Clinical trial NCT03782259: Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2
Official title: Effects of SGLT-2 Inhibition With Dapagliflozin on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI With T1- and T2-mapping in Patients With Type-2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Myocardial Fibrosis
Myocardial Inflammation
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2018-12-20
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind and placebo controlled cardiac MRI study
Primary purpose: SCREENING

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Men and women at least 18 years of age
2. Subjects with type-2 diabetes history \>=5 years
3. HbA1C 7-10% with glucose control medications including insulin, metformin or sulfonylurea
4. Medically stable
5. Willing to participate and sign informed consent.

Exclusion Criteria:

1. Contraindication to MRI
2. Currently or within last three months treatment with a SGLT2 inhibitor
3. Currently taking glucagon-like peptide (GLP)-1 receptor antagonist
4. Glomerular filtration rate (GFR) \<60 mL/min/1.73 m2
5. Unstable or rapidly progressive renal disease
6. Hypotension with systolic blood pressure (SBP) \<100 mmHg
7. Hypersensitivity to dapagliflozin or any excipients
8. Patients with severe hepatic impairment (Child-Pugh class C)
9. Patients with active hepatitis B or C infection
10. Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator:

    1. Myocardial infarction
    2. Cardiac surgery or revascularization (CABG/PTCA)
    3. Unstable angina
    4. Heart Failure - New York Heart Association (NYHA) Class IV
    5. Transient ischemic attack (TIA) or significant cerebrovascular disease
    6. Unstable or previously undiagnosed arrhythmia
    7. Established peripheral artery disease (PAD)

(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.

Primary outcomes:
measure: Extracellular Volume Fraction (ECV)
timeFrame: Approximately 12 Months
measure: Global Myocardial Strain
timeFrame: Approximately 12 Months
Secondary outcomes:
measure: T2 Relaxation Time
timeFrame: Approximately 12 Months
Other outcomes:
measure: Fasting Glucose
timeFrame: Approximately 12 Months
measure: HbA1C
timeFrame: Approximately 12 Months
measure: hsCRP
timeFrame: Approximately 12 Months
Locations:
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington
name: Xue-Qiao Zhao, MD
role: PRINCIPAL_INVESTIGATOR
References: