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| ID | Type | Description | Link |
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| ESR 17-13124 | Other Identifier | AstraZeneca Pharmaceuticals, LP |
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| Name | Class |
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| AstraZeneca | INDUSTRY |
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There is an unmet need for Cardiovascular Disease (CVD) risk reduction in patients with Type 2 Diabetes. In recent trials there has been promising findings of more effective glucose management and reductions in overall CVD events and hospitalization for heart failure with SGLT-2 inhibition. Using the capability of cardiac MRI with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a clinical trial to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial strain, fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.
Over approximately 12 months subjects will have 6 clinical visits at the investigators research clinic. During this time subjects will be randomized to receive either active 10mg dapagliflozin or a matching placebo. 2 MRI scans at one of the two University of Washington research imaging centers will take place. One at randomization and the second scan will occur approximately 12 months after the first scan.
Given the unmet needs for CVD risk reduction in patients with Type 2 Diabetes Mellitus (T2DM), the promising findings of more effective glucose management and reductions in overall CVD events and hospitalization for heart failure with SGLT-2 inhibition demonstrated in recent trials, and the capability of cardiac MRI (CMRI) with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a staged research program using adaptive study design to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial strain, fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.
A total of 60 subjects with >=18 years of age, type-2 diabetes history >=5 years and HbA1C 7-10% will be randomized at 1:1 to Dapagliflozin 10mg or matching placebo once daily for 1 year. All subjects will be followed every 3 months for clinical and laboratory evaluations and assessments. All subjects will undergo CMRI at baseline and 1 year.
The primary myocardial strain endpoint includes global myocardial longitudinal strain (GLS). Myocardial fibrosis endpoint is change in extracellular volume fraction (ECV) as assessed by T1-mapping over 12 months. ECV combines native and contrast-enhanced T1 mapping. The change of the T1 relaxation rate (i.e., 1/T1) in blood between pre- and post-contrast imaging is converted with the blood hematocrit into a reference for plasma T1, which serves as reference for the T1 changes in tissue.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 10mg tabs placebo matching dapagliflozin. |
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| Active | Active Comparator | 10mg tabs of dapagliflozin |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| dapagliflozin | Drug | Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study. |
| Measure | Description | Time Frame |
|---|---|---|
| Extracellular Volume Fraction (ECV) | Cardiac MRI using T1-mapping is capable of quantifying myocardial extracellular volume (ECV), a surrogate of fibrosis, with excellent inter- and intra-observer variability. Cardiac fibrosis was assessed by cardiac MRI T1 mapping to calculate ECV at two timepoints, baseline and at approximately 1 year. ECV combines native and contrast-enhanced T1 mapping. Extracellular Volume (ECV) maps were generated offline using MATLAB software. ECV was calculated from native and post-contrast T1 values for blood and myocardial tissue, the partition coefficient lambda (λ), and hematocrit using the following formulas: ECV = λ(1-hematocrit); λ = (1/T1 myocardium post-contrast-1/T1 myocardium-native)/(1/T1 blood post-contrast-1/T1 blood-native). | Approximately 12 Months |
| Global Myocardial Strain | Global myocardial strain measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain from the Balanced Steady State Free Precession (bSSFP) short-axis and long-axis cine images. Long-axis cine images will be further used to compute global myocardial strain. Ancova test with adjusted for baseline global myocardial strain will be used to compare change in global myocardial strain over 12 months between 2 treatment groups. Global myocardial strain reported as longitudinal, radial, and circumferential at baseline and 1 year. | Approximately 12 Months |
| Measure | Description | Time Frame |
|---|---|---|
| T2 Relaxation Time | Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months | Approximately 12 Months |
| Measure | Description | Time Frame |
|---|---|---|
| Fasting Glucose | Fasting glucose assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported | Approximately 12 Months |
| HbA1C | Hemoglobin A1c (HbA1c) assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported |
Inclusion Criteria:
Exclusion Criteria:
Contraindication to MRI
Currently or within last three months treatment with a SGLT2 inhibitor
Currently taking glucagon-like peptide (GLP)-1 receptor antagonist
Glomerular filtration rate (GFR) <60 mL/min/1.73 m2
Unstable or rapidly progressive renal disease
Hypotension with systolic blood pressure (SBP) <100 mmHg
Hypersensitivity to dapagliflozin or any excipients
Patients with severe hepatic impairment (Child-Pugh class C)
Patients with active hepatitis B or C infection
Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator:
(18) Active bladder cancer (19) Recent episode of Diabetic ketoacidosis (DKA), frequent episodes of DKA (20) High risk of fractures, amputations and fibrosis (21) Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopausal) who have a positive pregnancy test at enrollment or randomization, OR women who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator, from the time of signing the informed consent until two weeks after the last dose of study drug, OR women who are breast-feeding.
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| Name | Affiliation | Role |
|---|---|---|
| Xue-Qiao Zhao, MD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Washington | Seattle | Washington | 98104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41629250 | Derived | Naumova AV, Cunha GM, Kim NJ, Lu J, Isquith D, Chu B, Maynard C, Mahdavi A, Firoozeh N, Ordovas K, Zhao XQ, Kim F. Dapagliflozin-Associated Reduction in Liver Fat Is Independent of Weight Loss in Patients With Type 2 Diabetes. Obesity (Silver Spring). 2026 Mar;34(3):622-629. doi: 10.1002/oby.70134. Epub 2026 Feb 2. | |
| 38849829 | Derived |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | 10mg tabs placebo matching dapagliflozin. Placebo: Placebo |
| FG001 | Dapagliflozin | 10mg tabs of dapagliflozin dapagliflozin: Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 12, 2022 |
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Randomized, double-blind and placebo controlled cardiac MRI study
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| Placebo | Other | Placebo |
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| Approximately 12 Months |
| hsCRP | Inflammatory marker hsCRP assessed at Baseline and every 6 months for approximately 12 months, Baseline and 12 months reported | Approximately 12 Months |
| Wang DD, Naumova AV, Isquith D, Sapp J, Huynh KA, Tucker I, Balu N, Voronyuk A, Chu B, Ordovas K, Maynard C, Tian R, Zhao XQ, Kim F. Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure. Cardiovasc Diabetol. 2024 Jun 7;23(1):197. doi: 10.1186/s12933-024-02294-z. |
| 38585865 | Derived | Wang D, Naumova A, Isquith D, Sapp J, Huynh KA, Tucker I, Balu N, Voronyuk A, Chu B, Ordovas K, Maynard C, Tian R, Zhao XQ, Kim F. Dapagliflozin Reduces Systemic Inflammation in Patients with Type 2 Diabetes Without Known Heart Failure. Res Sq [Preprint]. 2024 Mar 25:rs.3.rs-4132581. doi: 10.21203/rs.3.rs-4132581/v1. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | 10mg tabs placebo matching dapagliflozin. Placebo: Placebo |
| BG001 | Dapagliflozin | 10mg tabs of dapagliflozin dapagliflozin: Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
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| Hypertension | Count of Participants | Participants |
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| Diabetes mellitus | Count of Participants | Participants |
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| Hyperlipidemia | Count of Participants | Participants |
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| Current smoker | Count of Participants | Participants |
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| Family history myocardial infarction | Count of Participants | Participants |
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| Family history stroke | Count of Participants | Participants |
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| History myocardial infarction | Count of Participants | Participants |
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| Angina | Count of Participants | Participants |
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| Coronary artery bypass surgery | Count of Participants | Participants |
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| Percutaneous coronary intervention | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Extracellular Volume Fraction (ECV) | Cardiac MRI using T1-mapping is capable of quantifying myocardial extracellular volume (ECV), a surrogate of fibrosis, with excellent inter- and intra-observer variability. Cardiac fibrosis was assessed by cardiac MRI T1 mapping to calculate ECV at two timepoints, baseline and at approximately 1 year. ECV combines native and contrast-enhanced T1 mapping. Extracellular Volume (ECV) maps were generated offline using MATLAB software. ECV was calculated from native and post-contrast T1 values for blood and myocardial tissue, the partition coefficient lambda (λ), and hematocrit using the following formulas: ECV = λ(1-hematocrit); λ = (1/T1 myocardium post-contrast-1/T1 myocardium-native)/(1/T1 blood post-contrast-1/T1 blood-native). | Posted | Mean | Standard Deviation | Percentage of total tissue volume | Approximately 12 Months |
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| Primary | Global Myocardial Strain | Global myocardial strain measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain from the Balanced Steady State Free Precession (bSSFP) short-axis and long-axis cine images. Long-axis cine images will be further used to compute global myocardial strain. Ancova test with adjusted for baseline global myocardial strain will be used to compare change in global myocardial strain over 12 months between 2 treatment groups. Global myocardial strain reported as longitudinal, radial, and circumferential at baseline and 1 year. | Posted | Mean | Standard Deviation | Change in length as a percentage | Approximately 12 Months |
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| Secondary | T2 Relaxation Time | Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months | Posted | Mean | Standard Deviation | milliseconds | Approximately 12 Months |
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| Other Pre-specified | Fasting Glucose | Fasting glucose assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported | Posted | Median | Standard Deviation | mg/dL | Approximately 12 Months |
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| Other Pre-specified | HbA1C | Hemoglobin A1c (HbA1c) assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported | Posted | Mean | Standard Deviation | percentage | Approximately 12 Months |
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| Other Pre-specified | hsCRP | Inflammatory marker hsCRP assessed at Baseline and every 6 months for approximately 12 months, Baseline and 12 months reported | Posted | Mean | Standard Deviation | mg/dL | Approximately 12 Months |
|
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Study screening visit to subject completion, approximately 13 months per subject.
Adverse events were assessed at each of the subject visits.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | 10mg tabs placebo matching dapagliflozin. Placebo: Placebo | 0 | 31 | 1 | 31 | 0 | 31 |
| EG001 | Active | 10mg tabs of dapagliflozin dapagliflozin: Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study. | 0 | 31 | 0 | 31 | 0 | 31 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Non-ST-elevation myocardial infarction | Cardiac disorders | Systematic Assessment | PI determined not related to study intervention with causality as pre-existing/underlying disease - ASCVD, Diabetes. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Francis Kim, MD | University of Washington | 206-744-8305 | fkim@uw.edu |
| Oct 23, 2023 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 1, 2020 | Oct 23, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D009205 | Myocarditis |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D009202 | Cardiomyopathies |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C529054 | dapagliflozin |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Difference (1 year - baseline) |
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