We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02742129
First Posted: April 18, 2016
Last Update Posted: November 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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
  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: Triple (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.


Enrollment: 105
Study Start Date: August 2016
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: December 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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02742129


Locations
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Boston V.A. Healthcare System
West Roxbury, Massachusetts, United States, 02132
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
University of Missouri Health System
Columbia, Missouri, United States, 65212
V.A St. Louis Health Care System
Saint Louis, Missouri, United States, 63106
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Stony Brook University Medical Center
Stony Brook, New York, United States, 11794
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Ohio
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States, 44106
Metro Health System
Cleveland, Ohio, United States, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Abington Memorial Hospital
Abington, Pennsylvania, United States, 19001
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States, 19104
Jefferson Medical College
Philadelphia, Pennsylvania, United States, 19107
United States, Vermont
The University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, United States, 05401
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 )
First Submitted: April 8, 2016
First Posted: April 18, 2016
Last Update Posted: November 8, 2017
Last Verified: November 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