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

• ClinicalTrials.gov Identifier: NCT02742129
• Recruitment Status: Completed
• First Posted: April 18, 2016
• Results First Posted: March 13, 2019
• Last Update Posted: March 13, 2019
• Sponsor: Adrian Hernandez
• 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

Tracking Information

• First Submitted Date: April 8, 2016
• First Posted Date: April 18, 2016
• Results First Submitted Date: December 6, 2018
• Results First Posted Date: March 13, 2019
• Last Update Posted Date: March 13, 2019
• Actual Study Start Date: August 10, 2016
• Actual Primary Completion Date: December 13, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 18, 2019)

Peak VO2 [ Time Frame: End of Phase 1 & End of Phase 2 ]

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.

Original Primary Outcome Measures (submitted: April 13, 2016)

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.

Current Secondary Outcome Measures (submitted: February 18, 2019)

• Average Arbitrary Accelerometer Units (AAU) [ Time Frame: End of Phase 1 & End of Phase 2 ]
  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). An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based upon patient movement. Higher values indicate more movement. Zero indicates no movement.
• Medial E/e' Ratio as Measured by Echocardiography Core Lab [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether AIR001 improves Medial E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity for diastolic evaluation) in comparison to placebo.
• Left Atrial Volume Index as Measured by Echocardiography [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
• Pulmonary Artery Systolic Pressure as Measured by Echocardiography [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
• Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score [ Time Frame: End of Phase 1 & End of Phase 2 ]
  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). Higher values of the overall KCCQ score are considered to be better than lower values.
• N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) [ Time Frame: End of Phase 1 & End of Phase 2 ]
  Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
• NYHA (New York Heart Association) Class [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether AR001 improves NYHA Class in comparison to placebo. NYHA class was measured at the end of each phase. The site physician evaluated the patient based upon the criteria for NYHA class I-IV used by the American Heart Association. NYHA functional classification provides a way of classifying the extent of heart failure. Class I (least severe): No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV (most severe): Unable to carry on any physical activity without discomfort.
• Patient Preference for AIR001 Treatment at the End of Study [ Time Frame: End of Phase 2 ]
  Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
• VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of Ve/VCO2 during study drug administration. The Ve/VCO2 slope is defined as the slope of the linear relationship between ventilation and carbon dioxide output and is a measure of the velocity.
• VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab [ Time Frame: End of Phase 1 & End of Phase 2 ]
  To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 (rate of oxygen consumption measured during incremental exercise) at ventilatory threshold during study drug administration.

Original Secondary Outcome Measures (submitted: April 13, 2016)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
• Official Title: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
• 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)

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Heart Failure

Intervention

• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Nebulized Sodium Nitrite
  • Drug: Placebo
• 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.
  Interventions:

  • Drug: Nebulized Sodium Nitrite
  • Drug: Placebo

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 6, 2017): 105
• Original Estimated Enrollment (submitted: April 13, 2016): 100
• Actual Study Completion Date: December 27, 2017
• Actual Primary Completion Date: December 13, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02742129
• Other Study ID Numbers: Pro00071526; 5U10HL084904 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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.

• Current Responsible Party: Adrian Hernandez, Duke University
• Original Responsible Party: Same as current
• Current Study Sponsor: Adrian Hernandez
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: Duke University
• Verification Date: February 2019