Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

NCT02742129 | Completed Phase 2 Results DMC

• 2 other identifiers: Pro000715265U10HL084904
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 20

Brief Summary

A randomized, double-blind, placebo-controlled crossover study to assess the effect of inorganic nitrite (NO2) on aerobic capacity (peak VO2) after four weeks of dosing. Approximately 100 participants will be enrolled in this 2\*2 crossover study.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• Peak VO2

  The primary endpoint will be the peak VO2 after 4 weeks treatment with inorganic nitrite as compared to the peak VO2 after 4 weeks treatment with placebo as assessed by cardiopulmonary exercise testing (CPET) performed at peak drug levels.

  End of Phase 1 & End of Phase 2

Secondary Outcomes (10)

• Average Arbitrary Accelerometer Units (AAU)

  End of Phase 1 & End of Phase 2

• Medial E/e' Ratio as Measured by Echocardiography Core Lab

  End of Phase 1 & End of Phase 2

• Left Atrial Volume Index as Measured by Echocardiography

  End of Phase 1 & End of Phase 2

• Pulmonary Artery Systolic Pressure as Measured by Echocardiography

  End of Phase 1 & End of Phase 2

• Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score

  End of Phase 1 & End of Phase 2

Study Arms (2)

AIR001 Crossover to Placebo

EXPERIMENTAL

Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug Nebulized Sodium Nitrite (AIR001) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Placebo instead of AIR001.

Drug: Nebulized Sodium Nitrite; Drug: Placebo

Placebo crossover to AIR001

PLACEBO COMPARATOR

Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug (Placebo) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Nebulized Sodium Nitrite (AIR001) instead of Placebo.

Drug: Nebulized Sodium Nitrite; Drug: Placebo

Interventions

Nebulized Sodium Nitrite DRUG

Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.

Also known as: AIR001

AIR001 Crossover to Placebo; Placebo crossover to AIR001

Placebo DRUG

Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.

AIR001 Crossover to Placebo; Placebo crossover to AIR001

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 (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
• EF ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
• One of the following :
• Previous hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or
• Catheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP ≥18) or with exercise (PCWP ≥25) or
• Elevated NT-proBNP (\>400 pg/ml) or 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 loop 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
• \. Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2\* Criteria (ml/kg/min) 7. No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for \>1 SL nitroglycerin per week) within last 7 days 8. No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study 9. Ambulatory (not wheelchair / scooter dependent) 10. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 kg/m2 but belt may fit some persons outside this range) 11. Willingness to wear the accelerometer belt for the duration of the trial 12. Willingness to provide informed consent

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 90 days prior to randomization
• GFR \< 20 ml/min/1.73 m2 within 90 days prior to randomization
• Systolic blood pressure \< 115 mmHg seated or \< 90 mmHg standing just prior to test dose
• Resting HR \> 110 just prior to test dose
• Previous adverse reaction to the study drug which necessitated withdrawal of therapy
• Significant chronic obstructive pulmonary disease thought to contribute to dyspnea
• Ischemia thought to contribute to dyspnea
• Documentation of previous EF \< 45%
• 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)
• PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months
• Primary hypertrophic cardiomyopathy
• Infiltrative cardiomyopathy (amyloid)
• Constrictive pericarditis or tamponade

Sponsors & Collaborators

• Adrian Hernandez: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Aires Pharmaceuticals, Inc.: collaborator
• University of Vermont: collaborator
• Université de Montréal: collaborator
• Mayo Clinic: collaborator
• Massachusetts General Hospital: collaborator

Study Sites (20)

Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Boston V.A. Healthcare System

West Roxbury, Massachusetts, 02132, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of Missouri Health System

Columbia, Missouri, 65212, United States

Location

V.A St. Louis Health Care System

St Louis, Missouri, 63106, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Stony Brook University Medical Center

Stony Brook, New York, 11794, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Metro Health System

Cleveland, Ohio, 44109, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Abington Memorial Hospital

Abington, Pennsylvania, 19001, United States

Location

University of Pennsylvania Health System

Philadelphia, Pennsylvania, 19104, United States

Location

Jefferson Medical College

Philadelphia, Pennsylvania, 19107, United States

Location

The University of Vermont - Fletcher Allen Health Care

Burlington, Vermont, 05401, United States

Location

Related Publications (3)

• Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.

  PMID: 32150314 DERIVED

• Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, Margulies KB, Smith AL, Tang WHW, Whellan DJ, Chen HH, Davila-Roman VG, McNulty S, Desvigne-Nickens P, Hernandez AF, Braunwald E, Redfield MM; National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA. 2018 Nov 6;320(17):1764-1773. doi: 10.1001/jama.2018.14852.

  PMID: 30398602 DERIVED

• Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM, Borlaug BA. INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design. Circ Heart Fail. 2017 May;10(5):e003862. doi: 10.1161/CIRCHEARTFAILURE.117.003862.

  PMID: 28476756 DERIVED

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Adrian Hernandez
• Organization: Duke Clinical Research Institute

Adrian.Hernandez@duke.edu

919-668-7515

Study Officials

• Kevin Hernandez, MD

  Duke Clinical Research Institute

  PRINCIPAL INVESTIGATOR

• Eugene Braunwald, MD

  Harvard University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI

Study Record Dates

• First Submitted: April 8, 2016
• First Posted: April 18, 2016
• Study Start: August 10, 2016
• Primary Completion: December 13, 2017
• Study Completion: December 27, 2017
• Last Updated: March 13, 2019
• Results First Posted: March 13, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will share

Locations

US (20)