Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF) (INABLE-Training) (INABLE)

• ClinicalTrials.gov Identifier: NCT02713126
• Recruitment Status: Completed
• First Posted: March 18, 2016
• Last Update Posted: May 3, 2022
• Sponsor: Barry Borlaug
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Barry Borlaug, Mayo Clinic

Study Description

Brief Summary:

Participants with heart failure with preserved ejection fraction will undergo 12 weeks of cardiac rehabilitation for exercise training (ET) and be randomized to either oral sodium nitrite capsules or oral placebo capsules through the training period. Study drug is administered 3 times daily during daytime hours with one of these doses being 30 minutes prior to onset of ET sessions throughout the12 week trial. The objective is to determine if the oral sodium nitrite improves the clinical responses and tolerability of ET.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Drug: Placebo Solution; Drug: Oral Sodium Nitrite; Device: Accelerometer; Other: Cardiac Exercise Training	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF)
• Study Start Date: September 2016
• Actual Primary Completion Date: April 12, 2022
• Actual Study Completion Date: April 12, 2022

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Subjects will undergo cardiac exercise training and receive oral placebo capsules three times per day for 12 weeks while wearing an accelerometer	Drug: Placebo Solution; Placebo capsule administered orally, taken every 4 hours or 3 times per day during waking hours for 12 weeks; Device: Accelerometer; External triaxial accelerometer is worn externally at the hip during exercise training sessions, and day/night to continuously measure activity levels, removed for bathing only.; Other: Cardiac Exercise Training; Cardiac rehabilitation exercise training consisting of supervised endurance and strength exercise training of approximately one hour, 3 times per week for 12 weeks.
Active Comparator: Sodium Nitrite; Subjects will undergo cardiac exercise training and receive oral sodium nitrite capsules three times per day for 12 weeks while wearing an accelerometer	Drug: Oral Sodium Nitrite; Oral Sodium Nitrite, 40 mg administered orally, taken every 4 hours or 3 times per day during waking hours for 12 weeks; Other Name: Nitrite; Device: Accelerometer; External triaxial accelerometer is worn externally at the hip during exercise training sessions, and day/night to continuously measure activity levels, removed for bathing only.; Other: Cardiac Exercise Training; Cardiac rehabilitation exercise training consisting of supervised endurance and strength exercise training of approximately one hour, 3 times per week for 12 weeks.

Outcome Measures

Primary Outcome Measures :

1. Change in exercise capacity [ Time Frame: Baseline, 12 weeks ]
   Change in exercise capacity as measured by peak oxygen consumption

Secondary Outcome Measures :

1. Change in daily activity levels [ Time Frame: Baseline, 12 weeks ]
   Change in daily activity as assessed by accelerometer data; device worn continuously
2. Change in hemodynamics [ Time Frame: Baseline, 12 weeks ]
   Change in hemodynamics and ventricular function measured during echocardiography
3. Change in Quality of Life score [ Time Frame: Baseline, 12 weeks ]
   Change in Quality of Life score, as measured using the Kansas City Cardiomyopathy Questionnaire
4. Change in symptoms of heart failure [ Time Frame: Baseline, 12 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥ 40 years
• Symptoms of dyspnea (II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
• Ejection Fraction (EF) of > or = 50% determined on most recent imaging study within the preceding 5 years, with no change in clinical status suggesting potential for deterioration in systolic function

• One of the following:

  • Previous hospitalization for Heart Failure (HF) with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or
  • Catheterization documented elevated filling pressures at rest (Pulmonary Capillary Wedge Pressure (PCWP)= ≥15 or Left Ventricular End-Diastolic Pressure (LVEDP) ≥18) or with exercise (PCWP ≥25) or
  • Elevated Natruretic Peptide-proBNP (>400 pg/ml) or B-Type Natriuretic Peptide (BNP)(>200 pg/ml) or
  • Echo evidence of diastolic dysfunction/elevated filling pressures manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a diuretic for signs or symptoms of heart failure
• Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question:

My ability to be active is most limited by:

1. Joint, foot, leg, hip or back pain
2. Shortness of breath and/or fatigue and/or chest pain
3. Unsteadiness or dizziness

4. Lifestyle, weather, or I just don't like to be active

   • No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 sublingual nitroglycerin per week).
   • No daily use of phosphodiesterase 5 (PDE5) inhibitors or soluble guanylyl cyclase activators and willing to withhold as needed use of PDE5 inhibitors for duration of study
   • Ambulatory (not wheelchair / scooter dependent)
   • Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process.
   • Willingness to wear the accelerometer belt for the duration of the trial

Exclusion Criteria:

• Recent (< 1 month) hospitalization for heart failure
• Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
• Hemoglobin (Hgb) < 8.0 g/dl within 30 days prior to randomization
• Glomerular Filtration Rate (GFR) < 20 ml/min/1.73 m2 within 30 days prior to randomization
• Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing
• Resting Heart Rate > 110
• Previous adverse reaction to the study drug which necessitated withdrawal of therapy
• Significant chronic obstructive pulmonary disease that is a primary contributor to symptoms, in the opinion of the Investigator.
• Ischemia thought to contribute to dyspnea, in the opinion of the Investigator.
• Documentation of previous Ejection Fraction < 40%
• Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
• Percutaneous Coronary Intervention, coronary artery bypass grafting, or new biventricular pacing within past 3 months
• Obstructive hypertrophic cardiomyopathy
• Known infiltrative cardiomyopathy (amyloid)
• Constrictive pericarditis or tamponade
• Active myocarditis
• Complex congenital heart disease
• Active collagen vascular disease
• More than mild aortic or mitral stenosis
• Intrinsic (prolapse, rheumatic) valve disease with more than moderate mitral, tricuspid or aortic regurgitation
• Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, International Normalized Ratio (INR) > 1.7 in the absence of anticoagulation treatment
• Terminal illness (other than HF) with expected survival of less than 1 year
• Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
• Inability to comply with planned study procedures
• Pregnancy or breastfeeding mothers

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Barry Borlaug

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Barry A Borlaug, MD; Mayo Clinic

More Information

Additional Information:

Mayo Clinic Clinical Trials 

• Responsible Party: Barry Borlaug, MD, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02713126
• Other Study ID Numbers: 16-001467; R01HL128526 ( U.S. NIH Grant/Contract )
• First Posted: March 18, 2016
• Last Update Posted: May 3, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases