Clinical trial NCT02742129: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
Official title: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Aires Pharmaceuticals, Inc.
name: University of Vermont
name: Université de Montréal
name: Mayo Clinic
name: Massachusetts General Hospital
First posted: 2016-04-18
Enrollment: 105
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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)

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

Primary outcomes:
measure: Peak VO2
timeFrame: End of Phase 1 & End of Phase 2
Secondary outcomes:
measure: Average Arbitrary Accelerometer Units (AAU)
timeFrame: End of Phase 1 & End of Phase 2
measure: Medial E/e' Ratio as Measured by Echocardiography Core Lab
timeFrame: End of Phase 1 & End of Phase 2
measure: Left Atrial Volume Index as Measured by Echocardiography
timeFrame: End of Phase 1 & End of Phase 2
measure: Pulmonary Artery Systolic Pressure as Measured by Echocardiography
timeFrame: End of Phase 1 & End of Phase 2
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score
timeFrame: End of Phase 1 & End of Phase 2
measure: N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)
timeFrame: End of Phase 1 & End of Phase 2
measure: NYHA (New York Heart Association) Class
timeFrame: End of Phase 1 & End of Phase 2
measure: Patient Preference for AIR001 Treatment at the End of Study
timeFrame: End of Phase 2
measure: VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab
timeFrame: End of Phase 1 & End of Phase 2
measure: VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab
timeFrame: End of Phase 1 & End of Phase 2
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: West Roxbury
country: United States
facility: Boston V.A. Healthcare System
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri Health System
state: Missouri
city: Saint Louis
country: United States
facility: V.A St. Louis Health Care System
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Metro Health System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson Medical College
state: Pennsylvania
city: Burlington
country: United States
facility: The University of Vermont - Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Duke Clinical Research Institute
name: Kevin Hernandez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Braunwald, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.