NCT03648762: EXT-HF

Exercise Therapy to Reduce Heart Failure Symptoms; Sorting Mechanisms of Benefit

Completed NA Results posted Last updated 24 June 2024

What this trial tests

NA trial testing Aerobic Exercise Intervention in Heart Failure in 65 participants. Completed in 30 September 2019.

Timeline

8 May 2017

Primary endpoint
30 September 2019

30 September 2019

Quick facts

Lead sponsor	VA Office of Research and Development
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	65
Start date	8 May 2017
Primary completion	30 September 2019
Estimated completion	30 September 2019
Sites	2 locations across United States

Drugs / interventions tested

• Aerobic Exercise Intervention
• Combined Aerobic and Strength Exercise Intervention
• Inspiratory Muscle Training Exercise Intervention

Conditions studied

• Heart Failure — all drugs for Heart Failure →

Sponsor

VA Office of Research and Development — full company profile →

Who can join

50 and older, any sex, with Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Oxygen Uptake (VO2) Peak Primary · baseline and through study completion an average of 14 weeks

a cardiopulmonary exercise test will be performed to determined peak VO2 in ML/KG/Min

Baseline

Group	Value	95% CI
Aerobic Exercise Intervention	1778.1	± 679.1
Combined Aerobic and Strength Exercise Intervention	1228.2	± 519.4
Inspiratory Muscle Training Exercise Intervention	1393.7	± 305.3

Follow-up

Group	Value	95% CI
Aerobic Exercise Intervention	1763.6	± 736.6
Combined Aerobic and Strength Exercise Intervention	1295.4	± 499.4
Inspiratory Muscle Training Exercise Intervention	1405.9	± 370.7

One Repetition Maximum- Leg Press Primary · baseline and through study completion an average of 14 weeks

Leg press will be performed on the Keiser Leg press and measured in kilograms (kg)

1 Rep Max Leg press baseline

Group	Value	95% CI
Aerobic Exercise Intervention	430.3	± 208.6
Combined Aerobic and Strength Exercise Intervention	348.2	± 143.0
Inspiratory Muscle Training Exercise Intervention	421.1	± 100.1

1 Rep Max Leg press follow-up

Group	Value	95% CI
Aerobic Exercise Intervention	433	± 232.7
Combined Aerobic and Strength Exercise Intervention	355.5	± 160.3
Inspiratory Muscle Training Exercise Intervention	409.5	± 136.4

Metabolomics Secondary · baseline and through study completion an average of 14 weeks

Nitric Oxide Bioavailability (uM) Metabolomics The scientific direction of our analyses for this measure has shifted over time. The investigators will pursue RNA seq and metabolomics to provide an unbiased path forward on viable targets in the muscle.

Baseline Nitric Oxide (uM)

Group	Value	95% CI
Aerobic Exercise Intervention	6.2	± 3.7
Combined Aerobic and Strength Exercise Intervention	7.7	± 2.5
Inspiratory Muscle Training Exercise Intervention	7.2	± 3.5

Follow-up Nitric Oxide (uM)

Group	Value	95% CI
Aerobic Exercise Intervention	5.6	± 2.4
Combined Aerobic and Strength Exercise Intervention	10.8	± 8.9
Inspiratory Muscle Training Exercise Intervention	6.6	± 3.1

Skeletal Muscle Gene Expression Secondary · baseline and through study completion an average of 14 weeks

Skeletal muscle gene expression will be measured in RNA isolated from skeletal muscle biopsy samples via Illumina platform. The measure "Number" indicates the number of differentially expressed genes, and units are fold change over baseline. To investigate how the lifestyle interventions impacted gene expression at the mRNA level in skeletal muscles of our research participants we performed high-throughput RNA-Sequencing (Illumina HiSeq paired-end 150 base pairs). Differential gene expression analysis was performed on the RNA-seq. data using DeSEQ2 to determine differentially expressed genes

Group	Value	95% CI
Aerobic Exercise Intervention	0
Combined Aerobic and Strength Exercise Intervention	1
Inspiratory Muscle Training Exercise Intervention	1

Quality of Life and Daily Function Questionnaires Secondary · baseline and through study completion an average of 12 weeks

Participants completed the Kansas City Cardiomyopathy questionnaire (KCCQ) and Duke Activity Status (DASI) Index standardized questionnaires. The KCCQ is scored on a scale of 0 to 100 with a higher score representing better health status. DASI is a 12-item questionnaire that is scored on a scale of 0 to 58.2, with a higher score representing a higher functional status.

KCCQ Baseline Score

Group	Value	95% CI
Aerobic Exercise Intervention	36	± 10.6
Combined Aerobic and Strength Exercise Intervention	37.7	± 12.0
Inspiratory Muscle Training Exercise Intervention	39.5	± 16.2

KCCQ Follow-up Score

Group	Value	95% CI
Aerobic Exercise Intervention	40	± 14.0
Combined Aerobic and Strength Exercise Intervention	38	± 13.2
Inspiratory Muscle Training Exercise Intervention	43	± 19.1

DASI Baseline Overall Score

Group	Value	95% CI
Aerobic Exercise Intervention	37.3	± 14.6
Combined Aerobic and Strength Exercise Intervention	34.7	± 15.4
Inspiratory Muscle Training Exercise Intervention	33.4	± 12.2

DASI Follow-up Overall Score

Group	Value	95% CI
Aerobic Exercise Intervention	37.3	± 15.2
Combined Aerobic and Strength Exercise Intervention	32.9	± 13.0
Inspiratory Muscle Training Exercise Intervention	33.4	± 15.9

Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults - Frequency Component Secondary · baseline and through study completion an average of 12 weeks

Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults as part of the Quality of Life and Daily Function study outcome. The CHAMPS questionnaire assesses duration and frequency of self-reported weekly physical activities of varying intensities in older adults. One component of the CHAMPS score is the frequency per week (i.e. number or count of events per week) that the participant reported that they engaged in all exercise related activities, and the frequency per week that the participant engaged in moderat

Baseline Mean Frequency of all Physical Activity bouts per week (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	14.7	± 9.2
Combined Aerobic and Strength Exercise Intervention	13.6	± 9.3
Inspiratory Muscle Training Exercise Intervention	9.5	± 4.2

Follow-up Mean Frequency of all Physical Activity bouts per week (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	23.5	± 10.9
Combined Aerobic and Strength Exercise Intervention	22.5	± 11.8
Inspiratory Muscle Training Exercise Intervention	19.5	± 9.1

Baseline Mean Frequency of Moderate-Vigorous Physical Activity bouts per week (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	5.5	± 5.6
Combined Aerobic and Strength Exercise Intervention	6.3	± 4.9
Inspiratory Muscle Training Exercise Intervention	3.0	± 2.9

Follow-up Mean Frequency of Moderate-Vigorous Physical Activity bouts per week (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	12.1	± 8.1
Combined Aerobic and Strength Exercise Intervention	10.6	± 6.7
Inspiratory Muscle Training Exercise Intervention	7.7	± 4.9

Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults - Duration Component Secondary · baseline and through study completion an average of 12 weeks

Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults as part of the Quality of Life and Daily Function study outcome. The CHAMPS questionnaire assesses duration and frequency of self-reported weekly physical activities of varying intensities in older adults. One component of the CHAMPS score is the self-reported duration in hours per week of all exercise-related activities, and duration in hours per week of moderate-vigorous exercise-related activities. The mean duration of all exercise-related activities

Baseline Mean Duration of all Physical Activity bouts (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	15.2	± 8.1
Combined Aerobic and Strength Exercise Intervention	7.7	± 4.5
Inspiratory Muscle Training Exercise Intervention	5.7	± 3.2

Follow-up Mean Duration of all Physical Activity bouts (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	21.8	± 15.9
Combined Aerobic and Strength Exercise Intervention	14.3	± 8.6
Inspiratory Muscle Training Exercise Intervention	14.4	± 9.6

Baseline Mean Duration of Moderate-Vigorous Physical Activity bouts (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	6.8	± 8.5
Combined Aerobic and Strength Exercise Intervention	3.5	± 2.7
Inspiratory Muscle Training Exercise Intervention	1.8	± 1.9

Follow-up Mean Duration of Moderate-Vigorous Physical Activity bouts (CHAMPS)

Group	Value	95% CI
Aerobic Exercise Intervention	11.6	± 11.7
Combined Aerobic and Strength Exercise Intervention	7.4	± 6.2
Inspiratory Muscle Training Exercise Intervention	5.5	± 5.4

Inflammation - C-reactive Protein Secondary · baseline and through study completion an average of 14 weeks

Inflammation - C-reactive protein (CRP) will be measured through blood

Baseline CRP (mg/L)

Group	Value	95% CI
Aerobic Exercise Intervention	3.3	± 1.5
Combined Aerobic and Strength Exercise Intervention	3.8	± 2.5
Inspiratory Muscle Training Exercise Intervention	1.8	± 1.6

Follow-up CRP (mg/L)

Group	Value	95% CI
Aerobic Exercise Intervention	4.1	± 4.1
Combined Aerobic and Strength Exercise Intervention	4.2	± 3.4
Inspiratory Muscle Training Exercise Intervention	2.1	± 2.1

Dual-energy X-ray Absorptiometry Secondary · Baseline and through study completion an average of 14 weeks

dual-energy x-ray absorptiometry will look at muscle mass change in kg

Appendicular Lean Mass Baseline

Group	Value	95% CI
Aerobic Exercise Intervention	3.96	± 1.14
Combined Aerobic and Strength Exercise Intervention	3.08	± 0.45
Inspiratory Muscle Training Exercise Intervention	3.08	± 0.49

Appendicular Lean Mass Follow-up

Group	Value	95% CI
Aerobic Exercise Intervention	8.73	± 1.29
Combined Aerobic and Strength Exercise Intervention	7.74	± 1.28
Inspiratory Muscle Training Exercise Intervention	7.72	± 0.99

Adverse events — posted to ClinicalTrials.gov

Time frame: After consent through study completion, up to 12 weeks. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Aerobic Exercise Intervention

Serious: 10/16 (63%)

Deaths: 0/16

Combined Aerobic and Strength Exercise Intervention

Serious: 3/17 (18%)

Deaths: 0/17

Inspiratory Muscle Training Exercise Intervention

Serious: 5/12 (42%)

Deaths: 0/12

Consented But Withdrew Pre-randomization

Serious: 5/5 (100%)

Deaths: 0/5

Serious adverse events (25 terms)

Reaction	System	Aerobic Exercise Intervent…	Combined Aerobic and Stren…	Inspiratory Muscle Trainin…	Consented But Withdrew Pre…
Influenza	Infections and infestations	—	—	—	—
Gout	Musculoskeletal and connective tissue disorders	—	—	—	—
Chest wall pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Eye Surgery	Surgical and medical procedures	—	—	—	—
Shoulder fracture	Musculoskeletal and connective tissue disorders	—	—	—	—
Mechanical Fall with Fractures	Musculoskeletal and connective tissue disorders	—	—	—	—
Acute Heart Failure	Cardiac disorders	—	—	—	—
Feeling faint	General disorders	—	—	—	—
Acute Heart Failure	Cardiac disorders	—	—	—	—
Hypertension	Cardiac disorders	—	—	—	—
LV thrombus	Cardiac disorders	—	—	—	—
Stomach, Chest pain	General disorders	—	—	—	—
Shoulder pain after fall on ice	Musculoskeletal and connective tissue disorders	—	—	—	—
Chest Pain	Cardiac disorders	—	—	—	—
dizziness, SOB, fogginess after medication change	General disorders	—	—	—	—
Unknown Respiratory Disorder	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Hypotension	Cardiac disorders	—	—	—	—
Mechanical fall on head	Musculoskeletal and connective tissue disorders	—	—	—	—
Hypoglycemia	Endocrine disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Thigh skin flap removal	Skin and subcutaneous tissue disorders	—	—	—	—
Lightheadedness after starting new medication	General disorders	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—
Edema	General disorders	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—

Other adverse events (1 terms — click to expand)

Reaction	System	Aerobic Exercise Intervent…	Combined Aerobic and Stren…	Inspiratory Muscle Trainin…	Consented But Withdrew Pre…
Spinal stenosis	Musculoskeletal and connective tissue disorders	—	—	—	—

Most-reported serious reactions: Influenza, Gout, Chest wall pain, Eye Surgery, Shoulder fracture, Mechanical Fall with Fractures, Acute Heart Failure, Feeling faint.

Data from ClinicalTrials.gov NCT03648762 adverse events section.

Sponsor's own description

The purpose of this research study is to better understand how exercise training in older adults (≥65 years) with heart failure (HF) affects skeletal muscle both intrinsically and in respect to its impact on functional capacity. While many conceptualize HF as a pathophysiology that exclusively affects the heart, skeletal muscle atrophy and weakening are also elemental to the disease. While reduced exercise capacity is typically associated with HF, this may be related more to disease effects in skeletal muscle than the heart. This is a clinical study that focuses on exercise training which compares functional endpoints before and after training. Patients are randomized to one of three exercise training interventions (aerobic vs. aerobic and strength vs. inspiratory muscle training) for 12 weeks and are assessed pre- and post-training to determine if any differences occur in their skeletal muscle and functional capacity. Skeletal muscle biopsies before and after the exercise training intervention in order to study changes in skeletal muscle histology and biology.

Functional endpoints in this study include ventilatory gas indices from cardiopulmonary exercise testing, lower body strength testing, grip strength, sit-to-stand, six-minute-walk distance, gait speed, inspiratory muscle strength, and quality of life and physical activity-oriented questionnaires, including the Kansas City Cardiomyopathy Questionnaire, Duke Activity Status Index, and CHAMPS Physical Activity Questionnaire for Older Adults. Body composition is measured with Dual Energy X-ray (DXA) scanning. Skeletal muscle biopsies are completed in the vastus lateralis of the non-dominant leg to assess histology and biologic endpoints.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. The role of maximal inspiratory pressure on functional performance in adults with heart failure.
   Shah RV, Cahalin LP, Haus JM, Allsup K, et al · · 2024 · cited 5× · PMID 39161120 · DOI 10.1002/ehf2.14984