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

NCT02713126 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 16-001467R01HL128526
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Change in Daily Activity Levels

  Baseline, 12 weeks

• Change in Cardiac Hemodynamics

  Baseline, 12 weeks

• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score

  Baseline, 12 weeks

• Change in Six Minute Walk Test

  Baseline, 12 weeks

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer

Drug: Placebo; Device: Accelerometer; Other: Cardiac Exercise Training

Sodium Nitrite

ACTIVE COMPARATOR

Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer

Drug: Sodium Nitrite; Device: Accelerometer; Other: Cardiac Exercise Training

Interventions

Placebo DRUG

administered orally or inhaled, taken every 4 hours or 3 times per day during waking hours for 12 weeks

Placebo

Sodium Nitrite DRUG

administered orally or inhaled, 40 mg, taken every 4 hours or 3 times per day during waking hours for 12 weeks

Also known as: Nitrite

Sodium Nitrite

Accelerometer DEVICE

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.

Placebo; Sodium Nitrite

Cardiac Exercise Training OTHER

Cardiac rehabilitation exercise training consisting of supervised endurance and strength exercise training of approximately one hour, 3 times per week for 12 weeks.

Placebo; Sodium Nitrite

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Joint, foot, leg, hip or back pain
• Shortness of breath and/or fatigue and/or chest pain
• Unsteadiness or dizziness
• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Barry Borlaug: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• Borlaug BA, Koepp KE, Reddy YNV, Obokata M, Sorimachi H, Freund M, Haberman D, Sweere K, Weber KL, Overholt EA, Safe BA, Omote K, Omar M, Popovic D, Acker NG, Gladwin MT, Olson TP, Carter RE. Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction: The INABLE-Training Trial. Mayo Clin Proc. 2024 Feb;99(2):206-217. doi: 10.1016/j.mayocp.2023.08.031. Epub 2023 Dec 21.

  PMID: 38127015 DERIVED

• Alogna A, Koepp KE, Sabbah M, Espindola Netto JM, Jensen MD, Kirkland JL, Lam CSP, Obokata M, Petrie MC, Ridker PM, Sorimachi H, Tchkonia T, Voors A, Redfield MM, Borlaug BA. Interleukin-6 in Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2023 Nov;11(11):1549-1561. doi: 10.1016/j.jchf.2023.06.031. Epub 2023 Aug 9.

  PMID: 37565977 DERIVED

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Heart Failure

Interventions

Sodium Nitrite; Nitrites

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds; Anions; Ions; Electrolytes; Organic Chemicals

Limitations and Caveats

Manufacturer discontinuation of the inhaled drug supply forced the investigator to modify the study and change the route of administration of sodium nitrite from inhaled to oral. The oral formulation achieved similar pharmacokinetics and therefore it was scientifically justified to combine the data.

Results Point of Contact

• Title: Dr. Barry Borlaug
• Organization: Mayo Clinic

borlaug.barry@mayo.edu

507-255-1051

Study Officials

• Barry A Borlaug, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: March 15, 2016
• First Posted: March 18, 2016
• Study Start: September 1, 2016
• Primary Completion: April 12, 2022
• Study Completion: April 12, 2022
• Last Updated: April 26, 2023
• Results First Posted: April 26, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)