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Trial registered on ANZCTR


Registration number
ACTRN12612000684820
Ethics application status
Approved
Date submitted
22/06/2012
Date registered
26/06/2012
Date last updated
3/07/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Novel Interventions in Heart Failure with Preserved Ejection Fraction using Tadalafil
Scientific title
Novel Interventions in Heart Failure with Preserved Ejection Fraction -a single centre, randomised double blind placebo cross-over pilot study using Tadalafil, to assess the effect on 6 minute walk test, peak oxygen consumption and New York Heart Association class of symptoms, from the Flinders Clinical Research , Flinders University.
Secondary ID [1] 280725 0
Nil
Universal Trial Number (UTN)
U1111-1132-0591
Trial acronym
NIHEF-2012T
(Novel Interventions in Heart Failure with Preserved Ejection Fraction using Tadalafil) 20- refers to the number of patients in the trial, 2012- refers to the year of study, T refers to first letter in Tadalafil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with Preserved Ejection Fraction 286771 0
Condition category
Condition code
Cardiovascular 287079 287079 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Effect of Tadalafil in Heart failure with preserved ejection fraction
Dose of Tadalafil-40mg once daily, oral capsules
For 8 weeks and then, there is a 2 week wash out period and they will be crossed over to placebo for 8 weeks
Intervention code [1] 285148 0
Treatment: Drugs
Comparator / control treatment
Placebo-microcellulose oral capsule
Control group
Placebo

Outcomes
Primary outcome [1] 287402 0
Improvement in 6 minute walk test
Timepoint [1] 287402 0
Baseline, 8 and 18 weeks after randomistaion
Primary outcome [2] 287403 0
Peak oxygen consumption based on Cardiopulmonary exercise testing. The VO2 is calculated from the heart rate difference between rest and peak exercise.
During the cardiopulmonary exercise test, Heart rate, Blood pressure and the inspired oxygen levels are continously measured by ECG and other monitors.
Timepoint [2] 287403 0
Baseline, 8 and 18 weeks after randomistaion
Primary outcome [3] 287404 0
New York Heart Association Class, as assessed by interview
Timepoint [3] 287404 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [1] 298070 0
RV volume as assessed on cardiac magnetic resonance imaging
Timepoint [1] 298070 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [2] 298071 0
RVEF as assessed on cardiac magnetic resonance imaging
Timepoint [2] 298071 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [3] 298072 0
LV diastolic parameters (E/A, E/E') as assessed on Echocardiogram
Timepoint [3] 298072 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [4] 298073 0
Pulmonary artery pressure as assessed on Echocardiogram
Timepoint [4] 298073 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [5] 298074 0
Cardiac output as assessed on cardiac magnetic resonance imaging
Timepoint [5] 298074 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [6] 298075 0
BNP levels on blood test sample
Timepoint [6] 298075 0
Baseline, 8 and 18 weeks after randomistaion

Eligibility
Key inclusion criteria
Age greater than or equal to 18 years
HF-PEF (LVEF greater than or equal to 50% within 6m of randomisation)
NYHA II-III
Diastolic dysfunction on echo
E/A equal to 1, E/E’ equal to 15, deceleration time less than or equal to 140ms
Systolic pulmonary artery pressure over 30 mm of Hg
Stable disease, confirmed by no hospital admissions or HF medication changes within 3m prior to randomisation
Informed consent
No other causes for exertional dyspnoea
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Contraindications to Tadalafil ; Nitrate use in any form
Contraindications to MRI
Significant valvular or coronary disease as primary cause of HF
Hypertrophic cardiomyopathy, cardiac amyloidosis, sarcoidosis
GFR greater than or equal to 45 ml/min

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)
20 patients recruited for the study will be randomised to receive Tadalafil or placebo once daily for 8 weeks in addition to their usual medications. They will then be crossed over to the other treatment for 8 weeks after a 2 week wash-out period.
Allocation is done by numbered containers by the company that does the randomisation for us.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation to study drug or placebo is based on a block randomisation. Blocking is used to ensure that comparison groups will be generated according to a predetermined ratio, usually 1:1 or groups of approximately the same size.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
24/07/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 285507 0
Self funded/Unfunded
Name [1] 285507 0
Country [1] 285507 0
Primary sponsor type
Other Collaborative groups
Name
South Australian Health and Medical Reseasrch Institute
Address
Box 15,Level 1b,
Mark Oliphant Building
Laffer Drive,Science Park
Bedford Park, SA 5042
Country
Australia
Secondary sponsor category [1] 284347 0
None
Name [1] 284347 0
Address [1] 284347 0
Country [1] 284347 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287522 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 287522 0
Flinders Medical Centre,The Flats G5, Room 3 and 4,Flinders Drive, Bedford Park, SA-5042, Australia
Ethics committee country [1] 287522 0
Australia
Date submitted for ethics approval [1] 287522 0
Approval date [1] 287522 0
13/06/2012
Ethics approval number [1] 287522 0
207.12b

Summary
Brief summary
It is estimated that over 300,000 Australians have heart failure (HF) at any given time and the incidence increases with increase in life expectancy. The point prevalence of chronic heart failure (CHF) has been about 1% in people aged 50–59 years, 10% in people aged over 65 years, and over 50% in people aged greater than 85 years. Despite therapeutic advances, HF remains a disease with unacceptably high mortality rates, poor quality of life and massive socioeconomic cost. Heart failure with preserved ejection fraction (HF-PEF) previously known as diastolic heart failure accounts for about 50% of patients with heart failure. HF-PEF refers to a clinical syndrome of symptoms and clinical signs of HF, normal or near normal left ventricular (LV) systolic function (EF> 50%) and evidence of diastolic dysfunction in the form of abnormal LV filling and elevated filling pressures. This can be objectively confirmed on echocardiogram.
There is no difference in morbidity between patients with heart failure with reduced ejection fraction and those with preserved ejection fraction and some studies have shown similar mortality in the two conditions. The efficacy for beta blockers, angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) and aldosterone antagonists is well established in the treatment of HF with reduced EF. The efficacy for these drugs in HF-PEF is not well established. The I-PRESERVE trial studied the effects of Irbesartan (ARB) in symptomatic patients with HF-PEF. 4128 patients were enrolled and followed up for 4 years. There was no improvement in outcomes in patients on Irbesartan. The CHARM preserved trial studied Candesartan in 3000 patients with HF-PEF for a period of 3 years. There was only a small reduction in hospital admissions for heart failure in the Candesartan group.The PEP-CHF trial assessed the efficacy of Perindopril (ACE-I) in 850 patients over the age of 70 with HF-PEF. At one year there were fewer unexpected hospital admissions for heart failure in the perindopril group although the trial when completed showed no difference in its primary end point. Although therapies have proven effective in reducing morbidity and mortality from heart failure with reduced ejection fraction, mortality from HF-PEF remains unchanged. No therapies thus far have been proven to correct the abnormalities seen in HF-PEF, halt its progression, reduce its mortality or conclusively reduce its morbidity.
Rationale.
1. That the addition of the phosphodiestrase-5 (PDE-5) inhibitor tadalafil will improve symptoms, exercise tolerance, pulmonary arterial pressure, right ventricular (RV) function and LV relaxation in patients with HF- PEF.
Objectives.
The primary objective of the study is to trial a novel agent in the treatment of HF-PEF as patients continue to be symptomatic on currently available medications.
1. We propose to use the PDE-5 inhibitor tadalafil which selectively dilates pulmonary vessels and has beneficial effects on RV function in patients with HF-PEF and assess the effect on symptoms, exercise tolerance, echocardiographic and Cardiovascular Magnetic Resonance (CMR) imaging parameters of heart failure.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34356 0
Address 34356 0
Country 34356 0
Phone 34356 0
Fax 34356 0
Email 34356 0
Contact person for public queries
Name 17603 0
Dr. Govindarajan Srinivasan
Address 17603 0
Department of Cardiovascular Medicine
Flinders Medical Centre,1 Flinders Drive
Bedford Park, SA, 5042
Country 17603 0
Australia
Phone 17603 0
+61-08-8201 7700
Fax 17603 0
+61-08-82017701
Email 17603 0
[email protected]
Contact person for scientific queries
Name 8531 0
Dr. Govindarajan Srinivasan
Address 8531 0
Department of Cardiovascular Medicine
Flinders Medical Centre,1 Flinders Drive
Bedford Park, SA, 5042
Country 8531 0
Australia
Phone 8531 0
+61-08-8201 7700
Fax 8531 0
+61-08-82017701
Email 8531 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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