Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000710820
Ethics application status
Approved
Date submitted
22/06/2012
Date registered
3/07/2012
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 ivabradine
Scientific title
Novel Interventions in Heart Failure with Preserved Ejection Fraction -a single centre, randomised double blinded placebo cross-over pilot study using IVABRADINE, 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 group, Flinders University.
Secondary ID [1] 280723 0
Nil
Universal Trial Number (UTN)
U1111-1132-0432
Trial acronym
NIHEF-2012i(Novel Interventions in Heart Failure with Preserved Ejection Fraction using ivabradine)
20 refres to the number of patients, 2012 refres the year of study, i- refers to first letter in ivabradine
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with Preserved Ejection Fraction 286769 0
Condition category
Condition code
Cardiovascular 287077 287077 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Effect of Ivabradine in Heart failure with preserved ejection fraction
Ivabradine 5-7.5 mg oral tablets twice daily depending on heart rate at the time of randomisation for 8 weeks followed by a 2 week wash out period and cross over to microcelullose placebo for 8 weeks.
Intervention code [1] 285146 0
Treatment: Drugs
Comparator / control treatment
Placebo- microcellulose oral capsule twice daily
Control group
Placebo

Outcomes
Primary outcome [1] 287400 0
Improvement in 6 minute walk test
Timepoint [1] 287400 0
Baseline, 8 and 18 weeks after randomistaion
Primary outcome [2] 287409 0
Peak VO2 as assessed by cardio-pulmonary exercise testing. The Vo2 is calculated using the difference between the heart rate at rest and at peak exercise. The heart rate blood pressure and concentaration of inspired oxygen will be monitored regularlr by monitors.
Timepoint [2] 287409 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [1] 298067 0
RV volume as assessed on cardiac magnetic resonance imaging
Timepoint [1] 298067 0
Baseline, 8 and 18 weeks after randomistaion
Secondary outcome [2] 298088 0
Diastolic parametres of E/E', E/A ratio on echocardiogram
Timepoint [2] 298088 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 or greater than 15, deceleration time less than or equal to 140ms
Heart rate over 70/min
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
Atrial Fibrillation
Contraindications to MRI
Significant valvular or coronary disease as primary cause of HF
Hypertrophic cardiomyopathy, cardiac amyloidosis, sarcoidosis
GFR equal to or greater than 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 Ivabradine or placebo twice 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 by numberedcontainers, which is done by the randomisation company.
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] 285505 0
Self funded/Unfunded
Name [1] 285505 0
Country [1] 285505 0
Primary sponsor type
Other Collaborative groups
Name
South Australian Health and Medical Research Institute
Address
Box 15, lEVEL 1B
Mark Oliphant Building
Laffer Drive, Science Park
Bedford Park, SA 5042
Country
Australia
Secondary sponsor category [1] 284345 0
None
Name [1] 284345 0
Address [1] 284345 0
Country [1] 284345 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287520 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 287520 0
Flinders Medical Centre,The Flats G5, Room 3 and 4,Flinders Drive, Bedford Park, SA-5042, Australia
Ethics committee country [1] 287520 0
Australia
Date submitted for ethics approval [1] 287520 0
Approval date [1] 287520 0
13/06/2012
Ethics approval number [1] 287520 0
207.12a

Summary
Brief summary
Background.
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 above 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.
Reducing heart rate with Ivabradine will improve symptoms, exercise tolerance 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.
We propose to use Ivabradine which is a selective heart rate lowering agent 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 34354 0
Address 34354 0
Country 34354 0
Phone 34354 0
Fax 34354 0
Email 34354 0
Contact person for public queries
Name 17601 0
Dr. Govindarajan Srinivasan
Address 17601 0
Department of Cardiovascular Medicine
Flinders Medical Centre, 1,Flinders Drive
Bedford Park, SA, 5042
Country 17601 0
Australia
Phone 17601 0
+61-08-82017916
Fax 17601 0
+61-08-82017701
Email 17601 0
[email protected]
Contact person for scientific queries
Name 8529 0
Dr. Govindarajan Srinivasan
Address 8529 0
Department of Cardiovascular Medicine
Flinders Medical Centre, 1, Flinders Drive
Bedford Park, SA, 5042
Country 8529 0
Australia
Phone 8529 0
+61-08-82017916
Fax 8529 0
+61-08-82017701
Email 8529 0
[email protected]

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