Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000174189
Ethics application status
Approved
Date submitted
29/01/2019
Date registered
6/02/2019
Date last updated
6/02/2019
Date data sharing statement initially provided
6/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise as medicine for heart failure
Scientific title
Exercise as medicine for heart failure: A novel intervention to improve outcomes
Secondary ID [1] 297189 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
heart failure
 311240 0
Condition category
Condition code
Cardiovascular 309932 309932 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The current project aims to trial a new form of exercise, utilising eccentric muscular contractions, which have unique characteristics that allows for peripheral (muscular) gains at lower oxygen consumption and promisingly suggests enhanced functional benefits at lower cardiovascular risk. Participants randomised to the intervention group will receive eccentric cycle training.

Eccentric training of the lower limb muscles will be performed on an eccentric cycle ergometer that uses a motor to drive a bicycle crank in reverse. The eccentric exercise will be performed over the same duration and at a cardiovascular intensity equivalent to the comparator (concentric cycling) group (up to 70% HRR).

Exercise prescription will be undertaken in the Exercise Physiology Laboratory and Cardiac Gymnasia at Fiona Stanley Hospital, under the supervision of an exercise specialist with experience working with advanced HF patients. Our approach is to individually prescribe exercise predicated on baseline assessment. Exercise training is initiated one-on-one, and then continues in closely supervised small groups, to ensure strict adherence to the principles of the study’s exercise intervention. Participants will be continuously monitored with ECG telemetry. Facilities have full resuscitation equipment and rapid response, hospital accredited emergency support should that be required.

The intervention is a total of 16 weeks in duration. All sessions will be supervised by an accredited exercise physiologist to ensure participant safety, and robust adherence to exercise prescription. Participants will be continuously monitored with ECG telemetry, and technique, intensity monitored by the investigators.

Familiarization: Participants will undertake an initial 4 week familiarization block, of low level eccentric cycling to mitigate the potential of any exercise-induced muscle soreness or damage.

Progression: Training will then be progressed over several sessions to a workload corresponding to 50% of heart rate reserve (HRR), determined during baseline aerobic capacity assessment, with further progression up to 70% HRR (as individually tolerated).

Training Session format: Each group will undergo warm up and stretching routine for 10mins, followed by a total of 40mins of eccentric cycle training, then a 5min cool down. Training will occur 2 times per week. Borg’s Category Scale will be used to rate perceived exertion between the two modes of training.
Intervention code [1] 313487 0
Rehabilitation
Comparator / control treatment
Participants randomised to the comparator group will receive concentric (traditional) cycle training. Concentric cycle training will be performed on a standard cycle ergometer. Concentric cycling is routinely prescribed in patients with HF and therefore participants allocated to this group will constitute the usual care (control) group.

Concentric training of the lower limb muscles will be performed on an regular (concentric) cycle ergometer. The concentric exercise will be performed over the same duration and at a cardiovascular intensity equivalent to the eccentric cycle group (up to 70% HRR).

Exercise prescription will be undertaken in the Exercise Physiology Laboratory and Cardiac Gymnasia at Fiona Stanley Hospital, under the supervision of an exercise specialist with experience working with advanced HF patients. Our approach is to individually prescribe exercise predicated on baseline assessment. Exercise training is initiated one-on-one, and then continues in closely supervised small groups, to ensure strict adherence to the principles of the study’s exercise intervention. Participants will be continuously monitored with ECG telemetry. Facilities have full resuscitation equipment and rapid response, hospital accredited emergency support should that be required.

The intervention is a total of 16 weeks in duration. All sessions will be supervised by an accredited exercise physiologist to ensure participant safety, and robust adherence to exercise prescription. Participants will be continuously monitored with ECG telemetry, and technique, intensity monitored by the investigators.

Familiarization: Participants will undertake an initial 4 week familiarization block, of low level concentric cycling to mitigate the potential of any exercise-induced muscle soreness or damage.

Progression: Training will then be progressed over several sessions to a workload corresponding to 50% of heart rate reserve (HRR), determined during baseline aerobic capacity assessment, with further progression up to 70% HRR (as individually tolerated).

Training Session format: Each group will undergo warm up and stretching routine for 10mins, followed by a total of 40mins of cincentric cycle training, then a 5min cool down. Training will occur 2 times per week. Borg’s Category Scale will be used to rate perceived exertion between the two modes of training.
Control group
Active

Outcomes
Primary outcome [1] 318854 0
Changes in aerobic capacity, as assessed by VO2peak.
Exercise testing will be performed on a conventional cycle ergometer using 3 minute stages. Heart rate and rhythm and oxygen saturation will be measured continuously by 12-lead ECG and pulse oximeter respectively. Blood pressure, rating of perceived exertion (Borg Scale) and perceived dyspnoea (Borg Scale) will be recorded during the final 30 seconds of each stage. Indirect calorimetry will be measured employing a metabolic analysis system to establish.
Timepoint [1] 318854 0
Assessments will be made prior to, and immediately following the 16 week intervention
Secondary outcome [1] 366258 0
Preferred walking speed, assessed in our Biomechanics Gait Laboratory at the University of WA using motion capture, combined with mechanical work capacity, assessed simultaneously using force-plate work measurements. will be used as a measure of a functional task of every day living.
Timepoint [1] 366258 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [2] 366259 0
Activity levels will be assessed using a compact heart rate monitor with an integrated tri-axial accelerometer (Actiheart, Cambridge Neurotechnology) which is worn consecutively for 7 days. The total weight of the Actiheart is 8g and it is attached to the subject via two standard ECG chest electrodes.
The combination of HR and accelerometry enhances the prediction of energy expenditure, where movement may be low but heart rate is elevated (e.g. cycling). Daily heart rate and accelerometry data are displayed simultaneously, allowing for minute-by-minute analysis, examination of energy expenditure (kcal) and classification of activity into sedentary, light, moderate, or vigorous. R-R interval data are similarly derived and summarised for assessment of sympathetic and autonomic nervous system activity.
Timepoint [2] 366259 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [3] 366260 0
Muscle mechanics assessed using the Biodex system

We will combine dynamometry with muscle size measurements to estimate maximal voluntary specific strength (torque/physiological cross sectional area (PCSA) of muscle), following protocols similar to those previously adopted by our group. We have published data showing that the muscles of HF patients are both substantially smaller (~30%) and weaker compared to healthy controls matched for age, gender and activity level and that muscle size and strength are directly correlated to VO2peak in HF patients (r=0.75, P<0.01).
Timepoint [3] 366260 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [4] 366261 0
Body composition, as measured by a dual emission x-ray absorptiometry (DXA).
A full body scan performed on the GE lunar prodigy will be used to assess total and regional fatness and lean body mass composition
Timepoint [4] 366261 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [5] 366262 0
Cardiac echocardiograms will be used to measure chamber sizes (cavity dimensions and wall thicknesses) and myocardial masses will be calculated.
Timepoint [5] 366262 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [6] 366263 0
Ultrasonography with FMD (flow mediated dilation) will be obtained using non-invasive high resolution Duplex ultrasound (Terason t3300). Measures will be analysed using edge-detection and wall-tracking software, invented in our lab.
Timepoint [6] 366263 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [7] 366264 0
Psychosocial outcomes (Minnesota Living with Heart Failure Questionnaire). This questionnaire assesses perception of how emotional and physical state are impaired.
Timepoint [7] 366264 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [8] 366337 0
Functional capacity, as assessed by the six minute walk and timed get up and go tests
A 6-min walk test and an 8-foot (2.44m) ‘up-and-go’ test will be used
Timepoint [8] 366337 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [9] 366338 0
For specific muscular strength assessment, maximal voluntary contractions will be performed isometrically at a range of joint angles in a robotic dynamometer (Biodex). Muscle PCSA will be assessed using a 3D ultrasound approach recently developed in our lab, given that many HF patients have defibrillators or pacemakers and are unable to undergo MRI. We expect that eccentric training performed at the same HR as concentric training will result in greater strength; when matched for HR, eccentric cycling results in work output 20-30% greater than concentric cycling, which gives greater mechanical stimulus to leg muscles.
Timepoint [9] 366338 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [10] 366339 0
Arterial stiffness will be measured via pulse wave velocity (PWV), which strongly relates to atherosclerotic disease. Aortic PWV will be assessed using sensors placed on the carotid and femoral arteries. We will also measure arterial stiffness using a Sphygmocor XCEL device which collects BP waveforms, estimates PWV and enables pulse wave analysis.
Timepoint [10] 366339 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention
Secondary outcome [11] 366464 0
Cardiac echocardiograms will be used to determine regional diastolic/ systolic function (incorporating tissue-Doppler and myocardial speckle imaging). Interrogation of different sector scans will allow the determination of segmental function in radial, circumferential and longitudinal planes. Circumferential analysis will determine rotation, rotation rates, torsion and torsion rates.
Timepoint [11] 366464 0
All secondary measures will be collected immediately prior to, and following the 16 week intervention

Eligibility
Key inclusion criteria
NYHA Class II-IIIb with systolic dysfunction (HFrEF, EF <40%).
Willing and able to sign written informed consent prior to trial entry
Suitable to participate in a 16-week exercise training program, as determined by the medical history and physical examination
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Current smoking or smoking in the past 12 months,
Renal impairment (stage 4 or 5 CKD),
Exercise-induced ischaemia at a low workload (<3 METS),
Hypertension (>165/95mmHg)
Diagnosed peripheral artery disease

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)
Allocation will be performed using a clinical trials allocation system operated by a 3rd party
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomized to eccentric exercise training (ET) program or concentric exercise training (CT) program, using a clinical trials allocation system operated by a 3rd party.
Groups will be block randomized by age, gender and NYHA class.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis will be conducted on an intent-to-treat basis (i.e. analyzed as randomised) and per-protocol. For the primary research hypothesis, linear regression models will be used to estimate group difference and 95%CI for change in, using post-treatment measures as the outcome, and conditioning by baseline measures, with treatment condition as a fixed factor. Similar generalized linear regression models will be used to estimate the treatment effect and corresponding 95%CIs for secondary outcomes (muscular strength, endurance, mechanics; vascular function; cardiac function; physical activity; psychosocial outcomes), with final choice of model dependent upon the outcome distribution.

A mediation analysis will be performed using a product of coefficients approach, with bias-corrected bootstrapped confidence intervals, to test the extent to which mechanical and physiological changes are mediators of treatment effects on the primary outcome, peak VO2. Whilst we acknowledge the study is not specifically powered for this secondary analysis, the use of bias-corrected bootstrap methods and inclusion of blocking variables (age, gender and NYHA class) will maximise power. Simulation studies have suggested a sample size of 35 per group is sufficient to detect mediation in cases where, as expected in this situation, the treatment effect on the mediator and the mediator effect on the outcome are both of at least medium standardised effect size.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/03/2019
Actual
Date of last participant enrolment
Anticipated
1/09/2022
Actual
Date of last data collection
Anticipated
22/12/2022
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 13008 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 25492 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 301742 0
Government body
Name [1] 301742 0
National health an Medical Research Council
Country [1] 301742 0
Australia
Primary sponsor type
University
Name
The University of western Australia
Address
35 Stirling Highway Crawley, Western Australia 6009
Country
Australia
Secondary sponsor category [1] 301536 0
None
Name [1] 301536 0
Address [1] 301536 0
Country [1] 301536 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302465 0
South Metropolitan Health Services Human Ethics Committee
Ethics committee address [1] 302465 0
Level 2, Education Building, Fiona Stanley Hospital
14 Barry Marshall Parade
MURDOCH WA 6150
Ethics committee country [1] 302465 0
Australia
Date submitted for ethics approval [1] 302465 0
Approval date [1] 302465 0
23/07/2018
Ethics approval number [1] 302465 0
RGS586
Ethics committee name [2] 302505 0
The University of Western Australia Human Ethics Committee
Ethics committee address [2] 302505 0
35 Stirling highway, Crawley, WA 6009
Ethics committee country [2] 302505 0
Australia
Date submitted for ethics approval [2] 302505 0
Approval date [2] 302505 0
27/07/2018
Ethics approval number [2] 302505 0
RA/4/20/4728

Summary
Brief summary
Although impaired cardiac function initiates the syndrome, subsequent skeletal muscle and vascular abnormalities are major determinant of functional capacity and quality of life in the heart failure (HF) syndrome.
Exercise based rehabilitation is a cornerstone of HF therapy. Improvements in functional capacity resulting from exercise training predict prognosis, enhance quality of life, and reduces frailty and hospitalizations. An impediment to exercise rehabilitation for heart failure patients is the early physical deconditioning which is a trademark characteristic of this patient group which can limit classical aerobic and concentric strengthening exercise prescription.
The current project aims to trial a new form of exercise, utilising eccentric muscular contractions, which have unique characteristics that allows for peripheral (muscular) gains at lower oxygen consumption and promisingly suggests enhanced functional benefits at lower cardiovascular risk.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90314 0
Prof Daniel Green
Address 90314 0
The University of Western Australia
M408, 35 Stirling Highway
Crawley
WA 6009
Country 90314 0
Australia
Phone 90314 0
+61 8 6488 2361
Fax 90314 0
Email 90314 0
[email protected]
Contact person for public queries
Name 90315 0
Dr Louise Naylor
Address 90315 0
The University of Western Australia
M408, 35 Stirling Highway
Crawley
WA 6009
Country 90315 0
Australia
Phone 90315 0
+61 8 6488 2361
Fax 90315 0
Email 90315 0
[email protected]
Contact person for scientific queries
Name 90316 0
Dr Louise Naylor
Address 90316 0
The University of Western Australia
M408, 35 Stirling Highway
Crawley
WA 6009
Country 90316 0
Australia
Phone 90316 0
+61 8 6488 2361
Fax 90316 0
Email 90316 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified primary outcome data (VO2peak) underlying published results will be shared
When will data be available (start and end dates)?
Data will be completed immediately following publication, with no end date
Available to whom?
Anyone who wishes to access it
Available for what types of analyses?
The data will be available for analysis only to achieve the aims in the approved proposal
How or where can data be obtained?
Data will be available through the University of Western Australia Research Repository (https://research-repository.uwa.edu.au/)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1203Informed consent form    376814-(Uploaded-29-01-2019-21-25-06)-Study-related document.docx



Results publications and other study-related documents

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