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Trial registered on ANZCTR


Registration number
ACTRN12610001087044
Ethics application status
Approved
Date submitted
11/11/2010
Date registered
13/12/2010
Date last updated
13/12/2010
Type of registration
Retrospectively registered

Titles & IDs
Public title
Use of exercise and medical therapies to improve cardiac function among patients with exertional shortness of breath due to lung congestion
Scientific title
Exertional dyspnoea with increased filling pressure - Mechanisms and treatment strategies
Secondary ID [1] 253054 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diastolic dysfunction, heart failure with preserved ejection fraction (HFpEF) 258617 0
Condition category
Condition code
Cardiovascular 258761 258761 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomly allocated to; daily oral doses of ivabradine 5mg, isosorbide mononitrate 120mg, or placebo for 7 days. Assessment of cardiovascular function will be performed at rest and exercise at baseline and after the intervention.

After a 2 week wash-out, patients will be re-randomised to an exercise training intervention, daily oral spironolactone 25mg or placebo (matching) tablet for 6 months. The exercise intervention will be supervised by an exercise physiologist, and will comprise aerobic and resistance training, for 3 x 60 minute sessions per week at 65-70% maximum heart rate. Assessment of cardiovascular function will be repeated after the intervention.
Intervention code [1] 257578 0
Treatment: Drugs
Intervention code [2] 257735 0
Lifestyle
Comparator / control treatment
Placebo (oral tablet comprising inactive filler)
Control group
Placebo

Outcomes
Primary outcome [1] 259621 0
Reduction of exercise filling pressure, as estimated by echo-Doppler assessment of E/e'
Timepoint [1] 259621 0
7 days
After phase 1 randomisation to ivabradine, nitrate or placebo
Primary outcome [2] 259622 0
Improvement in exercise capacity, as estimated by treadmill VO2
Timepoint [2] 259622 0
6 months
After phase 2 re-randomisation to exercise, spironolactone or placebo
Primary outcome [3] 259642 0
Post-exercise LV filling pressure, as estimated by echo-Doppler assessment of E/e'
Timepoint [3] 259642 0
7 days and 6 months
Secondary outcome [1] 266274 0
Prevention of the hypertensive response to exercise, as measured by sphygmomanometry.
Timepoint [1] 266274 0
After phase 1 randomisation to ivabradine, nitrate or placebo (7 days)

After phase 2 re-randomisation to exercise, spironolactone or placebo (6 months)
Secondary outcome [2] 266275 0
Reduction of aortic stiffness and central blood pressure, as estimated by arterial tonometry
Timepoint [2] 266275 0
After phase 1 randomisation to ivabradine, nitrate or placebo (7 days)

After phase 2 re-randomisation to exercise, spironolactone or placebo (6 months)
Secondary outcome [3] 266304 0
Improvements in myocardial deformation properties, as estimated by Doppler and 2D speckle assessment of LV strain
Timepoint [3] 266304 0
7 days and 6 months

Eligibility
Key inclusion criteria
We intend to recruit patients who are found to demonstrate increased E/e’ at exercise echo with reduced exercise capacity. Exercise intolerance will be defined by either a previous exercise test with exercise capacity reduced >20% from published normal ranges or reduction of predicted exercise capacity based on the Duke Activity Status questionnaire
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) atrial fibrillation (variations in cycle length may be problematic for calculating E/E’), (2) ischemia evidenced by angina or a positive diagnostic test (where improvement of exercise capacity may be due to reduction of ischemia), (3) patients already on nitrate, ivabradine or spironolactone and (4) patients with renal impairment (creatinine > 0.18) 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)
Patients will be identified from an large outpatient exercise echocardiography department. Patients meeting the inclusion criteria will be approached and informed of the study. After recruitment, patients will undergo a comprehensive screening assessment of myocardial (echocardiography) and arterial function (central blood pressure and arterial stiffness) at rest and exercise. If patients meet the inclusion criteria (reduced exercise capacity and raised E/e'), the hospital pharmacy will randomly allocate patients to either ivabradine, nitrate or placebo for 7 days (phase 1) and after a 2-week wash-out period, will re-randomise to exercise training, spironolactone or placebo for 6 months (phase 2).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization will be performed from computerized sequence generation to distribute patients into the randomisation groups. Both the patients and investigators will be blinded (i.e. double blind) to treatment option. The pharmacy will control the randomisation code and is responsible for the randomisation process.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

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)

Funding & Sponsors
Funding source category [1] 258030 0
Government body
Name [1] 258030 0
NHMRC
Address [1] 258030 0
GPO Box 1421
Canberra ACT 2601
Country [1] 258030 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Slip Road
St Lucia QLD 4072 Australia
Country
Australia
Secondary sponsor category [1] 257222 0
None
Name [1] 257222 0
Address [1] 257222 0
Country [1] 257222 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260025 0
Princess Alexandra Hospital Human Research Ethics Committee
Ethics committee address [1] 260025 0
Princess Alexandra Hospital,
Ipswich Road, Woolloongabba, Qld 4102
Ethics committee country [1] 260025 0
Australia
Date submitted for ethics approval [1] 260025 0
23/11/2006
Approval date [1] 260025 0
15/03/2007
Ethics approval number [1] 260025 0
2006/165
Ethics committee name [2] 260039 0
University of Queensland
Ethics committee address [2] 260039 0
St Lucia
Ethics committee country [2] 260039 0
Australia
Date submitted for ethics approval [2] 260039 0
16/03/2007
Approval date [2] 260039 0
02/05/2007
Ethics approval number [2] 260039 0
2007000580

Summary
Brief summary
Previous studies of “diastolic heart failure” have been limited by confusion about the definition of this entity, and evidence for specific treatments are undefined. The characterization of IFPE will permit us to identify a homogeneous group. However, the most appropriate therapeutic response to increased filling pressure causing exertional dyspnea is undefined.
Trial website
Trial related presentations / publications
Holland D, Prasad S, Marwick TH. Contribution of exercise echocardiography to the diagnosis of heart failure with preserved ejection fraction. Heart 2010 Apr 20. [Epub ahead of print]
Holland D, Prasad S, Marwick TH. Prognostic implications of estimated left ventricular filling pressure with exercise. Circulation CV Imaging 2010;3:149-56.
Public notes

Contacts
Principal investigator
Name 31891 0
Address 31891 0
Country 31891 0
Phone 31891 0
Fax 31891 0
Email 31891 0
Contact person for public queries
Name 15138 0
UQ School of Medicine
Address 15138 0
Princess Alexandra Hospital
Ipswich Road, Woolloongabba, Qld 4102
Country 15138 0
Australia
Phone 15138 0
+61 7 3176 5324
Fax 15138 0
+61 7 3176 5344
Email 15138 0
tom_marwick@hotmail.com
Contact person for scientific queries
Name 6066 0
Dr B Haluska
Address 6066 0
Princess Alexandra Hospital
Ipswich Road, Woolloongabba 4102 Qld
Country 6066 0
Australia
Phone 6066 0
+61 7 3176 5324
Fax 6066 0
+61 7 3176 5344
Email 6066 0
b.haluska@uq.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