PRIME HFrEF: Novel Exercise for Older Patients With Heart Failure With Reduced Ejection Fraction

Study Overview
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Brief Summary
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This study is trying to find out whether performing a hybrid aerobic-resistance exercise training program (titled PRIME: Peripheral Remodeling via Intermittent Muscular Exercise) results in better health outcomes than the traditional exercise training program (called COMBO) that is used in individuals with heart failure with reduced ejection fraction (HFrEF). Participants will be randomized (like the flip of a coin) to either PRIME (investigational) or the traditional exercise program (standard of care).

Detailed Description
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This study is a two-arm, prospective randomized clinical trial with participants randomized, in a 1:1 ratio to 4 weeks of either standard progressive whole-body aerobic plus resistance training (COMBO) or PRIME training (Phase 1), followed by 8 weeks of progressive whole-body COMBO assigned to all participants (Phase 2). The objective of this study is to determine whether PRIME exercise training can outperform traditional (COMBO) exercise training to improve outcomes in HFrEF patients. The study aims to test 92 HFrEF patients (46 randomized to PRIME and 46 to COMBO training) over a 5-year period. Data will be collected at each visit and patients will return for a 6-month follow up from the date of the final visit.

Official Title
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PRIME HFrEF: Novel Exercise for Older Patients With Heart Failure With Reduced Ejection Fraction

Conditions
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Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Other: PRIME
* Other: COMBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. Subjects may be of either sex with age > 65 years. Subjects must be diagnosed with HFrEF as per established echocardiographic criteria (New York Heart Association Class II-III) with an ejection fraction <40%. Cardiologist approve after thorough chart review and physical examination Hemoglobin of at least 10.0 g/dL Exclusion Criteria: Progressive worsening of exercise tolerance or dyspnea at rest or on exertion over previous 3-5 days Significant ischemia at low exercise intensities (<2 METS or  50 W) Uncontrolled diabetes (HbA1c >10%) Acute systemic illness of fever Recent embolism (in the 6 weeks) Deep Vein Thrombophlebitis Active pericarditis or myocarditis Severe aortic stenosis (aortic valve area <1.0 cm2) Regurgitant valvular heart disease requiring surgery Myocardial infarction within previous 3 weeks New onset atrial fibrillation (in the last 4 weeks) Resting Heart Rate >120bpm

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized open-label blinded endpoint (PROBE) parallel-group design. Participants will be randomized to PRIME or COMBO training for an initial four weeks (Phase 1). Following this, all participants will complete an additional eight weeks of COMBO training (Phase 2). Participants will be randomized in a 1:1 ratio by an independent statistician James Patrie (permuted block randomization with block size of 4, stratified by gender), with treatment allocation revealed after baseline exercise testing. Outcomes will be assessed at baseline, four weeks and eight weeks and 36 weeks (exploratory aim 5) by a blinded assessor (UVA SoM Exercise Core Laboratory).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRIME + COMBO<br>PRIME training (Phase 1), followed by 8 weeks of progressive whole-body COMBO training. | Other: PRIME<br>* PRIME is a a 'hybrid' aerobic-resistance (cardio and weights) program designed to target all major muscle groups and address the muscle limitations responsible for reduced fitness in the elderly. This occurs by minimizing the central limitations to more traditional exercise by delivering an ideal exercise stimulus to muscles in a way in which the heart is not a limiting factor. Each exercise involves contractions of specific isolated muscle groups with a moderate load, defined as 40%-50% of their maximal voluntary capacity.<br>* Other names: Exercise;Other: COMBO<br>* COMBO training includes both aerobic (cardio) and resistance (weightlifting) exercises. The aerobic component will be done on the stationary bicycle at 10-15 min duration at a target exercise intensity of 40-50% of VO2peak. This will feel like an intensity that is fairly light to somewhat hard, progressing gradually according to tolerance up to 20 mins. Intensity will be adjusted so that the difficulty remains in the target zone. The resistance component involves eight exercises, two sets of 10 repetitions, initially prescribed at 50-60% 1 repetition max. Subject will lift about half of their predicted maximal strength, 10 times, on 2 separate occasions with a rest between. Thereafter, the difficulty will be increased by approximately 10% when difficulty drops below the target range.<br>* Other names: Exercise;|
| Other: COMBO only<br>4 weeks of standard progressive whole-body aerobic plus resistance training (COMBO) followed by 8 weeks continued COMBO training. | Other: COMBO<br>* COMBO training includes both aerobic (cardio) and resistance (weightlifting) exercises. The aerobic component will be done on the stationary bicycle at 10-15 min duration at a target exercise intensity of 40-50% of VO2peak. This will feel like an intensity that is fairly light to somewhat hard, progressing gradually according to tolerance up to 20 mins. Intensity will be adjusted so that the difficulty remains in the target zone. The resistance component involves eight exercises, two sets of 10 repetitions, initially prescribed at 50-60% 1 repetition max. Subject will lift about half of their predicted maximal strength, 10 times, on 2 separate occasions with a rest between. Thereafter, the difficulty will be increased by approximately 10% when difficulty drops below the target range.<br>* Other names: Exercise;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VO2peak | Change in cardiorespiratory fitness (peak oxygen consumption [V̇O2peak]) after 12 weeks of training. The primary null hypothesis will test if mean change in V̇O2peak after 12 weeks of training is the same for subjects who initially undergo 4 weeks of PRIME before undergoing 8 weeks of progressive whole-body COMBO, versus subjects who undergo the whole 12 weeks of progressive COMBO. The alternative hypothesis is that the mean change in V̇O2peak after 12 weeks of training is not the same for subjects who initially undergo 4 weeks of PRIME training before undergoing 8 weeks of progressive COMBO, versus subjects who undergo the whole 12 weeks of progressive COMBO. Secondary endpoints include blood pressure, vascular function [arterial stiffness, endothelial function (FMD)] muscle characteristics and histochemistry, blood chemistry, physical fitness testing, quality of life questionnaires, and adherence. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscular fitness | Evaluated using 1 repetition maximal strength [1RM] measured in kg units | 40- weeks | 
| Physical Function | Evaluated by the Senior Fitness Test scores [SFT], measured in percentile units. | 40- weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFrEF, VO2peak