TABLE 5

Currently recruiting trials investigating the role of nitrate and nitrite in Heart Failure

Identifier	Trial Name	Lead Investigators	Design	No. of Patients	Key Inclusion Criteria	Agent and Dose	Delivery	Treatment Duration	Primary/Powered Outcomes	Key Additional Measures
NCT02713126	Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure with Preserved Ejection Fraction (HFpEF) (INABLE-Training)	Barry Borlaug MD	Phase II Randomized Double blind Placebo-controlled	100	HFpEF (LVEF >50%) NYHA II–IV, age >40 Enrolled in cardiac rehabilitation (exercise training)	Sodium nitrite, 40 mg TDS	Oral Capsules	12 wk	• Peak VO2 on CPEX	• Change in daily activity levels (accelerometer)
										• Change in cardiac hemodynamics by Echo
										• QoL assessment
ACTRN12615000906550	Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Heart Failure	Prof. Jason D. Allen	Phase I/II Randomized Placebo-controlled Crossover (minimum 2-wk washout)	15 HFpEF + 15 HFrEF	HFpEF and HFrEF, age 18–85	Sodium nitrate, ∼16 mmol OD	Beetroot juice	7 days	• Peak VO2 on CPEX	• Change in tissue oxygenation
									• Time to exhaustion on CPEX	• Plasma NOx levels
									• Plasma nitrite levels	• Change in mitochondrial function (muscle biopsy)
										• Brachial artery flow-mediated dilatation
										• Vascular stiffness (PWA and PWV)
										• Hemodynamic parameters on Echo
NCT02918552	Oral Nitrite for Older Heart Failure with Preserved Ejection Fraction (ONOH)	Mark Gladwin MD	Phase II Randomized Double blind Placebo-controlled	16	HFpEF (LVEF >40%), age >70	Sodium nitrite, 20–40 mg TDS	Oral capsules	8 wk active treatment	• Peak VO2 on CPEX	• Perceived fatiguability during exercise
										• Change in daily activity levels (accelerometer)
										• Measures of pulmonary hemodynamics (by right heart catheter)
										• Skeletal muscle bioenergetics
										• Plasma nitrate
										• BNP
HFrEF
NCT01682356	Dietary Nitrates for Heart Failure	Linda Peterson MD + Andrew Coggan MD	Phase II Randomized Double blind Placebo-controlled Crossover (7-day washout)	126	HFrEF in transplant workup (NYHA III/IV) or pulmonary hypertension, age >18	Dietary nitrate, 5 to 6 mmol OD	Beetroot juice	4 wk	• Peak power with neuromuscular power test	• Peak VO2 on CPEX
									• Change in cardiac mass after LVAD	• Pulmonary artery pressure by right heart catheter (if clinically indicated)
										• Cardiac function by Echo or cardiac MRI (if clinically indicated)
										• Submaximal exercise tolerance (6MWT)
NCT03511248	Investigation of Dietary Nitrate Optimisation by Hyperuricaemia Stratification in Heart Failure (DiNOmo-HF)	Dr. C.P. and A.A.	Phase II Randomized Double blind Placebo-controlled	92	HFrEF (LVEF <40%) NYHA II/III, age >18 Elevated BNP/NT-proBNP Stable medical therapy for 3 months	Dietary nitrate, 5 to 6 mmol OD	Beetroot juice	12 wk	• Change in uric acid levels between strata (< and ≥ 9.8 mg/dl)	• Sub-maximal exercise capacity (6MWT)
									• LVEF	• QoL questionnaire
									• NOx levels	• NT-proBNP and BNP
										• Measures of oxidative stress
										• Erythrocyte XOR activity
ACTRN12616000951459	Feasibility and Effects of Inorganic Nitrate in Acute Decompensated Heart Failure (FINO-ADHF)	Prof. Christopher Neil	Phase I/II Randomized Double blind Placebo-controlled	40	Acute decompensated HF, age >18	Sodium nitrate, 8.4 mmol over four 12-h intervals	Beetroot juice + capsules	48 h	• Plasma NOx levels	• Vascular stiffness (PWA and PWV)
									• A change in vasorelaxation as assessed by systemic vascular resistance index	• Change in renal function by cystatin C levels
										• Change in oxygenation using pulse oximetry
										• Dyspnea relief
										• Cardiac troponin T
										• Change in natriuresis measured by urinary sodium
										• Changes in cardiac function by Echo
NCT02797184	Inorganic Nitrate and Exercise Performance in Heart Failure (iNIX-HF): Dose Response	Linda Peterson MD + Andrew Coggan MD	Phase II Double blind Dose crossover (7-day washout)	25	HFrEF (LVEF <45%) NYHA II–IV, age 18–74 Stable medical therapy for 30 days	Potassium nitrate, 10 and 20 mmol once	Oral capsules	7 days between acute dosing	• Peak VO2 on CPEX (acute: 2.5 h postdose)	• Peak muscle power (quadriceps)
										• Plasma NOx levels
										• Breath NO level
ACTRN12613000689774 (withdrawn)	Randomized double blind controlled pilot trial investigating the effect dietary nitrate in the treatment of acute decompensated heart failure	Prof. David Kaye	Phase II Randomized Double blind Placebo-controlled	20	Acute decompensated HF (LVEF <40%) NYHA III/IV, age 18–75	Dietary nitrate, 5 to 6 mmol	Beetroot juice	5 days	• Change in endothelial function by EndoPAT
									• QoL questionnaire
									• Treatment success: a composite of patient-reported improvement in dyspnea with no criteria for failure
NCT03658174	Upregulating the Nitric Oxide Pathway to Restore Autonomic Phenotype (UNTRAP)	Dr. Zakiryya Vali and Dr. Andre Ng	Double blind Placebo-controlled Crossover (unspecified washout)	20	HFrEF (LVEF <40%) NYHA II/III, age >18 Sinus rhythm with ICD in situ	Dietary nitrate, 5 to 6 mmol	Beetroot juice	4 wk with each intervention (unspecified washout)	Change in:	• Systolic and diastolic function by Echo
									• heart rate variability	• Peak VO2 on CPEX
									• QT variability index	• QoL questionnaire
									• Regional Restitution Instability Index (marker of ventricular arrhythmia and SCD)
									• Peak ECG Restitution Slope (marker of ventricular arrhythmia and SCD)

CPEX, cardiopulmonary exercise test; Echo, echocardiography; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; 6MWT, 6-minute walk test; OD, once daily; PWA, pulse wave analysis; QoL, quality of life; SCD, sudden cardiac death; TDS, three times daily; VO2, maximal oxygen consumption.