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

Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF)

Participants with heart failure with preserved ejection fraction will undergo 12 weeks of cardiac rehabilitation for exercise training (ET) and be randomized to either sodium nitrite or placebo through the training period. Study drug is administered 3 times daily 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 sodium nitrite improves the clinical responses and tolerability of ET.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Device: Accelerometer; Other: Cardiac Exercise Training; Drug: Placebo; Drug: Sodium Nitrite

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer	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.; Drug: Placebo; administered orally or inhaled, taken every 4 hours or 3 times per day during waking hours for 12 weeks
Active Comparator: Sodium Nitrite; Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer	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.; Drug: Sodium Nitrite; administered orally or inhaled, 40 mg, taken every 4 hours or 3 times per day during waking hours for 12 weeks; Other Names: Nitrite

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Rate of Oxygen (VO2)	Exercise capacity as measured by the peak rate of oxygen (VO2) consumption achieved during exercising testing. Peak VO2 is expressed as milliliters of oxygen per kilogram of body mass per minute.	Baseline, 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Daily Activity Levels	The change in daily activity levels as assessed by accelerometer data and reported as average accelerometry units.	Baseline, 12 weeks
Change in Cardiac Hemodynamics	The change in cardiac hemodynamics as measured by echocardiography. The E/e' ratio is a marker used to evaluate the left ventricular (LV) filling pressures during exercise. An E/e' ratio of <8 is considered to be normal, a ratio >15 is considered to reflect an increase in the LV filling pressure.	Baseline, 12 weeks
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered questionnaire that provides a measure of symptoms and physical limitations associated with heart failure. The overall summary score ranges from 0-100, where the higher the score the better the health status.	Baseline, 12 weeks
Change in Six Minute Walk Test	The six minute walk test is an exercise test used to assess aerobic capacity and endurance. The total distance covered over six minutes is measured in meters.	Baseline, 12 weeks

Collaborators and Investigators

• Sponsor: Barry Borlaug
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Barry A Borlaug, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Actual): April 12, 2022
• Study Completion (Actual): April 12, 2022

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimate): March 18, 2016

Study Record Updates

• Last Update Posted (Actual): April 26, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 16-001467; R01HL128526 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No