NCT02742129: INDIE-HFpEF

Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Completed Phase 2 Results posted Last updated 13 March 2019

What this trial tests

Phase 2 trial testing Nebulized Sodium Nitrite in Heart Failure in 105 participants. Completed in 27 December 2017.

Timeline

10 August 2016

Primary endpoint
13 December 2017

27 December 2017

Quick facts

Lead sponsor	Adrian Hernandez
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	triple
Primary purpose	treatment
Enrollment	105
Start date	10 August 2016
Primary completion	13 December 2017
Estimated completion	27 December 2017
Sites	20 locations across United States

Drugs / interventions tested

• Nebulized Sodium Nitrite — full drug profile →
• Placebo

Conditions studied

• Heart Failure — all drugs for Heart Failure →

Sponsor

Adrian Hernandez — full company profile →

Who can join

40 and older, any sex, with Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Peak VO2 Primary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	13.4	± 3.2
Placebo Crossover to AIR001	13.8	± 3.8

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	13.7	± 3.0
Placebo Crossover to AIR001	13.6	± 3.6

Average Arbitrary Accelerometer Units (AAU) Secondary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	5692	± 2886
Placebo Crossover to AIR001	5341	± 3115

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	5688	± 2950
Placebo Crossover to AIR001	5289	± 2976

Medial E/e' Ratio as Measured by Echocardiography Core Lab Secondary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	15.4	± 8.3
Placebo Crossover to AIR001	18.3	± 11.8

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	15.0	± 7.3
Placebo Crossover to AIR001	17.4	± 11.1

Left Atrial Volume Index as Measured by Echocardiography Secondary · End of Phase 1 & End of Phase 2

To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	36.3	± 16.5
Placebo Crossover to AIR001	40.1	± 20.6

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	37.2	± 13.9
Placebo Crossover to AIR001	39.1	± 20.4

Pulmonary Artery Systolic Pressure as Measured by Echocardiography Secondary · End of Phase 1 & End of Phase 2

To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	38.2	± 9.7
Placebo Crossover to AIR001	39.6	± 13.5

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	35.0	± 7.3
Placebo Crossover to AIR001	37.3	± 9.2

Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score Secondary · 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 he

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	65.6	± 18.8
Placebo Crossover to AIR001	59.8	± 18.4

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	64.1	± 18.4
Placebo Crossover to AIR001	59.4	± 21.1

N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) Secondary · End of Phase 1 & End of Phase 2

Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	494.8	± 542.3
Placebo Crossover to AIR001	550.4	± 746.5

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	513.9	± 606.0
Placebo Crossover to AIR001	545.2	± 784.5

NYHA (New York Heart Association) Class Secondary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	1
Placebo Crossover to AIR001	0
AIR001 Crossover to Placebo	21
Placebo Crossover to AIR001	29
AIR001 Crossover to Placebo	26
Placebo Crossover to AIR001	20
AIR001 Crossover to Placebo	1
Placebo Crossover to AIR001	0

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	0
Placebo Crossover to AIR001	1
AIR001 Crossover to Placebo	24
Placebo Crossover to AIR001	22
AIR001 Crossover to Placebo	24
Placebo Crossover to AIR001	25
AIR001 Crossover to Placebo	1
Placebo Crossover to AIR001	0

Patient Preference for AIR001 Treatment at the End of Study Secondary · End of Phase 2

Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)

Phase 1 Patient Felt Better

Group	Value	95% CI
AIR001 Crossover to Placebo	23
Placebo Crossover to AIR001	15

Phase 2 Patient Felt Better

Group	Value	95% CI
AIR001 Crossover to Placebo	17
Placebo Crossover to AIR001	20

No Preference

Group	Value	95% CI
AIR001 Crossover to Placebo	8
Placebo Crossover to AIR001	12

VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab Secondary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	31.8	± 5.7
Placebo Crossover to AIR001	33.9	± 6.9

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	32.1	± 6.0
Placebo Crossover to AIR001	33.6	± 7.3

VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab Secondary · 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.

Phase 1

Group	Value	95% CI
AIR001 Crossover to Placebo	7.8	± 1.6
Placebo Crossover to AIR001	8.0	± 1.9

Phase 2

Group	Value	95% CI
AIR001 Crossover to Placebo	7.9	± 1.6
Placebo Crossover to AIR001	7.8	± 1.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Consent to 2 weeks post end of Phase 2. Reporting threshold: 4%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

AIR001

Serious: 5/103 (5%)

Deaths: 1/103

Placebo

Serious: 4/102 (4%)

Deaths: 0/102

Serious adverse events (11 terms)

Reaction	System	AIR001	Placebo
Pneumonia	Infections and infestations	—	—
Crohn's Disease	Gastrointestinal disorders	—	—
Chest Pain	General disorders	—	—
Sudden Death	General disorders	—	—
Foreign body in gastrointestinal tract	Injury, poisoning and procedural complications	—	—
Diabetic ketoacidosis	Metabolism and nutrition disorders	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Sepsis	Infections and infestations	—	—
Staphylococcal bacteraemia	Infections and infestations	—	—
Fall	Injury, poisoning and procedural complications	—	—
Syncope	Nervous system disorders	—	—

Other adverse events (10 terms — click to expand)

Reaction	System	AIR001	Placebo
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Dizziness	Nervous system disorders	—	—
dsypnoea	Respiratory, thoracic and mediastinal disorders	—	—
Throat irritation	Respiratory, thoracic and mediastinal disorders	—	—
Headache	Nervous system disorders	—	—
Productive Cough	Respiratory, thoracic and mediastinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Chest discomfort	General disorders	—	—

Most-reported serious reactions: Pneumonia, Crohn's Disease, Chest Pain, Sudden Death, Foreign body in gastrointestinal tract, Diabetic ketoacidosis, Hypoglycaemia, Sepsis.

Data from ClinicalTrials.gov NCT02742129 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Pulmonary hypertension due to left heart disease.
   Vachiéry JL, Tedford RJ, Rosenkranz S, Palazzini M, et al · · 2019 · cited 361× · PMID 30545974 · DOI 10.1183/13993003.01897-2018
2. Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction.
   Kumar AA, Kelly DP, Chirinos JA. · · 2019 · cited 228× · PMID 30856000 · DOI 10.1161/circulationaha.118.036259
3. Arterial Stiffening With Exercise in Patients With Heart Failure and Preserved Ejection Fraction.
   Reddy YNV, Andersen MJ, Obokata M, Koepp KE, et al · · 2017 · cited 214× · PMID 28683960 · DOI 10.1016/j.jacc.2017.05.029
4. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial.
   Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, et al · · 2018 · cited 197× · PMID 30398602 · DOI 10.1001/jama.2018.14852
5. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity.
   Reddy YNV, Rikhi A, Obokata M, Shah SJ, et al · · 2020 · cited 180× · PMID 32150314 · DOI 10.1002/ejhf.1788
6. Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.
   Borlaug BA, Melenovsky V, Koepp KE. · · 2016 · cited 122× · PMID 27458234 · DOI 10.1161/circresaha.116.309184
7. Pulsatile arterial haemodynamics in heart failure.
   Weber T, Chirinos JA. · · 2018 · cited 114× · PMID 29947746 · DOI 10.1093/eurheartj/ehy346
8. Interleukin-6 in Patients With Heart Failure and Preserved Ejection Fraction.
   Alogna A, Koepp KE, Sabbah M, Espindola Netto JM, et al · · 2023 · cited 84× · PMID 37565977 · DOI 10.1016/j.jchf.2023.06.031