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Trial registered on ANZCTR


Registration number
ACTRN12617001143314
Ethics application status
Approved
Date submitted
25/07/2017
Date registered
4/08/2017
Date last updated
4/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A physician-led l(L)ifestyle i(I)nterv(V)entional program with goals of weight loss and e(E)xercise participation in overweight and obese patients with heart failure and reduced (REDUCED) ejection fraction.
Scientific title
A physician-led l(L)ifestyle i(I)nterv(V)entional program with goals of weight loss and e(E)xercise participation in overweight and obese patients with heart failure and reduced (REDUCED) ejection fraction.
Secondary ID [1] 292516 0
Nil
Universal Trial Number (UTN)
Trial acronym
LIVE-REDUCED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart failure 304182 0
Obesity 304216 0
Overweight 304217 0
Condition category
Condition code
Cardiovascular 303507 303507 0 0
Other cardiovascular diseases
Diet and Nutrition 303508 303508 0 0
Obesity
Metabolic and Endocrine 303509 303509 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is designed as a prospective, local multi-centre randomised control trial. A total of 150 patients will be randomised in a 1:1 ratio to enrol in a physician-led interventional lifestyle program (pathway A), or standard medical management (pathway B). At the time of consent, all participants will be assigned either Pathway A or B. Depending upon on recruitment rates, the trial may be expanded to other Australian sites.

Group A (Lifestyle and Weight loss intervention):

For patients randomised to the intervention (Group A), a structured, motivational and goal-directed program using face-to-face physician-led counselling will be used for weight reduction. The overall duration of the intervention is 12 months. This lifestyle intervention clinic will deliver risk factor management to the patient with the help of a research assistant. Patients will be encouraged to utilise support counselling and schedule more frequent reviews as required after the initial intensive phase. Initial weight reduction will be attempted by a meal plan and behaviour modification. Meals plans will consist of high protein and low glycemic index, calorie controlled foods, targeted to a maximum of 1500 calories per day. If patients lose <3% of weight after 3-months they will then be prescribed very-low-calorie (VLCD) meal replacement sachets (Nestle Health Sciences) for 1-2 meals per day with an aim of ~800-1000 calories per day.

The initial goal is to reduce body weight by 10%. After patients achieve the initial goal, meal replacement will be substituted to high protein and low glycemic index, calorie-controlled foods to achieve a target BMI of less than, or equal to, 25kg per m2. During periods of prescription of very-low-calorie meal replacement sachets, participants will undergo a protocol of electrolyte monitoring. As recommended on the Nestle Health Sciences product information sheet, patients on diuretics may need the dose reduced or the diuretic ceased altogether as postural hypotension may occur. Patients will be monitored closely, preferably under specialist caer and fluid restrictions will be modified if appropriate to suit individual requirements. Electrolytes will be monitored more frequently (twice per week during the intensive phase). If a study participant is prescribed VLCD, the guidance and assistance of a Clinical Dietician will occur and patients will be reviewed by a Clinical Dietician as they are commenced on this protocol.

During the intensive phase of the intervention (the 1st 12 weeks), initially weekly (for the 1st six weeks), and consequently fortnightly visits will be scheduled. The initial visit will be for 45mins to 1 hour, followed by 20 minutes for subsequent visits. After the intensive phase, a tailored program of visits will be scheduled for the duration of the intervention (monthly, or 2-monthly visits).

Exercise:

The American Heart Association has previously produced a scientific statement that documents the physiological benefits and safety of prescribed exercise in patients with a diagnosis of heart failure. Following the performance of the Cardio-pulmonary exercise test (CPET), a scheduled visit will occur with an Exercise Physiologist. This 45 minute consultation will involve a discussion regarding the results of the CPET and formulation of an individualised exercise plan. The personalised exercise plan will be adapted to an individual's musculoskeletal capacity, their baseline level of fitness and their personal ability to adapt to exercise in their weekly routines. In general terms for this study, low intensity aerobic exercise (walking, cycling, swimming), will be prescribed initially for 20-minutes thrice-weekly (with an aim of 60% of the individuals maximum predicted heart rate). This will then increasing to at least 200-minutes of moderate-intensity activity per week (which will include resistance training). The patients will be advised to maintain a lifestyle journal in which patients log their daily food intake, weight, blood pressure and exercise duration. This journal will be utilized for giving necessary exercise advice and assisting as an effective behavioural tool for modification.

Intervention code [1] 298718 0
Lifestyle
Intervention code [2] 298719 0
Behaviour
Intervention code [3] 298720 0
Treatment: Other
Comparator / control treatment
Group B (Controls):
•Group B will continue standard of care for HF management and follow-up. Medications will be prescribed by their treating cardiologists and referrals for device therapy will occur (where indicated). They will also have attention to management of comorbidities including sleep disorders, iron deficiency and depression.

A written information sheet will be provided to Group B regarding the standard of care for weight loss advice and exercise for patients with HF and obesity

Other Management:

All patients (Group A & Group B) enrolled in this study will have ongoing guideline targeted HF management. This will include medical management with up-titration of medical therapy where appropriate, utilisation of diuretic therapy to achieve euvoleumia and lifestyle advice including weight monitoring and fluid restriction where indicated. Referral for cardiac device therapy will occur when appropriate. Attention to monitoring for the presence of iron deficiency will occur and iron infusions will be prescribed in accordance with the latest ESC Guideline recommendations as appropriate. Patients will also be referred for cardiac transplantation assessment if indicated. There will be attention to addressing additional lifestyle factors such as smoking, alcohol and recreational drug use, with referral to multidisciplinary clinics where appropriate.

All patients will be supplied with a Patient Heart Failure Education Booklet. This is a thorough information booklet produced by The Alfred Hospital Heart Failure Service. It provides clinical information to patients on management of their heart failure, including lifestyle factors.
Control group
Active

Outcomes
Primary outcome [1] 302883 0
Primary Composite endpoint of 12 month change in quality of life score (as measured by Kansas City Cardiomyopathy Questionnaire Score); and change in exercise capacity (as by peak VO2 on CPET).
Timepoint [1] 302883 0
12 months
Secondary outcome [1] 337318 0
Change in six minute walk distance
Timepoint [1] 337318 0
12 months
Secondary outcome [2] 337319 0
Change in BDI-II (Depression) Score
Timepoint [2] 337319 0
12 months
Secondary outcome [3] 337320 0
Change in SF-36 Score
Timepoint [3] 337320 0
12 months
Secondary outcome [4] 337321 0
Change in International Physical Activity Questionnaire Score
Timepoint [4] 337321 0
12 months
Secondary outcome [5] 337322 0
Change in New York Heart Association Status
Timepoint [5] 337322 0
12 months
Secondary outcome [6] 337324 0
Change in serum biomarkers including
- B-Natriuretic Peptide (BNP) - biomarker of myocardial stretch with prognostic significant in heart failure.
- Galectin 3 levels (biomarker of fibrosis with prognostic value in heart failure).
Timepoint [6] 337324 0
12 months
Secondary outcome [7] 337325 0
Mortality
Timepoint [7] 337325 0
12 months
Secondary outcome [8] 337326 0
Rates of device therapy including high voltage device therapies from ICDs (using the data obtained on outpatient device checks periodically and from hospital medical records as well as remote monitoring downloads),
Timepoint [8] 337326 0
12 months
Secondary outcome [9] 337327 0
Number of hospitalisations (via patient reporting at each visit),
Timepoint [9] 337327 0
12 months
Secondary outcome [10] 337328 0
Echocardiographic measured cardiac structural effects:
Left atrial volume
Timepoint [10] 337328 0
12 months
Secondary outcome [11] 337329 0
Change in heart rate variability (as assessed from Holter monitoring).
Timepoint [11] 337329 0
12 months
Secondary outcome [12] 337330 0
Change in peak metabolic equivalents of task (METs) - A subgroup will undergo Exercise Stress Testing. 15 randomly selected participants in each sub-group will undergo an exercise stress test.
Timepoint [12] 337330 0
12 months
Secondary outcome [13] 337331 0
Cardiac Magnetic Reasonance Imaging (CMR) will be performed in 30 randomly selected participants from each subgroup. Cardiac MRI enabled measurement of left atrial ejection fraction.
Timepoint [13] 337331 0
12 months
Secondary outcome [14] 337332 0
Change in BMI
Timepoint [14] 337332 0
12 months
Secondary outcome [15] 337452 0
Requirement to proceed to cardiac transplantation and/or left ventricular assist device implantation (this will be assessed through data collected at clinical visits and the review of medical records).
Timepoint [15] 337452 0
Over 12 month period of the study.
Secondary outcome [16] 337453 0
Left ventricular ejection fraction measured using echocardiography.
Timepoint [16] 337453 0
Baseline and at 12 months
Secondary outcome [17] 337454 0
Interventricular septal wall thickness (mm) measured using parasternal long-axis image on trans-thoracic echocardiography.
Timepoint [17] 337454 0
12 months post enrolment.
Secondary outcome [18] 337455 0
Estimated pulmonary artery pressure on echocardiography (including the estimated right atrial pressure).
Timepoint [18] 337455 0
12 months
Secondary outcome [19] 337456 0
Mitral annulus, e' = cm/sec (average) - measured using tissue Doppler imaging on trans-thoracic echocardiography.
Timepoint [19] 337456 0
Baseline and at 12 months
Secondary outcome [20] 337457 0
Mitral annular S’ velocity (as measured using Tissue Doppler Imaging)
Timepoint [20] 337457 0
Baseline and at 12 months following enrolment.
Secondary outcome [21] 337458 0
Peak global longitudinal strain - measured using GE Software (offline) - images obtained with trans-thoracic echocardiography.
Timepoint [21] 337458 0
Baseline and at 12 months following enrolment.
Secondary outcome [22] 337535 0
Employment
Timepoint [22] 337535 0
12 months
Secondary outcome [23] 337563 0
Waist circumference (measured in centimetres)
Timepoint [23] 337563 0
Measured at baseline and at 12 months.
Secondary outcome [24] 337594 0
Cardiac MRI based measurement of LV mass
Timepoint [24] 337594 0
Baseline and at 12 months
Secondary outcome [25] 337595 0
Cardiac MRI based measurement of left ventricular ejection fraction.
Timepoint [25] 337595 0
Baseline and at 12 months.
Secondary outcome [26] 337596 0
Cardiac MRI enabled measurement of right ventricular ejection fraction.
Timepoint [26] 337596 0
Baseline and at 12 months.
Secondary outcome [27] 337597 0
Cardiac MRI enabled measurement of left atrial volume.
Timepoint [27] 337597 0
Baseline and at 12 months.
Secondary outcome [28] 337598 0
Cardiac MRI enabled measurement of LV global longitudinal strain.
Timepoint [28] 337598 0
Baseline and at 12 months.
Secondary outcome [29] 337599 0
Cardiac MRI enabled measurement of LV radial strain.
Timepoint [29] 337599 0
Baseline and at 12 months.
Secondary outcome [30] 337600 0
Cardiac MRI enabled measurement of LV circumferential strain.
Timepoint [30] 337600 0
Baseline and at 12 months.

Eligibility
Key inclusion criteria
Established diagnosis of HF-REF (as defined by the presence of the clinical syndrome of heart failure and documented cardiac systolic dysfunction on cardiac imaging, with a measured left ventricular ejection fraction <45%).
• On established medical therapy (not currently undergoing an active phase or program of up-titration of medical therapy).
• Age >18 and <80 at the time of enrolment.
• BMI >27kg/m2
• New York Heart Association Classification II, III or ambulatory class IV.
• > 1 month following a previous admission to hospital with exacerbation or diagnosis of HF
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Current listing for cardiac transplantation or placement of left ventricular assist device.
• History of myocardial infarction or cardiac surgery within the previous 3 months.
• Frequent hospitalisations with HF (>2 in the previous 6 months).
• Significant cardiac valvulopathy (with the exception of functional mitral and tricuspid regurgitation)
• Active malignancy, active autoimmune or systemic inflammatory disease; severe renal or hepatic failure.
• Acute & potentially reversible causes of HF (eg. Takostubo cardiomyopathy, acute myocarditis).
• Unstable ventricular arrhythmias in preceding 3 months
• Significant chronic disease that prevents enrolment in the program such as active malignancy, severe pulmonary disease, end-stage renal or hepatic failure, other physical disability resulting in inability to exercise.
• Pregnancy.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/08/2017
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 8617 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 8618 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 16725 0
5000 - Adelaide
Recruitment postcode(s) [2] 16726 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 297087 0
University
Name [1] 297087 0
University of Adelaide
Country [1] 297087 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute
Address
North Terrace, Adelaide, SA, 5000
Country
Australia
Secondary sponsor category [1] 296094 0
University
Name [1] 296094 0
University of Adelaide
Address [1] 296094 0
The University of Adelaide
North Terrace, Adelaide, SA 5000
Country [1] 296094 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298265 0
Central Adelaide Local Health Network Research Committee
Ethics committee address [1] 298265 0
North Terrace, Adelaide, SA, 5000
Ethics committee country [1] 298265 0
Australia
Date submitted for ethics approval [1] 298265 0
21/02/2017
Approval date [1] 298265 0
09/06/2017
Ethics approval number [1] 298265 0
HREC/17/RAH/56

Summary
Brief summary
This local-multicentre, prospective, randomised control study will aim to assess the impact of an intentional weight loss and a prescribed exercise program in overweight and obese patients with heart failure and reduced ejection fraction (HF-REF).

The impact of the program will be assessed by the measurement at 12 months of the change in exercise capacity (as measured by peak VO2 on CPET), and the change in KCCQ score compared with baseline measurements. These two parameters will be the composite endpoints. A number of secondary endpoints will be collected to assess the prognostic significance (including mortality, rate of hospitalisations, changes in New York Heart Association Classification (NYHA)), cardiac structural, functional, mood and cardiac biomarker effects of this program.

This study aims to assist in clarifying the degree of controversy and uncertainty about the appropriateness of advice to patients with obesity and established HF-REF. This is a result of a recurrently observed, but somewhat controversial ‘obesity paradox’ in a number of heart failure (HF) studies where patients with HF and higher body mass index (BMI) appear to have improved outcomes including less deterioration of functional class and lower mortality rates compared with those who have HF and a lower BMI.

There is a paucity of published clinical studies that have assessed the combined effects of an intentional weight loss and prescribed exercise program on heart failure outcomes including functional measures, hospitalisations, mortality, and cardiac structural changes along with measured serum biomarkers. This study will evaluate the effects of a structured lifestyle interventional program compared with standard of care in overweight and obese patients with heart failure and reduced ejection fraction.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76522 0
Prof Prashanthan Sanders
Address 76522 0
Centre For Heart Rhythm Disorders
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 76522 0
Australia
Phone 76522 0
+61 8 8222 2723
Fax 76522 0
+61 8 82222722
Email 76522 0
[email protected]
Contact person for public queries
Name 76523 0
Prashanthan Sanders
Address 76523 0
Centre For Heart Rhythm Disorders
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 76523 0
Australia
Phone 76523 0
+61 8 8222 2723
Fax 76523 0
+61 8 82222722
Email 76523 0
[email protected]
Contact person for scientific queries
Name 76524 0
Prashanthan Sanders
Address 76524 0
Centre For Heart Rhythm Disorders
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 76524 0
Australia
Phone 76524 0
+61 8 8222 2723
Fax 76524 0
+61 8 82222722
Email 76524 0
[email protected]

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