BPLACEBO_COMPARATORPlacebo plus Metformin
Dapagliflozin 1 mgEXPERIMENTALDapagliflozin: 1 mg
Dapagliflozin 2.5 mgEXPERIMENTALDapagliflozin: 2.5 mg
Arm 1EXPERIMENTAL -
Arm 2EXPERIMENTAL -
Arm 3PLACEBO_COMPARATOR -
Placebo + MetforminPLACEBO_COMPARATORParticipants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Dapagliflozin, 2.5 mg + MetforminEXPERIMENTALParticipants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Dapagliflozin, 5 mg + MetforminEXPERIMENTALParticipants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Dapagliflozin, 10 mg + MetforminEXPERIMENTALParticipants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Group 1: Dapagliflozin, 2.5 mg AMEXPERIMENTALParticipants with hemoglobin A1c (HbA1c) ≥7% and ≤10% at enrollment received dapagliflozin tablets, 2.5 mg, once each morning for up to 102 weeks.
Group 1: Dapagliflozin, 10 mg AMEXPERIMENTALParticipants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 10 mg, once each morning for up to 102 weeks.
Group 1: Dapagliflozin 2.5 mg PMEXPERIMENTALParticipants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 2.5 mg, once each evening for up to 102 weeks.
Group 1: Dapagliflozin, 5 mg PMEXPERIMENTALParticipants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 5 mg, once each evening for up to 102 weeks.
Group 1: Dapagliflozin, 10 mg PMEXPERIMENTALParticipants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 10 mg, once each evening for up to 102 weeks.
Group 2: Dapagliflozin, 5 mg AMEXPERIMENTALParticipants with HbA1c ≥10.1% and ≤12% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks.
Group 2: Dapagliflozin, 10 mg AMEXPERIMENTALParticipants with HbA1c ≥10.1% and ≤12% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks.
Group 1: Dapagliflozin placebo AM & PMEXPERIMENTALParticipants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin placebo once each morning and evening for up to 102 weeks.
Group 1: Dapaglifozon, 5 mg AMEXPERIMENTALParticipants with (HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks.
Dapagliflozin with dietary counselingEXPERIMENTALDaily oral administration of dapagliflozin tablet with dietary counseling to promote weight loss.
Placebo with dietary counselingPLACEBO_COMPARATORDaily oral administration of placebo tablet with dietary counseling to promote weight loss.
MetforminACTIVE_COMPARATORMetformin, 2 x 850 mg per day
ExerciseACTIVE_COMPARATORExercise, interval training
ControlNO_INTERVENTIONNo intervention
Dapagliflozin 10mgEXPERIMENTALTablets administered orally once daily for 24 weeks
Dapagliflozin 10mg + Saxagliptin 2.5mgEXPERIMENTALTablets administered orally once daily for 24 weeks
Omega-3 carboxylic acids 4g / dayEXPERIMENTAL -
Dapagliflozin, 10mg / dayEXPERIMENTAL -
Omega-3 carboxylic acids 4g/day+Dapagliflozin 10mg/dayEXPERIMENTAL -
Arm 1: Dapagliflozin (1 mg)EXPERIMENTAL -
Arm 2: Dapagliflozin (2.5 mg)EXPERIMENTAL -
Arm 3: Dapagliflozin (5 mg)EXPERIMENTAL -
Arm 4: Dapagliflozin (10 mg)EXPERIMENTAL -
Arm 5: Placebo matching DapagliflozinEXPERIMENTAL -
HydrochlorothiazideACTIVE_COMPARATOR -
5PLACEBO_COMPARATORPlacebo
Dapagliflozin (10 mg)ACTIVE_COMPARATOR -
Dapagliflozin (5 mg)ACTIVE_COMPARATOR -
Cohort 1EXPERIMENTAL20 mg
Cohort 2 - Arm 1EXPERIMENTAL10 mg
Cohort 2 - Arm 2EXPERIMENTAL20 mg
Cohort 2 - Arm 3PLACEBO_COMPARATOR -
Arm 4EXPERIMENTAL -
Arm 5EXPERIMENTAL -
Arm 6PLACEBO_COMPARATOR -
Arm 7ACTIVE_COMPARATOR -
Cohort 1 Treatment AEXPERIMENTALSingle-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (1000 mg) XR (Extended-release) FDC (Fixed-dose combination) tablet administered orally under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).
Cohort 1 Treatment BEXPERIMENTALSingle-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (850 mg) XR FDC tablet, administered orally under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).
Cohort 1 Treatment C (Reference product)ACTIVE_COMPARATORSingle-dose of Onglyza® (2.5 mg saxagliptin), Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin XR) co-administered under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).
Cohort 2 Treatment DEXPERIMENTALSingle-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (1000 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).
Cohort 2 Treatment EEXPERIMENTALSingle-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (850 mg) XR FDC tablet, administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).
Cohort 2 Treatment F (Reference Product)ACTIVE_COMPARATORSingle-dose of Onglyza® (2.5 mg saxagliptin), Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin) co-administered under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).
Cohort 3 Treatment GEXPERIMENTALSingle-dose dapagliflozin (5 mg) / metformin (1000 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).
Cohort 3 Treatment HEXPERIMENTALSingle-dose dapagliflozin (5 mg) / metformin (850 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).
Cohort 3 Treatment I (Reference Product)ACTIVE_COMPARATORSingle-dose Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin) co-administered under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).
Placebo Oral TabletsPLACEBO_COMPARATORtwo administrations identical to the experimental drug
dapagliflozin 5mgEXPERIMENTALdapagliflozin tablet 5mg
Dapagliflozin (T2DM)ACTIVE_COMPARATOR -
Dapagliflozin (Healthy Subjects)ACTIVE_COMPARATOR -
dapagliflozin (0.001 mg)EXPERIMENTALCohort 1
dapagliflozin (0.01 mg)EXPERIMENTALCohort 2
dapagliflozin (0.1 mg)EXPERIMENTALCohort 3
dapagliflozin (0.3 mg)EXPERIMENTALCohort 4
dapagliflozin (1 mg)EXPERIMENTALCohort 5
dapagliflozin (2.5 mg)EXPERIMENTALCohort 6
FDC of dapagliflozin/metformin XROTHER -
FDC of dapagliflozin/reduced mass metformin XROTHER -
dapagliflozin and Glucophage® XROTHER -
Dapagliflozin + WarfarinACTIVE_COMPARATOR -
WarfarinACTIVE_COMPARATOR -
Dapagliflozin + DigoxinACTIVE_COMPARATOR -
DigoxinACTIVE_COMPARATOR -
GlimepirideACTIVE_COMPARATOR -
Dapagliflozin + GlimepirideACTIVE_COMPARATOR -
SitagliptinACTIVE_COMPARATOR -
Dapagliflozin + SitagliptinACTIVE_COMPARATOR -
simvastatinACTIVE_COMPARATOR -
Dapagliflozin + simvastatinACTIVE_COMPARATOR -
valsartanACTIVE_COMPARATOR -
Dapagliflozin + valsartanACTIVE_COMPARATOR -

Interventions

NameTypeDescription
DapagliflozinDRUGDapagliflozin 10 mg tablets given once daily, per oral use
PlaceboDRUGPlacebo matching dapagliflozin 10 mg tablets given once daily, per oral use
SaxagliptinDRUGTablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily
Dapagliflozin placeboDRUGmatching placebo tablets, administered orally once daily, for the 24-week blinded treatment period. Dapagliflozin 10mg tablets administered orally once daily,for the 28-week site and subject blinded long term extension.
Placebo for DapagliflozinDRUGDoes not contain active ingredient, orally, Green, plain, diamond-shaped, film-coated tablet
Placebo for SaxagliptinDRUGDoes not contain active ingredient, orally, Plain, yellow, biconvex, round, film-coated tablet
Dapagliflozin 5 mgDRUGDapagliflozin, a blood glucose lowering drug. Oral dose
Dapagliflozin 10mgDRUGDapagliflozin, a blood glucose lowering drug. Oral dose
Dapagliflozin 10 mgDRUGTablets administered orally once daily for 24 weeks. Randomization will be stratified by pre-enrolment anti-hyperglycemic therapy
Matching Placebo for DapagliflozinDRUGMatching Placebo for Dapagliflozin tablets administered orally once daily for 24 weeks
Placebo tabletDRUGOral dose (od)
Placebo matching with DapagliflozinDRUGTablets, Oral, 0 mg, Once daily, Up to 52 weeks
Metformin immediate release (IR)DRUGTablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks
metforminDRUG\>/= 1500 mg total daily dose, tablets taken orally, twice daily
Placebo matching DapagliflozinDRUGTablets, Oral, 0 mg, once daily, Up to 12 weeks
Placebo-matching dapagliflozinDRUGOral tablets administered as 0 mg once daily for up to 12 weeks
PioglitazoneDRUGTablets, Oral, 15-45 mg (as needed for rescue based on protocol specific criteria), Up to 20 weeks
Metformin XRDRUGTablets, Oral, up to 2000 mg, once daily, 24 weeks
dapagliflozin matching PlaceboDRUGTablets
metformin HCl Modified Release matching PlaceboDRUGTablets
SitagliptinDRUGTablet oral 100 mg total daily dose once daily rescue medication
Thiazolidinedione (Pioglitazone)DRUGTablets, ≥ 30 mg, Once daily, up to 48 weeks
GlimepirideDRUGtablet oral 2.5, 5, or 10 mg total daily dose once daily 48 weeks
metformin hydrochlorideDRUGrescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
pioglitazone hydrochlorideDRUGrescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
RosiglitazoneDRUGrescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
glipizideDRUGCapsule oral 5, 10, or 20 mg total daily dose once or split/twice daily 208 weeks
Dapagliflozin TabletDRUGDaily oral administration of dapagliflozin with dietary counseling to promote weight loss. Dapagliflozin 5 mg tablet will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
ExerciseBEHAVIORALInterval training, 5 times per week, 30 min per session
Saxagliptin 2.5 mgDRUGTablets administered orally once daily for 24 weeks.
Matching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mgDRUGTablets administered orally once daily for 24 weeks.
Omega-3 carboxylic acidsDRUG4 g administered as 4 x 1 g capsules
HydrochlorothiazideDRUGTablets, Oral, 25 mg, once daily, 12 weeks
2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tabletDRUGUsed in Treatment B and Treatment E.
2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tabletDRUGUsed in Treatment A and Treatment D.
5 mg dapagliflozin / 850 mg metformin XR FDCDRUGUsed in Treatment H.
5 mg dapagliflozin / 1000 mg metformin XR FDCDRUGUsed in Treatment G.
2.5 mg ONGLYZA® (saxagliptin) tabletDRUGUsed in treatments C and F.
5 mg Forxiga® (dapagliflozin) tabletDRUGUsed in treatments C, F and I.
500 mg Glucophage XR®DRUGUsed in treatments C, F and I.
Placebo Oral TabletDRUGtwo administrations in the evening and 12 hours later
Dapagliflozin 5mgDRUGDapagliflozin, a blood glucose lowering drug. Oral dose
Dapagliflozin + Glucophage tablet fastedDRUGSingle oral doses of 5 mg dapagliflozin and 850 mg Glucophage® tablets administered together in the fasted state
Dapagliflozin/metformin IR FDC tablet fastedDRUGsingle oral dose of dapagliflozin/metformin (5 mg/850 mg) IR FDC tablet in the fasted state
Dapagliflozin + Glucophage tablet fedDRUGSingle oral doses of 5 mg dapagliflozin and 850 mg Glucophage® tablets administered together in the fed state
Dapagliflozin/metformin IR FDC tablet fedDRUGsingle oral dose of dapagliflozin/metformin (5 mg/850 mg) IR FDC tablet in the fed state
GlucophageDRUGTablets, Oral, 1000 mg, Single Dose
WarfarinDRUGTablets, Oral, 25 mg, Single Dose
DigoxinDRUGTablets, Oral, 0.25, Single Dose
simvastatinDRUGTablets, Oral, 20 mg, Single Dose
valsartanDRUGTablets, Oral, 320 mg, Single Dose
Dapagliflozin + GlimepirideDRUGTablets, Oral, Dapagliflozin 20 mg + Glimepiride 4 mg, once daily, single dose
Dapagliflozin + MetforminDRUGTablets, Oral, once daily, single dose Dapagliflozin: 20 mg Metformin: 1000 mg
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Eligibility Criteria

Age Range18 Years to 130 Years
SexALL
Healthy VolunteersNo
Study Sites103

Inclusion Criteria: * Participant must be ≥18 at the time of signing the informed consent * Confirmed MI, either STEMI or NSTEMI, according to the fourth universal definition of MI (Thygesen et al 2019), within the preceding 7 days, or 10 days if earlier randomisation is not feasible * Evidence of ...

Countries:SwedenUnited KingdomUnited StatesBrazilCanadaDenmarkJapanSlovakiaSouth AfricaSouth KoreaArgentinaBulgariaItalyBelgiumChinaCzechiaHungaryMexicoNetherlandsPeruPolandRomaniaRussiaSaudi ArabiaSpainTaiwanVietnamAustraliaChileColombiaFinlandIndiaIsraelMalaysiaNew ZealandPhilippinesThailandTurkey (Türkiye)UkraineGermanySwitzerlandAustriaFranceSingaporeHong KongPuerto RicoIreland
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Frequently asked questions about Dapagliflozin

What is Dapagliflozin used for?

Dapagliflozin is an investigational small molecule being developed for cardiovascular and metabolic conditions, including diabetes mellitus, chronic kidney disease, heart failure with preserved ejection fraction, and type 1 diabetes mellitus. It is also studied in healthy volunteers for bioequivalence assessments. The drug is in Phase 3 clinical development.

Who makes Dapagliflozin?

Dapagliflozin is developed by AstraZeneca PLC, a biopharmaceutical company listed on the stock exchange under the ticker AZN. The company is conducting clinical trials to evaluate the drug's safety and efficacy across multiple indications.

What phase is Dapagliflozin in?

Dapagliflozin is in Phase 3 clinical development. It has completed 20 clinical trials with a total enrollment of 17,379 participants. The trials are randomized, double-blind, and placebo-controlled, indicating a rigorous evaluation process for the drug's efficacy and safety.

What clinical trials is Dapagliflozin in?

Dapagliflozin has completed several clinical trials, including NCT01294436 in Japanese subjects with type 2 diabetes, NCT02279407 for liver fat in diabetic patients, NCT03877237 for heart failure with reduced ejection fraction, and NCT04856007 for bioequivalence in healthy Chinese subjects. All trials are completed.

Is Dapagliflozin the same as Farxiga?

Dapagliflozin is also known by the brand name Farxiga, which is a medication used to treat type 2 diabetes. In clinical trials, it is being studied for additional indications such as heart failure and chronic kidney disease. The drug is developed by AstraZeneca.