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Trial registered on ANZCTR


Registration number
ACTRN12619000253101
Ethics application status
Approved
Date submitted
30/11/2018
Date registered
20/02/2019
Date last updated
20/02/2019
Date data sharing statement initially provided
20/02/2019
Date results information initially provided
20/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Optimising clinical and functional outcomes in older adults with Heart Failure (HF) using the Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) approach: A pilot study
Scientific title
Optimising clinical and functional outcomes in older adults with Heart Failure (HF) using the Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) approach: A pilot study
Secondary ID [1] 296882 0
None
Universal Trial Number (UTN)
Trial acronym
PRIME-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Heart Failure 310473 0
Condition category
Condition code
Cardiovascular 309187 309187 0 0
Other cardiovascular diseases
Physical Medicine / Rehabilitation 309491 309491 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This pilot study will employ a randomised controlled, single-blinded parallel group design to test the hypothesis that 4 weeks of PRIME training, prior to 4 weeks of traditional HF rehabilitation (combination aerobic plus resistance exercise) is a feasible ‘primer’ to produce relevant additive gains in primary efficacy outcomes of aerobic capacity and muscle strength in comparison to 8 weeks of traditional HF rehabilitation, in elderly patients with HF.

Participants were randomised in a 1:1 ratio to PRIME or COMBO training for the first 4 weeks, after which all participants will complete a further 4 weeks of COMBO training.

All exercise-training sessions lasted 60 minutes, including warm-up, training, and cooldown and were conducted twice per week for a total of 8 weeks. Participants were supervised by an accredited exercise physiologist’s and an attendance record kept and documented daily. Exercise sessions were conducted at the Victoria University Clinical Exercise Rehabilitation Clinic and/or the Western Centre for Health, Research and Education. In the case of missed exercise sessions, catch up sessions were offered.

The PRIME protocol included eight exercises completed within 60 min including warm-up, rest periods, stretching between exercises, and cooldown activities (see Table 1 in attached research protocol). Each exercise started at approximately 50% of 1RM at a cadence of 1 concentric phase every 4 seconds for a period of 5 minutes. During each exercise subjects were allowed to take breaks as needed with each for a minimum of 30 seconds. Progression was made first by decreasing the number of required rest periods during each exercise. When the subject could complete the whole duration of the exercise (6 minutes) without rest the load was increased by ~10%.
Intervention code [1] 312954 0
Rehabilitation
Comparator / control treatment
All exercise-training sessions lasted 60 minutes, including warm-up, training, and cooldown and were conducted twice per week for a total of 8 weeks. Participants were supervised by an accredited exercise physiologist’s and an attendance record kept and documented daily. Exercise sessions were conducted at the Victoria University Clinical Exercise Rehabilitation Clinic and/or the Western Centre for Health, Research and Education. In the case of missed exercise sessions, catch up sessions were offered.

The COMBO protocol (best practice exercise control group) will completed a combination of aerobic exercise and resistance training, as recommended by several leading institutions. The aerobic component commenced at 10–15 min at target exercise intensity of RPE 11-13, on one, or a combination of of aerobic equipment at the participants choice, including cycle ergometry (upright and recumbents), treadmill walking, upper limb ergometry, progressing gradually according to patient’s progress and tolerance to 20 minutes. Depending on individual responses, the intensity was adjusted so that the RPE remained in the target zones. The resistance component involved 8 exercises including chest press, leg press, hack squat, upright row, seated row, latissimus pulldown, bicep curls and triceps cable pushdowns,, at a convention prescription of 2 sets of 10 respetitions at a startingintensity of 50% 1RM, corresponding to an RPE of 11-13. The load was increased by ~10% when the participant fell below the RPE target zones.
Control group
Active

Outcomes
Primary outcome [1] 308164 0
this study assessed the feasibility of conducting a future definitive trial, to determine if 4 weeks of PRIME training, followed by 4 weeks of traditional HF rehabilitation (combination aerobic plus resistance exercise) can produce relevant additive gains in aerobic capacity and muscle strength in comparison to 8 weeks of traditional HF rehabilitation, in elderly patients with HF. Feasibility was determined by indicators across viability, safety and acceptability, with success defined by the following criteria: i) recruitment rate of 2 patients per month, ii) <5% of participants experiencing adverse events, iii) >75% compliance with training protocol and v) < 5% drop out rate.

A record was kept for every patient screened against study eligibility at each clinic, detailing reasons for inclusion or exclusion. Major and minor adverse events, protocol deviations and dropouts were recorded on a daily basis by the study co-ordinator or supervising exercise physiologist, for the duration of the study.
Timepoint [1] 308164 0
The primary feasibility outcomes (viability, safety and acceptability) will be assessed for the duration of the study, and totals calculated after 8 weeks of intervention.
Secondary outcome [1] 354120 0
Aerobic capacity:
Maximal aerobic capacity (VO2peak) was obtained during a symptom limited CPEX on a Lode Corival cycle ergometer, including a 12-lead electrocardiogram. Heart rate (HR), blood pressure (BP) and Rating of Percieved Exertion (RPE) was recorded throughout. The protocol commenced at 20 watts and increased by 10 watts in 2-minute stages and was terminated when the patient achieved >17 on the RPE scale, and unable to continue cycling within 10rpm of target cadence, or on the appearance of clinical signs and symptoms. VO2 for each 10 second interval was calculated by the MedGraphics BREEZESUITE CPX Ultim system, which was calibrated prior to every visit.
Timepoint [1] 354120 0
Clinical outcomes will be assessed at baseline, at 4 weeks after starting the intervention, and after 8 weeks immediately following completion of the intervention.
Secondary outcome [2] 366367 0
Muscle strength
Total muscle voluntary contraction (Total MVC) was calculated as the sum of three repetition maximum (3RM) for 7 different upper and lower body exercises. Handgrip strength was also measured by a handgrip dynamometer and recorded as the maximum achieved during 3 trials for left and right hands.
Timepoint [2] 366367 0
Clinical outcomes will be assessed at baseline, at 4 weeks after starting the intervention, and after 8 weeks immediately following completion of the intervention.
Secondary outcome [3] 366368 0
Functional Capacity:
Several functional measures were collected to further assess efficacy and to develop methodology for a larger trial, and included the Timed Up and Go test (TUGT), 4 square step test (4SST), and 10-meter walk test (10MWT).
Timepoint [3] 366368 0
Clinical outcomes will be assessed at baseline, at 4 weeks after starting the intervention, and after 8 weeks immediately following completion of the intervention.

Eligibility
Key inclusion criteria
i) a diagnosis of HF with reduced ejection fraction (HFrEF) as defined by ESC Guidelines 2016 (left ventricular ejection fraction <40%) and confirmed by the study cardiologist
(ii) age greater than or equal to 65 years and
(iii) mild to moderate symptomatology (NYHA II-III).
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion from the study resulted from the presence of absolute contraindications to exercise training, as per reported criteria for participation in exercise for people with HF, including:
• Progressive worsening of exercise tolerance, dyspnoea or other symptoms suggestive of deterioration of heart failure or acute illness
• Severe aortic stenosis or severe valvular disease
• Unstable Angina
• Resting systolic pressure greater than or equal to 160 mmHg or diastolic BP greater than or equal to 95 mmHg
• Resting heart rate greater than or equal to 100 bpm
• Complex ventricular arrhythmia at rest or appearing with exertion
• Neuromuscular, musculoskeletal, or rheumatoid disorders that are exacerbated by exercise

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)
Study participants were randomised in a 1:1 ratio by an independent researcher from Victoria University who was not involved in the study. Due to the nature of the intervention patients and staff were unblinded to group allocation which was revealed after baseline exercise testing.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation with block size of 4, stratified by gender was used and sequence saved in sequentially numbered opaque sealed envelopes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This was a PROBE design (prospective randomized open blinded end-point), specifying blinded assessment of the primary efficacy outcome (VO2peak). Muscle strength and functional outcomes for two of the three assessment points (4 weeks and 8 weeks) due to resource limitations. Due to the nature of the intervention patients and staff were unblinded to group allocation
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Baseline characteristics are presented as mean (standard deviation) or frequency (percentage). The effect of intervention (PRIME versus COMBO) on the primary and secondary outcomes were analysed by intention to treat using 2-way multiple measures ANOVA with Sidac’s mutltiple comparisons, in GraphPad Prism Version 7.04 for Windows (GraphPad Software, La Jolla California USA, www.graphpad.com). Per protocol analysis was conducted to assess sensitivity. Data was assumed to be missing completely at random, and due to small sample size no imputation was performed thus missing data was excluded from all of the 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)
VIC
Recruitment hospital [1] 12441 0
Western Hospital - Footscray - Footscray
Recruitment hospital [2] 12442 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 24716 0
3011 - Footscray
Recruitment postcode(s) [2] 24717 0
3021 - St Albans

Funding & Sponsors
Funding source category [1] 301226 0
Hospital
Name [1] 301226 0
Western Health Research Grant 2016 (Sunshine Hospital)
Address [1] 301226 0
Western Centre for Health, Research and Education,
Sunshine Hospital, 176 Furlong Road, St Albans Victoria 3021
Country [1] 301226 0
Australia
Funding source category [2] 301236 0
University
Name [2] 301236 0
Victoria University PhD Funding
Address [2] 301236 0
Victoria University
Footscray Park Campus
Ballarat Road, Footscray VIC 3011
Country [2] 301236 0
Australia
Primary sponsor type
Hospital
Name
Western Health Research Grant 2016 (Sunshine Hospital)
Address
Western Centre for Health, Research and Education,
Sunshine Hospital, 176 Furlong Road, St Albans Victoria 3021
Country
Australia
Secondary sponsor category [1] 300859 0
University
Name [1] 300859 0
Victoria University
Address [1] 300859 0
Victoria University
Footscray Park Campus
Ballarat Road, Footscray VIC 3011
Country [1] 300859 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301969 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 301969 0
300 Grattan Street, Parkville Victoria 3050
Ethics committee country [1] 301969 0
Australia
Date submitted for ethics approval [1] 301969 0
03/06/2015
Approval date [1] 301969 0
23/06/2015
Ethics approval number [1] 301969 0
2015.015

Summary
Brief summary
Guidelines recommended moderate intensity aerobic exercise for all patients with HF, however many exercise training studies include a patient group much younger than the 'real world' patient with HF who is elderly.

This study was designed with a dual focus to address the age gap seen in HF exercise trials, while simultaneous gathering preliminary data for a novel rehabilitation technique called Peripheral Remodelling through Intermittent Muscular Exercise: “PRIME”. The PRIME approach offers a ‘hybrid’ aerobic-resistance solution for individuals with HF who may be unable to participate in conventional exercise training.

This study will assess the feasibility of conducting a future large trial, to determine if 4 weeks of PRIME training, followed by 4 weeks of traditional HF rehabilitation (combination aerobic plus resistance exercise) can produce superior gains in aerobic capacity and muscle strength in comparison to 8 weeks of traditional HF rehabilitation, in elderly patients with HF.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88710 0
A/Prof Christopher Neil
Address 88710 0
Western Centre for Health, Research and Education
Sunshine Hospital
176 Furlong Road, St Albans Victoria 3021
Country 88710 0
Australia
Phone 88710 0
+61 414919776
Fax 88710 0
Email 88710 0
Christopher.Neil@wh.org.au
Contact person for public queries
Name 88711 0
A/Prof Christopher Neil
Address 88711 0
Western Centre for Health, Research and Education
Sunshine Hospital
176 Furlong Road, St Albans Victoria 3021
Country 88711 0
Australia
Phone 88711 0
+61 414919776
Fax 88711 0
Email 88711 0
Christopher.Neil@wh.org.au
Contact person for scientific queries
Name 88712 0
A/Prof Christopher Neil
Address 88712 0
Western Centre for Health, Research and Education
Sunshine Hospital
176 Furlong Road, St Albans Victoria 3021
Country 88712 0
Australia
Phone 88712 0
+61 414919776
Fax 88712 0
Email 88712 0
Christopher.Neil@wh.org.au

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?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 351 0
Study protocol
Citation [1] 351 0
Link [1] 351 0
Email [1] 351 0
Other [1] 351 0
Type [2] 352 0
Ethical approval
Citation [2] 352 0
Link [2] 352 0
Email [2] 352 0
Other [2] 352 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary