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Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF)

This study is currently recruiting participants.
See Contacts and Locations
Verified November 2016 by Adrian Hernandez, Duke University Medical Center
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Aires Pharmaceuticals, Inc.
University of Vermont
Université de Montréal
Mayo Clinic
Massachusetts General Hospital
Information provided by (Responsible Party):
Adrian Hernandez, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT02742129
First received: April 8, 2016
Last updated: January 20, 2017
Last verified: November 2016
  Purpose
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.

Condition Intervention Phase
Heart Failure Drug: Nebulized Sodium Nitrite Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
Official Title: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Resource links provided by NLM:


Further study details as provided by Adrian Hernandez, Duke University Medical Center:

Primary Outcome Measures:
  • Peak VO2 [ Time Frame: 4-6 weeks & 10-12 weeks ]
    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.


Secondary Outcome Measures:
  • Average arbitrary accelerometer units (AAU) [ Time Frame: 4-6 weeks & 10-12 weeks ]
    Average arbitrary accelerometer units (AAU) during at least 14 days and up to 21 days of the maximally tolerated dose of study drug (from 28 days post Study Visit 1 until Study Visit 2 and from 28 days post Study Visit 2 until Study Visit 3)

  • Medial E/e' ratio as measured by echocardiography [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether AIR001 improves Medial E/e' ratio in comparison to placebo.

  • Left atrial volume index as measured by echocardiography [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.

  • Pulmonary artery systolic pressure as measured by echocardiography [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.

  • KCCQ [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether AR001 improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).

  • NT-proBNP [ Time Frame: 6 weeks & 12 weeks ]
    Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo

  • NYHA Class [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether AR001 improves NYHA Class in comparison to placebo

  • Patient preference for AIR001 treatment at the end of study [ Time Frame: 12 weeks ]
    Self-reported participant preference for study period 1 vs. study period 2.

  • VE/VCO2 slope (ventilatory efficiency) [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of VeVCO2 during study drug administration

  • VO2 at ventilatory threshold (submaximal exercise capacity) [ Time Frame: 6 weeks & 12 weeks ]
    To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 at ventilatory threshold during study drug administration.


Estimated Enrollment: 100
Study Start Date: August 2016
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AIR001 Crossover to Placebo
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
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.
Other Name: AIR001
Drug: Placebo
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.
Placebo Comparator: Placebo crossover to AIR001
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
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.
Other Name: AIR001
Drug: Placebo
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.

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  1. Age ≥ 40 years
  2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
  3. 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
  4. 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
  5. 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

6. 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

Exclusion Criteria:

  1. Recent (< 1 month) hospitalization for heart failure
  2. Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
  3. Hemoglobin (Hgb) < 8.0 g/dl within 90 days prior to randomization
  4. GFR < 20 ml/min/1.73 m2 within 90 days prior to randomization
  5. Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test dose
  6. Resting HR > 110 just prior to test dose
  7. Previous adverse reaction to the study drug which necessitated withdrawal of therapy
  8. Significant chronic obstructive pulmonary disease thought to contribute to dyspnea
  9. Ischemia thought to contribute to dyspnea
  10. Documentation of previous EF < 45%
  11. 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)
  12. PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months
  13. Primary hypertrophic cardiomyopathy
  14. Infiltrative cardiomyopathy (amyloid)
  15. Constrictive pericarditis or tamponade
  16. Active myocarditis
  17. Complex congenital heart disease
  18. Active collagen vascular disease
  19. More than mild aortic or mitral stenosis
  20. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
  21. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation treatment
  22. Terminal illness (other than HF) with expected survival of less than 1 year
  23. Regularly (> 1x per week) swims or does water aerobics
  24. Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
  25. Inability to comply with planned study procedures
  26. Pregnancy or breastfeeding mothers
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02742129

Contacts
Contact: Adrian Hernandez, MD 919-668-8700 Adrian.Hernandez@duke.edu
Contact: Pamela Monds 919-668-8695 pamela.monds@duke.edu

Locations
United States, Georgia
Emory University School of Medicine Recruiting
Atlanta, Georgia, United States, 30322
Contact: Gail Snell    404-712-0531    gsnell@emory.edu   
Principal Investigator: Robert Cole, MD         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Hamorabi Mkrdichian    312-926-2773    hmkrdich@nmh.org   
Principal Investigator: Sanjiv Shah, MD         
United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21287
Contact: Anita Bacher    410-614-8039    abach@jhmi.edu   
Principal Investigator: Ryan Tedford, MD         
United States, Massachusetts
Tufts Medical Center Recruiting
Boston, Massachusetts, United States, 02111
Contact: Patrick Arpin    617-636-5928    parpin@tuftsmedicalcenter.org   
Principal Investigator: Gordon Huggins, MD         
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Diane Cocca-Spofford    617-643-2155    cocca-spofford.diane@mgh.harvard.edu   
Principal Investigator: Marc Semigran, MD         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Mary Sheehan    617-732-6237    msheehan1@partners.org   
Principal Investigator: Michael Givertz, MD         
Boston V.A. Healthcare System Not yet recruiting
West Roxbury, Massachusetts, United States, 02132
Contact: Samantha Ly    857-203-6255    samantha.ly@va.gov   
Principal Investigator: Neal Lakdawala, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Janet Gatzke    507-538-7177    gatzke.janet@mayo.edu   
Principal Investigator: Margaret Redfield, MD         
United States, Missouri
University of Missouri Health System Recruiting
Columbia, Missouri, United States, 65212
Contact: Sarah Collins    573-884-4155    collinssar@health.missouri.edu   
Principal Investigator: Cristina Danila, MD         
V.A St. Louis Health Care System Not yet recruiting
Saint Louis, Missouri, United States, 63106
Contact: Marie White    314-652-4100    socorro.white@va.gov   
Principal Investigator: Illa Halatchev, MD         
Washington University School of Medicine Recruiting
St Louis, Missouri, United States, 63110
Contact: Donna Whitehead    314-454-8257    dwhitehe@dom.wustl.edu   
Principal Investigator: Victor Davila-Roman, MD         
United States, New York
Stony Brook University Medical Center Recruiting
Stony Brook, New York, United States, 11794
Contact: Indre Calkauskaite    631-444-2031    indre.caikauskaite@stonybrookmedicine.edu   
Principal Investigator: Javed Butler, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27705
Contact: Patricia Adams    919-668-8222    patricia.adams@duke.edu   
Principal Investigator: Michael Felker, MD         
United States, Ohio
University Hospitals Cleveland Medical Center Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Maria Scheutzow    216-844-3740    maria.scheutzow@uhhospitals.org   
Principal Investigator: Oliveira Guilherme, MD         
Metro Health System Recruiting
Cleveland, Ohio, United States, 44109
Contact: Julie Nichols    216-778-8747    jnichols@metrohealth.org   
Principal Investigator: Mark Dunlap, MD         
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Teresa Fonk    216-444-4724    fonkt@ccf.org   
Principal Investigator: Wilson Tang, MD         
United States, Pennsylvania
Abington Memorial Hospital Recruiting
Abington, Pennsylvania, United States, 19001
Contact: Deborah Wood    215-481-4661    deborah.wood@jefferson.edu   
Principal Investigator: Donald Haas, MD         
University of Pennsylvania Health System Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Todd Nicklas    215-662-4214    todd.nicklas@uphs.upenn.edu   
Principal Investigator: Kenneth Margulies, MD         
Jefferson Medical College Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Maura Fox    215-503-7420    maura.fox@jefferson.edu   
Principal Investigator: David Whellan, MD         
United States, Vermont
The University of Vermont - Fletcher Allen Health Care Recruiting
Burlington, Vermont, United States, 05401
Contact: Marilynn Roth    802-847-2741    marilynn.roth@uvmhealth.org   
Principal Investigator: Peter Van Buren, MD         
Sponsors and Collaborators
Adrian Hernandez
National Heart, Lung, and Blood Institute (NHLBI)
Aires Pharmaceuticals, Inc.
University of Vermont
Université de Montréal
Mayo Clinic
Massachusetts General Hospital
Investigators
Principal Investigator: Kevin Hernandez, MD Duke Clinical Research Institute
Study Chair: Eugene Braunwald, MD Harvard University
  More Information

Responsible Party: Adrian Hernandez, Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT02742129     History of Changes
Other Study ID Numbers: Pro00071526
5U10HL084904 ( U.S. NIH Grant/Contract )
Study First Received: April 8, 2016
Last Updated: January 20, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: After study completion, and upon site request, site specific participant data will be shared upon site requests. Sites may share this data with participants according to their individual institution's Institutional Review Board (IRB) policy.

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on July 27, 2017