Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000546752
Ethics application status
Approved
Date submitted
1/05/2013
Date registered
15/05/2013
Date last updated
15/11/2019
Date data sharing statement initially provided
15/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to test reduction in renal nerve activity as a possible treatment for heart failure.
Scientific title
A study of Renal Denervation for Heart Failure with Preserved Ejection Fraction to reduce left atrial volume index (LAVi) and/or left ventricular mass index (LVMi) on cardiac magnetic resonance imaging (cMRI).
Secondary ID [1] 282387 0
nil
Universal Trial Number (UTN)
Trial acronym
The RESPECT-HF Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with Preserved Ejection Fraction 288968 0
Condition category
Condition code
Cardiovascular 289306 289306 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Renal Denervation (RDN) is a simple catheter procedure removing excess nerve signals to and from the kidneys. The renal denervation system consists of a small steerable treatment catheter and an automatically-controlled treatment delivery generator. The treatment does not require open surgery.
A guiding catheter is inserted through a tiny incision in the groin into the femoral artery to direct the treatment catheter to the renal arteries. The treatment catheter delivers high-frequency radio waves, called RF waves, to 4–6 locations within each of the two renal arteries. The energy delivered is about 8 watts. This energy delivery aims to disrupt the nerves and lower blood pressure over a period of months. The procedure takes 40 -60 minutes. RDN has been able to reduce Blood Pressure (BP) in patients with high BP resistant to multi-drug treatment. Through removing excess nervous drive to the kidneys, heart and circulation this treatment has promise in Heart Failure (HF).
Intervention code [1] 287020 0
Treatment: Surgery
Intervention code [2] 287165 0
Treatment: Devices
Comparator / control treatment
Continued medical management will comprise management of all cardiovascular risk factors (hypertension, diabetes, dyslipidaemia) in accord with international guidelines. As there is no established evidence–based pharmacotherapy for Heart failure with Preserved Ejection Fraction (HFPEF) per se, therapy aimed at HF specifically will adopt treatments recommended for HFREF with prescription of diuretic, ACE inhibitor/ARB, beta blocker and mineralocorticoid antagonist accordingly.

Control group
Active

Outcomes
Primary outcome [1] 289416 0
Reduction in left atrial volume index (LAVi) and/or left ventricular mass index (LVMi) on cardiac magnetic resonance imaging (cMRI) in Heart Failure with Preserved Ejection Fraction (HFPEF).
Timepoint [1] 289416 0
6 months
Secondary outcome [1] 302426 0
Exercise capacity and functional status as assessed by maximal oxygen consumption (VO2max) on cardiopulmonary exercise testing and by 6-minute walk test.
Timepoint [1] 302426 0
6 months
Secondary outcome [2] 302432 0
Reduced chocardiographic grade of diastolic dysfunction as assessed by Tissue Doppler E/e’, (a non-invasive estimate of left atrial filling pressure).
Timepoint [2] 302432 0
6 months
Secondary outcome [3] 302433 0
Reduction of biomarkers of cardiac load and interstitial fibrosis as assessed by plasma assays of markers of ventricular and atrial haemodynamic load and other neurohormones contributing to HF pathophysiology as well as cytokine markers of inflammation and remodelling and markers of cardiac fibrosis and a marker of cardiomyocyte loss.
Timepoint [3] 302433 0
6 months
Secondary outcome [4] 302434 0
Improvement in ventricular-vascular function as evaluated by echocardiographic measures of arterial elastance, Left Ventricular (LV) end-systolic elastance, LV filling pressure, and LV diastolic stiffness.
Timepoint [4] 302434 0
6 months
Secondary outcome [5] 302435 0
Quality of life as assessed by the Minnesota Living with Heart Failure (MLWHF) scores
Timepoint [5] 302435 0
6 months
Secondary outcome [6] 302436 0
Reduction in the composite end-point of death or re-admission with Heart Failure.
Timepoint [6] 302436 0
6 months
Secondary outcome [7] 302437 0
The benefits listed above for renal denervation will apply to those with and without hypertension
Timepoint [7] 302437 0
6 months

Eligibility
Key inclusion criteria
*Patients with HFPEF (based upon ESC diagnostic criteria)
a. Symptoms and signs of heart failure; NYHA Class II or higher
b. Left ventricular ejection fraction 50% or greater on echocardiography
c. Echocardiographic evidence of left ventricular diastolic dysfunction (echo-Doppler E/e’ > 15 ) AND/OR plasma NTproBNP > 220pg/ml.
*Episode of acute decompensation (ADHF) requiring hospital admission within the 12 months prior to recruitment
*Patients with and without background hypertension may be recruited. In the case of patients with background hypertension (ie history of fulfilling the diagnostic WHO criteria for hypertension: SBP > 140 mmHg and/or DBP > 90 mmHg) those with both controlled (<140/90mmHg by 24 hour ambulatory BP) and inadequately controlled BP (on 3 anti-hypertensive drugs including a diuretic) can be recruited.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Known secondary cause of hypertension
*Renal artery stenosis >30% or anatomy otherwise unsuitable for RDN.
* Heart failure with reduced LV ejection fraction (LVEF < 50%).
*Estimated glomerular filtration rate (eGFR) of < 30mL/min/1.73m2 (MDRD calculation).
*Systolic blood pressure < 105mmHg.
*Implanted pacemaker, prosthetic heart valve or other precluding cMR scanning.
*Medical condition adversely affecting safety and/or effectiveness of the participant (including peripheral vascular disease, abdominal aortic aneurysm, thrombocytopenia or uncontrolled atrial fibrillation).
*Pregnant, nursing or planning to be pregnant.

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 recruited by regular systematic screening, by a local study coordinator, of ward admissions, clinic attendees and referrals of patients fulfilling inclusion but not exclusion criteria. Participants will provide informed, written and signed consent and the study protocol will be approved by local Institutional Review Boards. All initially eligible patients will undergo comprehensive echocardiography and if satisfying echo criteria and all inclusion criteria will proceed to a magnetic resonance (MR) study of renal artery anatomy. If unsuitable the procedure concludes and the patient is excluded. If anatomy is suitable the patient is then randomized (with allocation concealment by sealed opaque envelopes) to RDN or medical management (Those randomized then undergo blood flow measurements and renal perfusion studies and proceed to cardiac MR in the same session.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Using a randomisation table created by computer software (i.e. computerised sequence generation, participants will be assigned assigned 1:1 to renal angiography proceeding to RDN or to continued medical management.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary inter-group comparisons will be of change in Left Atrial volume index and Left Ventricular mass index between baseline and 6 month cardiac Magnetic Resonance Image scans. Primary and secondary continuous outcomes will be compared between randomised groups using a general linear model. This model will compare changes in the outcomes using baseline level as a covariate and stratum (Centre) and randomised group as fixed factors. Survival analysis (Cox regressions) will be used to compare the time to key clinical events (death, Heart Failure admission, other cardiovascular admissions including acute coronary syndromes, arrhythmia and all admissions) with randomised group and stratum as factors. Interaction analyses will be conducted for the possible influence of baseline blood pressure (hypertensive or normotensive).
The primary analysis will be undertaken on the intention to treat patient population with sensitivity analyses using the per-protocol population.
Sample size and power have been considered by our biostatistician co-investigator Associate Prof Chris Frampton. Given a standard deviation of LAVi of 5 ml/m2 and two-tailed alpha set to 0.025 (for dual primary end-points); group sizes of 60 provide 90% power to detect a difference in change between groups of 4 ml/m 2 and similar power to detect as little as 5gm inter-group difference in change in LVM.
For MVO2 given an SD of 5ml/min/kg this group size provides 90% power to detect a 3ml/min/kg difference. Given prior reports from a trial in HFPEF 26 we also anticipate adequate power to detect a 3 unit change in E/e’ , a 10 point fall in MLWHF score and 30% change in NTproBNP levels.
We will therefore recruit a total of 144 patients in expectation of 120 completing the protocol.
Documentation of clinical event rates will provide indicative information to power a phase 3 trial for cardinal clinical morbid and mortal endpoints although the current proposal is unlikely to have sufficient power to detect statistically significant effects for these endpoints.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/06/2013
Actual
18/10/2013
Date of last participant enrolment
Anticipated
1/06/2015
Actual
1/06/2015
Date of last data collection
Anticipated
Actual
31/12/2017
Sample size
Target
144
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 947 0
The Alfred - Prahran
Recruitment postcode(s) [1] 6800 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 5043 0
New Zealand
State/province [1] 5043 0
Country [2] 5044 0
Singapore
State/province [2] 5044 0
Country [3] 5045 0
Netherlands
State/province [3] 5045 0

Funding & Sponsors
Funding source category [1] 287165 0
Government body
Name [1] 287165 0
Health Research Council of New Zealand
Country [1] 287165 0
New Zealand
Funding source category [2] 287166 0
Commercial sector/Industry
Name [2] 287166 0
Medtronic International Ltd.
Country [2] 287166 0
Singapore
Primary sponsor type
Other
Name
Christchurch Heart Institute
Address
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 285932 0
None
Name [1] 285932 0
Address [1] 285932 0
Country [1] 285932 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289162 0
Health & Disability Ethics Committees
Ethics committee address [1] 289162 0
Ethics committee country [1] 289162 0
New Zealand
Date submitted for ethics approval [1] 289162 0
30/04/2013
Approval date [1] 289162 0
11/07/2013
Ethics approval number [1] 289162 0
13/CEN/64/AM01

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39514 0
Prof Mark Richards
Address 39514 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 39514 0
New Zealand
Phone 39514 0
+643 364 1063
Fax 39514 0
Email 39514 0
[email protected]
Contact person for public queries
Name 39515 0
Lorraine Skelton
Address 39515 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 39515 0
New Zealand
Phone 39515 0
+643 364 1063
Fax 39515 0
Email 39515 0
[email protected]
Contact person for scientific queries
Name 39516 0
Mark Richards
Address 39516 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 39516 0
New Zealand
Phone 39516 0
+643 364 1063
Fax 39516 0
Email 39516 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.