The DAPA-MEMRI Trial

Official title

An Observational Cross-sectional Study and a Double-blind Placebo Controlled Randomised Controlled Trial to Assess the Effect of Dapagliflozin on Myocardial Calcium-handling in Patients With Heart Failure- The DAPA-MEMRI Trial.

Overview

Diabetes mellitus is among the top 10 causes of death worldwide with an increasing incidence. Patients with diabetes are at risk of developing heart failure which is characterised by significant changes in the heart muscle including scarring and thickening. Contraction of the heart involves movement of calcium across the heart muscle and disruption of this process is an early change seen in heart failure. Recently, a drug therapy (SGLT2 inhibitor therapy) in patients with diabetes was shown to benefit patients with heart failure but the mechanisms of benefit are unknown. Our hypothesis is that calcium handling is altered in patients with either type 2 diabetes mellitus (T2DM) or heart failure and that SGLT2 inhibitors can improve this in heart failure irrespective of the presence of T2DM. Scanning the heart using magnetic resonance imaging (MRI) enables detailed assessment of its structure and function by using a new contrast 'dye' containing manganese that has shown advantages over traditional contrast. We plan to further test this new dye as it has the potential to track and quantify improvements in heart function over time and detect changes in calcium handling in the heart muscle, making it an ideal measure to identify the mechanisms of benefit from SGLT2 inhibitor therapy. The study population will comprise patients with heart failure with and without type 2 diabetes, patients with type 2 diabetes without heart failure and healthy volunteers. Baseline comparisons will be made between the four groups before progressing to the randomised controlled trial with heart failure patients only. Patients will have a clinical assessment and blood tests, electrocardiogram, echocardiogram and MRI of the heart at each visit. If successful, this study will give us significant insights into mechanisms of action of SGLT2 inhibitors in heart failure and will enable us to tailor specific treatments in heart failure patients.

Detailed description

The study is designed to investigate the myocardial calcium handling in patients with heart failure with or without type 2 diabetes mellitus and if Dapagliflozin (study drug) improves the myocardial calcium handling in patients with heart failure and diabetes mellitus.

We propose to conduct this study in two parts.

1. OBSERVATIONAL CROSS-SECTIONAL STUDY

An observational cross-sectional study will be undertaken to compare myocardial calcium in patients with diabetes mellitus and normal left ventricular ejection fraction (n=20), patients with heart failure in the absence of diabetes mellitus (n=60), and patients with both diabetes mellitus and heart failure (n=60). They will be compared with healthy volunteers (n=20).

There will be an initial meeting, where informed consent will be documented and a medical assessment including blood tests will be undertaken as well as an echocardiogram will be performed. Healthy volunteers will only undergo Manganese enhanced cardiac MRI scan. The other cohorts will undergo a gadolinium enhanced cardiac MRI scan on their first visit. On a subsequent visit, they will undergo 1 cardiac Manganese enhanced Manganese MRI scan (MEMRI) which lasts 45-60 minutes. Participants will be monitored with blood pressure and ECG monitoring throughout the MEMRI scan. Patients will be offered an anti-sickness medication if required following the MEMRI scan. 2. RANDOMISED CONTROLLED TRIAL

We will undertake a randomised double-blind placebo controlled trial of patients with heart failure with (n=60) and without (n=60) type 2 diabetes mellitus. These participants would have been recruited as part of the observational study as described above from out-patient clinics at the Edinburgh Heart Centre. If all eligibility criteria are met, patients will be randomised to receive treatment with either Dapagliflozin 10 mg, or matched placebo, once daily for 6 months at a ratio of 1:1. Detailed clinical assessment including history and examination, blood sampling, electrocardiogram, echocardiogram and cardiac MRI will be collected at baseline, 1 and 6 months.

There will also be a 3 month safety visit after randomisation to record any adverse events.

Interventions

• Drug Dapagliflozin 10 milligrams [Farxiga]
  Patients with heart failure with or without type 2 diabetes will be either randomised to 10mg Dapagliflozin once daily or matched placebo.
• Drug Placebo
  Patients with heart failure with or without type 2 diabetes will be either randomised to 10mg Dapagliflozin once daily or matched placebo.

Primary outcome measures

• Rate of change in myocardial T1 values with manganese enhanced cardiac MRI [Time frame: 6 months]

Secondary outcome measures (11)

• Left ventricular ejection fraction measured in percentage on cardiac MRI [Time frame: 6 months]
• Left ventricular mass measured in grams on cardiac MRI [Time frame: 6 months]
• Cardiac biomarkers like N-terminal pro B-type natriuretic peptide in nanogram per litre [Time frame: 6 months]
• Markers of diabetes control including glucose in millimoles per litre [Time frame: 6 months]
• Clinical measures such as heart rate in beats per minute [Time frame: 6 months]
• Extracellular volume in percentage as per cardiac MRI measurements [Time frame: 6 months]
• Global longitudinal strain in percentage as calculated on cardiac MRI [Time frame: 6 months]
• Clinical measures such as body weight in Kilograms [Time frame: 6 months]
• Clinical measures such as blood pressure in millimetres of mercury [Time frame: 6 months]
• Cardiac biomarkers like high sensitivity cardiac troponin I in nanogram per litre [Time frame: 6 months]
• Measures of glucose control like glycated haemoglobin (HbA1c) in millimoles per mole [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

Patients with heart failure (with or without type 2 diabetes mellitus)

• Aged over 18 years
• Diagnosis of symptomatic reduced ejection fraction heart failure for at least 2 months
• Left ventricular ejection fraction ≤40%
• Elevated N-terminal pro B-type natriuretic peptide (>125 pg/mL)
• Clinical diagnosis of type 2 diabetes mellitus for 50% of patient population - on stable therapy for at least 12 months or more.

Patients with Type 2 Diabetes Mellitus and no heart failure

• Aged over 18 years
• Clinical diagnosis of type 2 diabetes mellitus (diagnosed by either HbA1c of 48mmol/mol (6.5%) or greater or fasting plasma glucose level of 7mmol/L or greater at the time of diagnosis)

\- on stable therapy for at least 12 months or more.

• Normal left ventricular systolic ejection fraction

Healthy Volunteers

• Aged over 18 years
• Normal left ventricular ejection fraction and glycaemia
• No clinically significant co-morbid conditions

Exclusion criteria

Patients with heart failure (with or without type 2 diabetes mellitus)

• Receiving an SGLT2 inhibitor within 8 weeks of enrolment
• Previous intolerance of, or contraindication to, an SGLT2 inhibitor
• Standard magnetic resonance imaging safety exclusions
• Severe renal impairment (eGFR <30millilitre/min. 1.73m2)
• Type 1 diabetes mellitus
• Symptomatic hypotension or systolic blood pressure <95 mmHg
• Recent (within 12 weeks) hospitalisation for heart failure, acute cardiovascular event (such as myocardial infarction or stroke) or coronary re-vascularisation.
• 2nd or 3rd degree atrioventricular block Atrial fibrillation or flutter with poor ventricular rate control (>100 /min)
• Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease
• New York Heart Association grade IV heart failure
• Obstructive liver function testing abnormalities
• Concomitant digoxin, diltiazem or verapamil therapy.

Patients with type 2 diabetes mellitus and no heart failure

• Other major clinically significant co-morbid conditions
• History of ischaemic heart disease or present history suggestive of probable clinically significant underlying ischaemic heart disease
• Standard magnetic resonance imaging safety exclusions
• Moderate or severe renal impairment (eGFR <45 mL/min. 1.73m2)
• Receiving a SGLT2 inhibitor at any time
• Symptomatic hypotension or systolic blood pressure <95 mmHg
• Abnormal electrocardiogram
• Clinically significant abnormalities of clinical haematology or biochemistry measurements.

Healthy Volunteers

• Major or clinically significant cardiovascular disease
• Diabetes mellitus
• Receiving an SGLT2 inhibitor at any time
• Standard magnetic resonance imaging safety exclusions
• Moderate or severe renal impairment (eGFR <45 mL/min. 1.73m2)
• Symptomatic hypotension or systolic blood pressure <95 mmHg
• Abnormal electrocardiogram
• Clinically significant abnormalities of clinical haematology or biochemistry measurements.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Other

Study locations

United Kingdom · 1 center

• University of Edinburgh — Edinburgh

Identifiers

NCT: NCT04591639 · AC20006

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗