Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

NCT ID: NCT02742129

Last Updated: 2019-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 105 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-10
• Study Completion Date: 2017-12-27

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.

Detailed Description

Screen potential HFpEF patients for eligibility criteria and interest

Study Visit 1

• Initiate consent process and obtain written informed consent.

• Confirm with the participant that HF symptoms are the primary limitation to activity. If so, they proceed to CPET screening. If not, they are considered a screen fail.
• Obtain baseline bloods *- CBC, complete chemistry panel, biomarkers, biorepository and genetics (if agreed to participate) .
• Obtain CPET to verify patient eligibility peak VO2 ≤ 75% predicted and RER ≥ 1.0 (within 3 days prior to randomization) and establish baseline value.
• Qualifying patients perform additional baseline studies: history, assess NYHA class, physical exam, ECG, and KCCQ.
• Open label, single-dose run-in where patient receives maximal dose (80 mg) inhaled inorganic nitrite. Patients who do not tolerate the run-in are considered screen failures.
• Randomize qualifying patients.
• Dispense phase-1 study drug, nebulizers and accelerometers
• Participants take no study drug for two weeks (baseline).
• Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days.
• Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 2 (at least 42 days but up to 49 days post-baseline visit).
• If side effects develop, participants can down-titrate to the previous dose.
• Participants are called frequently to reinforce study procedures and assess compliance.

Study Visit 2 (42-49 Days Post Study Visit 1)

• Participant holds study drug on day of visit.

• Review history, assess NYHA class, perform physical exam and KCCQ.
• Obtain blood draws ** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
• Obtain limited echocardiogram **.
• Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
• Change out accelerometer and dispense phase-2 study drug.
• Participants take no study drug for two weeks (washout).
• Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days.
• Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 3 (at least 42 but up to 49 days after study visit 2).
• If side effects develop Participants can down-titrate to the previously tolerated dose.
• Participants are called frequently to reinforce study procedures and assess compliance.

Study Visit 3 (42-49 Days Post Study Visit 2) • Participant holds study drug on day of visit.

• Review history, assess NYHA class, perform physical exam and KCCQ

• Obtain blood draws** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
• Obtain limited echocardiogram**.
• Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
• Return accelerometer and phase-2 study drug.
• End of study drug (phase out).

Phone Visit and End of Study (14 Days Post Study Visit 3)

• A final phone visit is conducted to assess for adverse events.

*Visit 1: baseline blood draw needs to be completed prior to the CPET (if this is not feasible, then they cannot be obtained for at least 3 hours post the CPET and prior to the run-in test dose).

**Visit 2 and Visit 3: blood draws and limited echo need to be obtained prior to study drug administration (if this is not feasible, then it cannot be obtained for at least 3 hours post study drug administration)

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Nebulized Sodium Nitrite

Intervention Type: 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.

Placebo

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Nebulized Sodium Nitrite

Intervention Type: 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.

Placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

AIR001

Eligibility 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

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Aires Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

University of Vermont

OTHER

Sponsor Role: collaborator

Université de Montréal

OTHER

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Adrian Hernandez

OTHER

Sponsor Role: lead

Responsible Party

Adrian Hernandez

Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Kevin Hernandez, MD

Role: PRINCIPAL_INVESTIGATOR

Duke Clinical Research Institute

Eugene Braunwald, MD

Role: STUDY_CHAIR

Harvard University

Locations

Emory University School of Medicine

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Boston V.A. Healthcare System

West Roxbury, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Missouri Health System

Columbia, Missouri, United States

V.A St. Louis Health Care System

St Louis, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Stony Brook University Medical Center

Stony Brook, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Metro Health System

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Abington Memorial Hospital

Abington, Pennsylvania, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Jefferson Medical College

Philadelphia, Pennsylvania, United States

The University of Vermont - Fletcher Allen Health Care

Burlington, Vermont, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32150314 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30398602 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28476756 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

5U10HL084904

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro00071526

Identifier Type: -

Identifier Source: org_study_id