Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Heart Failure Clinical Trial

— INDIE-HFpEF  

Official title:

Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02742129
• Other study ID #: Pro00071526
• Secondary ID: 5U10HL084904
• Status: Completed
• Phase: Phase 2
• Start date: August 10, 2016
• Est. completion date: December 27, 2017

Study information

• Verified date: February 2019
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: December 27, 2017
• Est. primary completion date: December 13, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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

Related Conditions & MeSH terms

• 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.
• 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.

Locations

Country	Name	City	State
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	The University of Vermont - Fletcher Allen Health Care	Burlington	Vermont
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Metro Health System	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	University of Missouri Health System	Columbia	Missouri
United States	Duke University Medical Center	Durham	North Carolina
United States	Jefferson Medical College	Philadelphia	Pennsylvania
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	V.A St. Louis Health Care System	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Boston V.A. Healthcare System	West Roxbury	Massachusetts

Sponsors (7)

Lead Sponsor	Collaborator
Adrian Hernandez	Aires Pharmaceuticals, Inc., Massachusetts General Hospital, Mayo Clinic, National Heart, Lung, and Blood Institute (NHLBI), Université de Montréal, University of Vermont

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak VO2	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.	End of Phase 1 & End of Phase 2
Secondary	Average Arbitrary Accelerometer Units (AAU)	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.	End of Phase 1 & End of Phase 2
Secondary	Medial E/e' Ratio as Measured by Echocardiography Core Lab	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.	End of Phase 1 & End of Phase 2
Secondary	Left Atrial Volume Index as Measured by Echocardiography	To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.	End of Phase 1 & End of Phase 2
Secondary	Pulmonary Artery Systolic Pressure as Measured by Echocardiography	To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.	End of Phase 1 & End of Phase 2
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score	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.	End of Phase 1 & End of Phase 2
Secondary	N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)	Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo	End of Phase 1 & End of Phase 2
Secondary	NYHA (New York Heart Association) Class	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.	End of Phase 1 & End of Phase 2
Secondary	Patient Preference for AIR001 Treatment at the End of Study	Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)	End of Phase 2
Secondary	VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab	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.	End of Phase 1 & End of Phase 2
Secondary	VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab	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.	End of Phase 1 & End of Phase 2