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Trial registered on ANZCTR


Registration number
ACTRN12618001981213
Ethics application status
Approved
Date submitted
27/11/2018
Date registered
10/12/2018
Date last updated
10/12/2018
Date data sharing statement initially provided
10/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise effects of Dapagliflozin in type II diabetes and heart failure
Scientific title
SGLT2-inhibitor : Acute Effects Crossover Trial (SAECT)
Acute effects of SGLT2-inhibitor in type II diabetics with heart failure with reduced ejection fraction (HFrEF) on 6-minute walk test distance



Secondary ID [1] 296718 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SAECT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 310576 0
Condition category
Condition code
Cardiovascular 309289 309289 0 0
Other cardiovascular diseases
Metabolic and Endocrine 309368 309368 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Twenty five patients with existing T2DM who are admitted to hospital with acute decompensated heart will be given either placebo or the oral SGLT-2 inhibitor dapagliflozin at 10mg daily dose in this crossover trial with a two week window from hospital discharge and a two week washout period between crossover.
The participants will return to the clinic for regularly scheduled visits. They will have a randomisation visit 2 weeks after hospital discharge, and visits at 4, 6 and 8 weeks after randomisation. Their medication compliance will be assessed by study staff at 2 weekly intervals when they return.
Duration of treatment is that active study medication will only be given for 2 out of 8 weeks.

Participant follow up –The participants will be followed up in clinic at their scheduled visits and the following information will be collected:
Demographic profile: age, sex, marital status, social support, education, ethnicity and first language
-Medical history
-Treatment(s): existing prescribed medications and type of non-pharmacologic treatments (if any).
-HF therapy (ACE inhibitors/ARB, beta-blockers, mineralocorticoid antagonists, ivabradine, angiotensin receptor neprilysin inhibitor)
Permanent pacemaker/ Implantable Cardiac Defibrillator/ Cardiac Resynchronisation Therapy
--Medication review
- Clinical profile: this includes a physical assessment, height, weight, waist and hip circumference, vital signs (heart rate, blood pressure, and respiratory rate)
-NYHA class.
-6MWT and doorbell test
-Kansas City Cardiomyopathy Questionnaires (KCCQ)
-Echocardiogram and lung ultrasound at the time of echocardiogram
-Basic blood tests
-ECG, Holter monitor
-24 hour blood pressure wrist monitor
-Arterial tonometry and radial artery applanation tonography (SphygmoCor)

Intervention code [1] 313027 0
Treatment: Drugs
Comparator / control treatment
The crossover design allows for patients to act as their own controls thereby reducing study numbers needed and maintaining power.

The placebo tablets are green, plain, diamond shaped, film coated tablet (orally). Does not contain active ingredient Placbo formulation is Lactose monohydrate Microcrystalline cellulose Magnesium stearate
Control group
Active

Outcomes
Primary outcome [1] 308258 0
Change in 6-minute walk test
Timepoint [1] 308258 0
The patient will be consented at time 0, At 2 weeks they will have all assessments (baseline) and commence randomised drug or placebo. At 4 weeks they will again have all assessments and stop trial drug. They will then have a 2 week washout period and then crossover to drug or placebo for 2 weeks. they will then have their 3rd and final assessment (week 8).
To be clear baseline assessment is at 2 weeks, assessments are done again on all patients at week 4 and week 8 (each of which is after 2 weeks of drug or placebo treatment).
Secondary outcome [1] 354457 0
Quality of life
-Kansas City Cardiomyopathy Questionnaire (KCCQ)
Timepoint [1] 354457 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)
Secondary outcome [2] 354636 0
Cardiac function
This is a combined endpoint determined by:
-Echocardiogram – (cardiac chamber size and ejection fraction)
-Biochemistry: (NT proBNP by plasma assay, Troponin T by plasma assay)
Timepoint [2] 354636 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)
Secondary outcome [3] 354637 0
Conduction abnormalities
This is a combined endpoint determined by:
-Holter Monitor
-ECG parameters
Timepoint [3] 354637 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)
Secondary outcome [4] 354638 0
Vascular function
This is a combined endpoint determined by:
-24 hour blood pressure wrist monitor
-Peripheral artery applanation tonography (SphygmoCor) to assess for arterial stiffness and endothelial function
Timepoint [4] 354638 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)
Secondary outcome [5] 354639 0
Decongestion
This is a combined endpoint determined by:
-Biochemitry (NT proBNP by plasma assay, whole blood haematocrit calculation from the complete blood cell count using the Coulter Principle, urea by plasma assay, creatinine by plasma assay)
-Echocardiography (tricuspid regurgitation gradient, left atrial size, diastolic parameters)
-Clinical examination: JVP height, lung crepitations, peripheral oedema
-Lung ultrasound to determine extravascular lung water
Timepoint [5] 354639 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)
Secondary outcome [6] 354652 0
Doorbell test to assess for heart failure functional capacity.
(This is a 10 meter walk test to test functional capacity, where the patient is asked to imaging they are answering the doorbell and timed walking 10m. The test was developed at Flinders Medical Centre by the author and has been published as an abstract in Heart Lung and Circulation (the indexed journal of the Cardiac Society of Aust and NZ))
Timepoint [6] 354652 0
All assessments (for primary and secondary outcomes) are at week 2 (baseline), week 4 (after 2 weeks of treatment with drug or placebo) and week 8 (after a two week washout period and two weeks of crossover treatment with drug or placebo)

Eligibility
Key inclusion criteria
•Patients with previously diagnosed T2DM for which they are on prescribed glucose lowering therapy.
•Admission with an episode of decompensated heart failure.
•Heart failure with reduced ejection fraction (HFrEF) (documented EF <=40%)
•Qualify for add on SGLT2 inhibitor glucose lowering therapy for DM according to current guidelines
•Patients who are being prescribed an add-on SGLT2 inhibitor (long term) by the responsible hospital medical team on the basis of their medical judgment (independent of the trial) for the approved PBS indication of suboptimal glycaemic control.
•On guideline-recommended therapy for their heart failure (or documented reason why not)
•Clinically stable at the time of recruitment
•Live within a geographically accessible area for follow-up

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
•Age less than 18 years
•Unable to provide written informed consent to participate in the study (this includes the inability to communicate fluently with the investigator and cognitive incompetence)
•Valvular stenosis of > moderate severity
•Valvular regurgitation >=severe and planning corrective invasive therapy
•Oncologic (or other) life expectancy <12 months or any other medical condition (including pregnancy) that results in the belief (deemed by the Chief Investigators) that it is not medically appropriate for the patient to participate in this trial
•eGFR <60 ml/min/1.73m2
•Past history of ketoacidosis
•Past history of frequent or significant genital candidiasis
•Already taking or past intolerance to an SGLT2 inhibitor
•Pregnant, breastfeeding or women of child bearing potential without adequate contraception
•Elective surgery in the next 8 weeks

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)

The eligible participants for this trial will be randomised to dapagliflozin 10 mg and placebo in 1:1 ratio at randomisation (week 2).Randomisation will occur with sealed envelopes
The allocation involves contacting the holder of the allocation schedule who is at the site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be

Permuted block randomisation in blocks of 4 to double-blind treatment.
No stratified allocation will be used.

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Baseline descriptive statistics and the various outcome measures will be reported as counts and percentages for dichotomous and categorical variables, and compared by chi-square testing, while continuous variables, including the primary endpoint, will be reported as medians (25th-75th percentile) compared by Kruskal Wallis testing. Given that limited sample size, all comparisons will be considered exploratory, and no adjustment for multiple testing will be undertaken. A p value of <0.05 will be considered statistically significant and all analysis will be undertaken using STATA 15.1 (College Station, TX).
Hence 22 patients needed to have sufficient power to show significant difference in 6MWT

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 12563 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 24942 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 301273 0
Hospital
Name [1] 301273 0
Flinders Medical Centre
Address [1] 301273 0
Department of Cardiology
Flinders Medical Centre
1 Flinders Drive, Bedford Park SA 5042
Country [1] 301273 0
Australia
Primary sponsor type
Hospital
Name
Flinders Medical Centre
Address
Department of Cardiology
Flinders Medical Centre
1 Flinders Drive, Bedford Park SA 5042
Country
Australia
Secondary sponsor category [1] 300952 0
None
Name [1] 300952 0
Address [1] 300952 0
Country [1] 300952 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302015 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 302015 0
Southern Adelaide Local Health Network
Flinders Medical Centre,
Ward 6C, Room 6A219
1 Flinders Drive
Bedford Park SA 5042
Ethics committee country [1] 302015 0
Australia
Date submitted for ethics approval [1] 302015 0
19/07/2018
Approval date [1] 302015 0
14/11/2018
Ethics approval number [1] 302015 0
HREC/18/SAC/230

Summary
Brief summary
Type 2 Diabetes Mellitus (T2DM) is a major risk factor for heart failure (HF), with particularly poor prognosis and a 5 year survival rate of <25% in major studies. A central aim of DM management is optimal glycaemic control, however the impact of this on the development and progress of the heart failure syndrome is unknown. Prior to recent trials involving different SGLT-2 inhibitors, evidence that any glucose lowering therapy reduces the rates of cardiovascular events (in particular HF readmission) and death was not convincingly shown (ACCORD, ADVANCE, UKPDS, VADT)
The exact mechanisms of the benefits seen with the SGLT-2 Inhibitors, although postulated, are unclear.
It is proposed that SGLT-2 inhibitors could demonstrate short term improvements in functional capacity, congestion parameters, biochemical, electrocardiographic and ,echocardiographic structural and functional parameters in participants with clinical HF and T2DM.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88854 0
A/Prof Carmine De Pasquale
Address 88854 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 88854 0
Australia
Phone 88854 0
+61 8 8204 5457
Fax 88854 0
61 8 8204 5000
Email 88854 0
carmine.depasquale@sa.gov.au
Contact person for public queries
Name 88855 0
A/Prof Carmine De Pasquale
Address 88855 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 88855 0
Australia
Phone 88855 0
+61 8 8204 5457
Fax 88855 0
61 8 8204 5000
Email 88855 0
carmine.depasquale@sa.gov.au
Contact person for scientific queries
Name 88856 0
A/Prof Carmine De Pasquale
Address 88856 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 88856 0
Australia
Phone 88856 0
+61 8 8204 5457
Fax 88856 0
61 8 204 5000
Email 88856 0
carmine.depasquale@sa.gov.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 other documents available
Summary results
No Results