Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000187842
Ethics application status
Approved
Date submitted
11/11/2020
Date registered
22/02/2021
Date last updated
22/02/2021
Date data sharing statement initially provided
22/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Mechanisms of action of SGLT2 inhibitors in patients with heart failure with reduced ejection fraction (HFrEF)
Scientific title
Mechanisms of action of SGLT2 inhibitors in patients with heart failure with reduced ejection fraction (HFrEF)
Secondary ID [1] 302983 0
DAPA-HErEF
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with Reduced Ejection fraction 319716 0
Condition category
Condition code
Cardiovascular 317646 317646 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study medication of 10mg dapagliflozin (active) or 10mg of lactulose powder (control) tablets to be administered orally once daily in tablet formation at visit 2, following all inclusion and exclusion criteria having being met. At The next clinic visit (week 4 the patients will be asked to return study medication for tablet count and reconciliation to establish compliance. At the last clinic visit week 8 patients will be asked to return all unused study medication for further tablet reconciliation to establish compliance (>85%).
Intervention code [1] 319050 0
Treatment: Drugs
Comparator / control treatment
10mg of Lactose powder capsule to be taken orally once daily for 8 weeks.
Control group
Placebo

Outcomes
Primary outcome [1] 325693 0
To elucidate changes in haemodynamics as assessed by right heart catheter from the baseline visit prior to the commencement of treatment to the end of treatment 8 weeks later.
Right Heart catheter measurements obtained from procedures at baseline and at end of treatment, week 8. These include, Right Atrial , Pulmonary Artery and Pulmonary Capillary Wedge pressures and Cardiac Index, Arterial and mixed venous blood gases.
Timepoint [1] 325693 0
The timepoints will be at;
baseline prior to starting treatment;
At end of treatment (week 8)
Primary outcome [2] 326585 0
To elucidate changes in the anthropometric measurements including physical examination (including heart rate and blood pressure recordings), 12 lead electrocardiogram (ECG) from the baseline visit prior to the commencement of treatment, at the interim visit (week 4) to the end of treatment 8 weeks later.
Timepoint [2] 326585 0
The time points will be;
Baseline visit prior to starting treatment
Randomization Visit
Interim Visit (week 4)
End of study visit (week 8)
Secondary outcome [1] 388766 0

To measure the change in the trans-cardiac gradient for NT-proBNP. (cardiac natriuretic peptide) from baseline measurements prior to commencement of study treatment to the end of study treatment at 8 weeks.
Timepoint [1] 388766 0
The blood test for NT-proBNP measurement will be collected at;
Baseline-prior to starting treatment
Interim Visit (4 weeks)- mid way after starting treatment
8 weeks -End of treatment.
Secondary outcome [2] 389672 0
To assess the composite effects of SGLT2 inhibition on regional (cardiac, renal and hepatic) sympathetic activity, metabolic activity and inflammation by performing paired venous and arterial sampling across the coronary sinus, renal vein and the hepatic vein.
Timepoint [2] 389672 0
Regional cardiac, renal and hepatic blood sampling will be obtained at;
baseline, (prior to starting treatment)
end of treatment week 8
Secondary outcome [3] 389717 0
To assess changes in self-perception of heart failure severity using The Kansas City Cardiomyopathy Questionnaire (KCCQ)
Timepoint [3] 389717 0
The questionnaire will be administered at;
baseline (prior to starting treatment)
end of treatment at week 8.
Secondary outcome [4] 389718 0
To assess changes in Transthoracic echocardiography by measuring changes in the following parameters; LV volumes, LV ejection fraction, LA volume index, E/A ratio, E/e’ (averaged mitral annular velocity), global longitudinal strain, RV fractional area change, TAPSE at these two points in the study.
Timepoint [4] 389718 0
The transthoracic echocardiography test will be conducted at baseline visit, prior to commencement of treatment and repeated at end of treatment phase week 8.

Eligibility
Key inclusion criteria
LVEF less than or equal to 40%. NYHA II-IV.
Ischaemic or non-Ischaemic aetiology.
Stable heart failure therapy for 1 month (a <50% adjustment to diuretics is permissible between day -14 and day -28).
Patients may be non-diabetic or T2DM (on stable therapy >12 weeks defined as < ±20% variability in the average daily dose or oral agents and/or < ±10% daily variability in insulin dose).
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unstable heart failure or haemodynamics (eg SBP<90mmHg, poorly controlled AF – rate>90/min). Recent or active unstable coronary disease in the past 2 months or PCI with the past month or CABG within 3 months.
Type 1 diabetes.
Poorly controlled BSL (fasting plasma glucose level > 13.3 mmol/L).
History of ketoacidosis or hyperosmolar state/coma within 6 months.
Ongoing therapy with an SGLT2 inhibitor or GLP-1 receptor agonist.
On monoamine oxidase inhibitors or tricyclic antidepressants.
Body mass index (BMI) <20.0 kg/m2 or >40 kg/m2.
eGFR <30 ml/min/1.73 m2.
Other life limiting lesion (expected survival <2 years) including malignancy, advanced respiratory, GI, neurologic, haematologic disease. Active substance abuse including EtOH.
Inability to provide written informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/03/2021
Actual
Date of last participant enrolment
Anticipated
30/01/2023
Actual
Date of last data collection
Anticipated
26/03/2023
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18000 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 31959 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 307190 0
Charities/Societies/Foundations
Name [1] 307190 0
National Heart Foundation
Country [1] 307190 0
Australia
Primary sponsor type
Hospital
Name
The Alfred Hospital
Address
55 Commercial Road
Melbourne,
Vic 3004
Country
Australia
Secondary sponsor category [1] 307794 0
None
Name [1] 307794 0
Address [1] 307794 0
Country [1] 307794 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307299 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 307299 0
55 Commercial Road
Melbourne
VIC 3004
Ethics committee country [1] 307299 0
Australia
Date submitted for ethics approval [1] 307299 0
25/11/2020
Approval date [1] 307299 0
06/01/2021
Ethics approval number [1] 307299 0

Summary
Brief summary
While SGLT2inhibitor drugs have been demonstrated to favourably affect outcomes in heart failure, the responsible mechanism(s) are completely unknown. We plan to conduct a single centre, phase 2/3, randomised, double blind, placebo-controlled clinical trial with two parallel arms, to investigate the mechanism of action of dapagliflozin (10mg daily), an SGLT2inhibitor, in non-diabetic or diabetic patients heart failure with reduced ejection fraction. By understanding the mode of action, we will then be able to administer these drugs in a personalized manner and to develop better therapies that specific address the key molecular or physiologic targets.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106742 0
Prof David Kaye
Address 106742 0
Heart Centre, Alfred Hospital
3rd Floor Philip Block
55 Commercial Road
Melbourne
Victoria 3004
Country 106742 0
Australia
Phone 106742 0
+61 03 9076 3232
Fax 106742 0
Email 106742 0
D.Kaye@alfred.org.au
Contact person for public queries
Name 106743 0
Mrs Kaye Carter
Address 106743 0
Heart Centre, Alfred Hospital
3rd Floor Philip Block
55 Commercial Road
Melbourne
Victoria 3004
Country 106743 0
Australia
Phone 106743 0
+61 0390763040
Fax 106743 0
Email 106743 0
k.carter@alfred.org.au
Contact person for scientific queries
Name 106744 0
Prof David Kaye
Address 106744 0
Heart Centre, Alfred Hospital
3rd Floor Philip Block
55 Commercial Road
Melbourne
Victoria 3004
Country 106744 0
Australia
Phone 106744 0
+61 0390763232
Fax 106744 0
Email 106744 0
D.Kaye@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.