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Trial registered on ANZCTR


Registration number
ACTRN12614000088640
Ethics application status
Approved
Date submitted
6/01/2014
Date registered
23/01/2014
Date last updated
2/02/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Spironolactone in myocardial dysfunction with reduced exercise capacity
Scientific title
Effects of spironolactone or control on LV filling pressure and exercise capacity in patients with myocardial dysfunction with reduced exercise capacity
Secondary ID [1] 283848 0
None
Universal Trial Number (UTN)
Trial acronym
STRUCTURE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 290823 0
Condition category
Condition code
Cardiovascular 291191 291191 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral spironolactone will be administered in a dose of 25 mg daily for 6 months. Patients will be reviewed and serum electrolytes will be performed after a week, then monthly for 3 months, then at the end of the study: study medication will be withheld in the presence of hyperkalemia (>5.4 mmol/l), renal impairment (creatinine >0.18 mmol/l) or unacceptable side-effects. Adherence will be monitored by tablet counts.
Intervention code [1] 288528 0
Treatment: Drugs
Comparator / control treatment
Microcellulose 120 mg daily for 6 months
Control group
Placebo

Outcomes
Primary outcome [1] 291191 0
Exercise capacity measured by peak oxygen uptake and metabolic equivalents (from treadmill exercise time) at incremental treadmill exercise test to exhaustion.
Timepoint [1] 291191 0
6 months after initiation
Primary outcome [2] 291304 0
LV filling pressure estimated from echo-Doppler assessment of E/e'
Timepoint [2] 291304 0
6 months after initiation
Secondary outcome [1] 306209 0
Avoidance of a hypertensive response to exercise measured by blood pressure assessed using a cuff sphygmomanometer during treadmill exercise test.
Timepoint [1] 306209 0
6 months after initiation
Secondary outcome [2] 306471 0
Improvements in myocardial deformation measure by echocardiography
Timepoint [2] 306471 0
6 months after initiation

Eligibility
Key inclusion criteria
Patients with exercise intolerance, who are found to demonstrate increased E/E’ at exercise echo with reduced exercise capacity. Exercise intolerance will be defined by exercise capacity reduced from published normal ranges.
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) atrial fibrillation
(2) ischemia evidenced by angina or a positive diagnostic test (3) patients already on spironolactone
(4) patients with renal impairment (creatinine > 1.5 mg/dl) or hyperkalaemia (> 5.5 mmol/L).

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)
Sequentially-numbered, opaque, sealed envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerized
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
1. In patients with IFPE, treatment with spironolactone causes an improvement in exercise capacity.
An improvement in exercise capacity will be identified in the treatment group shows significant improvement of exercise time compared with placebo at paired t-testing. The contribution of therapy to exercise time independent of other variables (including strain and backscatter indices, age and other drugs) will be examined by multiple linear regression.
2. In patients with IFPE, treatment with spironolactone causes an improvement in post-exercise filling pressure.
An improvement in exercise capacity will be identified in the treatment group shows significant improvement of E/e’ compared with placebo at paired t-testing. The contribution of therapy independent of other variables (including strain and backscatter indices, age and other drugs) will be examined by multiple linear regression.
3. Reduction of IFPE is due to avoidance of a hypertensive response to exercise
This will be confirmed if exercise systolic BP is lower (t-test as continuous variable) or a hypertensive response to exercise (chi-square of a categorical variable, >220/100 in men and 200/100 in women) is less frequent in patients showing reduced E/E’ by each intervention. A general linear model will be used to identify whether exercise systolic BP is an independent correlate of a reduction in IFPE.
4. Reduction of IFPE is due to improvements in myocardial deformation properties
This will be confirmed if average myocardial strain rate is greater (t-test as continuous variable) in patients showing reduced E/E’ by each intervention than those who do not. A general linear model will be used to identify whether a change in strain rate is independently associated with reduction in filling pressure, independent of other haemodynamic responses.

Sample size: Sample size calculations have been calculated (Sample Power, release 1.2, SPSS Inc) based on the primary hypotheses. To our knowledge, this will be the first intervention trial with spironolactone with an exercise endpoint in this population, so the effect sizes are obtained from a 1 minute (~15%) increment in treadmill time from ACE/ARB therapy in our recent experience and an 18% increment of myocardial strain in our previous spironolactone study in our recent experience. Assuming a 15% effect size, and a standard deviation of 30% of exercise capacity, we will need 65 patients/group to show a difference in exercise capacity. To allow for a dropout of 15%, we will recruit 150 patients.

Recruitment
Recruitment status
Completed
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)
TAS
Recruitment hospital [1] 1903 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 7678 0
7000 - Hobart
Recruitment outside Australia
Country [1] 5717 0
Poland
State/province [1] 5717 0

Funding & Sponsors
Funding source category [1] 288507 0
Self funded/Unfunded
Name [1] 288507 0
Address [1] 288507 0
Country [1] 288507 0
Primary sponsor type
University
Name
Menzies Research Institute Tasmania, University of Tasmania
Address
17 Liverpool Street
Hobart, TAS 7000
Country
Australia
Secondary sponsor category [1] 287212 0
University
Name [1] 287212 0
Department of Cardiology
Wroclaw Medical University
Address [1] 287212 0
Wybrzeze L. Pasteura 1,
50-367 Wroclaw
Poland
Country [1] 287212 0
Poland

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290367 0
Health and Medical Ethics Committee
Ethics committee address [1] 290367 0
Office of Research Services, University of Tasmania, Private Bag 1, Hobart, TAS, 7001
Ethics committee country [1] 290367 0
Australia
Date submitted for ethics approval [1] 290367 0
Approval date [1] 290367 0
03/01/2013
Ethics approval number [1] 290367 0
H0012926

Summary
Brief summary
The main aim of this study is to use aldosterone blockade for the treatment of exercise intolerance in the presence of diastolic dysfunction (DD) and preserved LV systolic function. The responses will be sought by measurement of: 1) exercise capacity, 2) techniques to quantify myocardial structure and function.
Our primary hypotheses are that spironolactone therapy is associated with improved; 1. Exercise capacity by reduction of myocardial fibrosis and improvement in LV compliance with aldosterone blockade, 2. Post-exercise LV filling pressure.
Our secondary hypotheses are that spironolactone therapy is associated with; 3. Avoidance of a hypertensive response to exercise, 4. Improvements in myocardial deformation properties.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45310 0
Prof Thomas H Marwick
Address 45310 0
Menzies Research Institute Tasmania
17 Liverpool St
Hobart, Tas 7000
Country 45310 0
Australia
Phone 45310 0
+61 (0) 3 6226 7703
Fax 45310 0
Email 45310 0
tom.marwick@utas.edu.au
Contact person for public queries
Name 45311 0
Ms Leah Wright
Address 45311 0
Menzies Research Institute Tasmania
17 Liverpool St
Hobart, Tas 7000
Country 45311 0
Australia
Phone 45311 0
+61 (0) 3 6226 7703
Fax 45311 0
Email 45311 0
leah.wright@utas.edu.au
Contact person for scientific queries
Name 45312 0
Prof Thomas H Marwick
Address 45312 0
Menzies Research Institute Tasmania
17 Liverpool St
Hobart, Tas 7000
Country 45312 0
Australia
Phone 45312 0
+61 (0) 3 6226 7703
Fax 45312 0
Email 45312 0
tom.marwick@utas.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary