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The DAPA-MEMRI Trial (DAPA-MEMRI)

Primary Purpose

Heart Failure, Diabetic Cardiomyopathies

Status
Recruiting
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Dapagliflozin 10 milligrams [Farxiga]
Placebo
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Heart Failure focused on measuring Heart failure, Sodium glucose Co-transporter 2 inhibitor therapy, Manganese enhanced cardiac magnetic resonance imaging

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • University of EdinburghRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Patients with heart failure without type 2 diabetes

Patients with heart failure with type 2 diabetes

Arm Description

60 patients with heart failure without type 2 diabetes will be recruited and will either be randomised to placebo or Dapagliflozin after their baseline cardiac MRIs. They will have 2 cardiac MRIs (gadolinium and manganese enhanced) at baseline and further manganese enhanced cardiac MRI at 1 month post randomisation + gadolinium and manganese enhanced cardiac MRI at 6 months post randomisation.

60 patients with heart failure with type 2 diabetes will be recruited and will either be randomised to placebo or Dapagliflozin after their baseline cardiac MRIs. They will have 2 cardiac MRIs (gadolinium and manganese enhanced) at baseline and further manganese enhanced cardiac MRI at 1 month post randomisation + gadolinium and manganese enhanced cardiac MRI at 6 months post randomisation.

Outcomes

Primary Outcome Measures

Rate of change in myocardial T1 values with manganese enhanced cardiac MRI

Secondary Outcome Measures

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

Full Information

First Posted
August 14, 2020
Last Updated
October 12, 2020
Sponsor
University of Edinburgh
Collaborators
AstraZeneca, NHS Lothian
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1. Study Identification

Unique Protocol Identification Number
NCT04591639
Brief Title
The DAPA-MEMRI Trial
Acronym
DAPA-MEMRI
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.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Recruiting
Study Start Date
August 19, 2020 (Actual)
Primary Completion Date
August 19, 2023 (Anticipated)
Study Completion Date
August 19, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
AstraZeneca, NHS Lothian

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Diabetic Cardiomyopathies
Keywords
Heart failure, Sodium glucose Co-transporter 2 inhibitor therapy, Manganese enhanced cardiac magnetic resonance imaging

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
The observational component of the study will have 4 cohort of participants (patients with type 2 diabetes without heart failure, patients with heart failure with or without diabetes and healthy volunteers) The randomised controlled trial component of the study will have 2 groups of patients - heart failure with or without type 2 diabetes
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
As above
Allocation
Randomized
Enrollment
160 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patients with heart failure without type 2 diabetes
Arm Type
Other
Arm Description
60 patients with heart failure without type 2 diabetes will be recruited and will either be randomised to placebo or Dapagliflozin after their baseline cardiac MRIs. They will have 2 cardiac MRIs (gadolinium and manganese enhanced) at baseline and further manganese enhanced cardiac MRI at 1 month post randomisation + gadolinium and manganese enhanced cardiac MRI at 6 months post randomisation.
Arm Title
Patients with heart failure with type 2 diabetes
Arm Type
Other
Arm Description
60 patients with heart failure with type 2 diabetes will be recruited and will either be randomised to placebo or Dapagliflozin after their baseline cardiac MRIs. They will have 2 cardiac MRIs (gadolinium and manganese enhanced) at baseline and further manganese enhanced cardiac MRI at 1 month post randomisation + gadolinium and manganese enhanced cardiac MRI at 6 months post randomisation.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin 10 milligrams [Farxiga]
Intervention Description
Patients with heart failure with or without type 2 diabetes will be either randomised to 10mg Dapagliflozin once daily or matched placebo.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Patients with heart failure with or without type 2 diabetes will be either randomised to 10mg Dapagliflozin once daily or matched placebo.
Primary Outcome Measure Information:
Title
Rate of change in myocardial T1 values with manganese enhanced cardiac MRI
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Left ventricular ejection fraction measured in percentage on cardiac MRI
Time Frame
6 months
Title
Left ventricular mass measured in grams on cardiac MRI
Time Frame
6 months
Title
Cardiac biomarkers like N-terminal pro B-type natriuretic peptide in nanogram per litre
Time Frame
6 months
Title
Markers of diabetes control including glucose in millimoles per litre
Time Frame
6 months
Title
Clinical measures such as heart rate in beats per minute
Time Frame
6 months
Title
Extracellular volume in percentage as per cardiac MRI measurements
Time Frame
6 months
Title
Global longitudinal strain in percentage as calculated on cardiac MRI
Time Frame
6 months
Title
Clinical measures such as body weight in Kilograms
Time Frame
6 months
Title
Clinical measures such as blood pressure in millimetres of mercury
Time Frame
6 months
Title
Cardiac biomarkers like high sensitivity cardiac troponin I in nanogram per litre
Time Frame
6 months
Title
Measures of glucose control like glycated haemoglobin (HbA1c) in millimoles per mole
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Shruti Joshi, MBBS, MRCP
Phone
0131 650 1000
Email
sjoshi@ed.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
David Newby, PhD, BM, DM, MRCP, DSc, FRSE
Phone
0131 650 1000
Email
d.e.newby@ed.ac.uk
Facility Information:
Facility Name
University of Edinburgh
City
Edinburgh
State/Province
Scotland
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shruti Joshi, MBBS, MRCP
Phone
0131 650 1000
Email
sjoshi@ed.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
No

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The DAPA-MEMRI Trial

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