Effect of Dietary Nitrate Ingestion in Heart Failure

NCT03511248 | Terminated Phase 2 DMC

• 1 other identifier: 17/LO/1624
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This study evaluates the addition of inorganic dietary nitrate to the optimal treatment of patients diagnosed with heart failure with reduced ejection fraction. Some vegetables contain large amounts of inorganic nitrate, and research suggests that this nitrate has beneficial effects on the heart and blood vessels. We have shown in lab experiments that nitrate has positive effects on the heart. We wish to test whether dietary nitrate might be useful in halting deterioration and/or improving heart function in patients with heart failure, with a specific focus on a marker of poor outcome in heart failure: high uric acid levels. Half of the patients will receive nitrate-rich beetroot juice, and the other half a nitrate-deplete placebo beetroot juice.

Conditions

Heart Failure; Heart Failure, Systolic

Keywords

Heart Failure; Heart Failure with Reduced Ejection Fraction; Nitric Oxide; Inorganic Nitrate

Outcome Measures

Primary Outcomes (1)

• Change in serum uric acid levels

  Uric acid is a prognostic marker in patients with heart failure. The intervention proposed acts on the enzyme, xanthine oxidoreductase (XOR), that produces uric acid. We will therefore measure the change in serum uric acid level from baseline to assess whether dietary nitrate treatment decreases hyperuricaemia. We will stratify uric acid levels and undertake analysis between strata.

  12 +/- 2 weeks

Secondary Outcomes (4)

• Changes in plasma nitrate

  12 +/- 2 weeks

• Changes in plasma nitrite

  12 +/- 2 weeks

• Changes in cGMP as a marker for Nitric Oxide

  12 +/- 2 weeks

• Changes in cardiac pump function

  12 +/- 2 weeks

Other Outcomes (18)

• Changes in markers of oxidative stress: MDA

  12 +/- 2 weeks

• Changes in markers of oxidative stress: oxidised LDL

  12 +/- 2 weeks

• Changes in markers of oxidative stress: TBAR

  12 +/- 2 weeks

Study Arms (2)

Nitrate-rich Beetroot Juice

EXPERIMENTAL

Individuals will receive a once daily dose of dietary nitrate in the form of a beetroot juice concentrate (70mL) containing \~5-6mmol inorganic nitrate (James White Drinks, UK) for 12 +/- 2 weeks. This dose has been chosen due to several reports demonstrating efficacy in patients with cardiovascular disease.

Dietary Supplement: Nitrate-rich Beetroot Juice

Nitrate-deplete Beetroot Juice

PLACEBO COMPARATOR

The placebo control is an identical juice from which the nitrate anion has been removed using a standard anion exchange resin. Visually there is no detectable difference between the juices and previous spectral, ion concentration, sugar levels, ascorbate analysis and taste testing has confirmed no differences in colour and constituents. The process to extract nitrate from the juice is the same technique used to remove inorganic nitrate from general drinking water supplies, and has been approved for use by Ethics Committees. The nitrate-free juice is not considered a drug or medicine, and is classified as a foodstuff.

Dietary Supplement: Nitrate-deplete Beetroot Juice

Interventions

Nitrate-rich Beetroot Juice DIETARY_SUPPLEMENT

The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.

Nitrate-rich Beetroot Juice

Nitrate-deplete Beetroot Juice DIETARY_SUPPLEMENT

The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.

Also known as: Placebo

Nitrate-deplete Beetroot Juice

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years
• Diagnosed with heart failure with reduced ejection fraction on the basis of:
• LVEF ≤50% as assessed by Echocardiography (or cardiac MRI)
• raised BNP and/or NT-proBNP levels placing patients in the "high risk" category, to ensure heart failure is the cause of symptoms:
• stable heart failure: NT-proBNP \>600pg/mL and BNP \>150pg/mL
• hospitalisation within 12 months: NT-proBNP \>400pg/mL and BNP \>100pg/mL
• NYHA Class II-III symptoms
• On optimally-tolerated, stable (\>12 weeks) prognostic medical therapy (beta-blocker, ACE-inhibitor or ARB, mineralocorticoid therapy if deemed necessary)
• No heart failure-related hospitalisation for \>12 weeks
• Clinic systolic blood pressure ≥95mmHg
• Able and willing to give written informed consent

You may not qualify if:

• Use of anti-bacterial mouthwash or tongue scrapes (current or unwillingness to cease such mouthcare for at least one month prior to entering the study, and for the duration of the trial) as this interrupts the enterosalivary circuit and thus prevents the bioactivity of nitrate
• History of recurrent symptomatic gout or current treatment with xanthine oxidase inhibitors for hyperuricaemia
• Concomitant use of long acting organic nitrates or phosphodiesterase inhibitors (not including on an as required basis)
• Angina at CCS Class III/IV, requiring regular use of sublingual GTN (considered \>twice/week), or awaiting revascularisation
• If LVEF in the range 40-50%, impaires systolic function secondary to uncorrected valve disease, primary pulmonary hypertension, active myocarditis, constrictive pericarditis, restrictive cardiomyopathy or hypertrophic cardiomyopathy
• Renal failure with eGFR\<30 at screening
• History of symptomatic renal stone disease
• Current life-threatening condition that might prevent a patient-subject completing the study
• Allergy to SonoVue Echo contrast
• Pregnancy, breast feeding or planned pregnancy
• Anaemia, defined as Haemaglobin \<80g/L
• Subjects with any acute infection, or recent systemic antibiotics (oral or intravenous) within 3 months of screening, or significant trauma (burns, fractures)
• The subject has a three-month prior history of regular alcohol consumption exceeding an average weekly intake of \> 28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of \> 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine
• Mobility thought to be restricted significantly by other illnesses apart from heart failure
• Any other subject whom the Investigator deems unsuitable for the study (e.g. due to other medical reasons, laboratory abnormalities, expected study medication noncompliance, or subject's unwillingness to comply with all study-related study procedures)

Sponsors & Collaborators

• Queen Mary University of London: lead

Study Sites (1)

Queen Mary University of London

London, United Kingdom

Location

Related Publications (5)

• Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015 Feb;65(2):320-7. doi: 10.1161/HYPERTENSIONAHA.114.04675. Epub 2014 Nov 24.

  PMID: 25421976 BACKGROUND

• Velmurugan S, Gan JM, Rathod KS, Khambata RS, Ghosh SM, Hartley A, Van Eijl S, Sagi-Kiss V, Chowdhury TA, Curtis M, Kuhnle GG, Wade WG, Ahluwalia A. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2016 Jan;103(1):25-38. doi: 10.3945/ajcn.115.116244. Epub 2015 Nov 25.

  PMID: 26607938 BACKGROUND

• Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015 Jan 30;116(3):437-47. doi: 10.1161/CIRCRESAHA.116.305082. Epub 2014 Dec 15.

  PMID: 25512434 BACKGROUND

• Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tang WH, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Margulies KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Shah MR, Hernandez AF; NHLBI Heart Failure Clinical Research Network. Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation. 2015 May 19;131(20):1763-71. doi: 10.1161/CIRCULATIONAHA.114.014536. Epub 2015 Apr 14.

  PMID: 25986447 BACKGROUND

• Khambata RS, Ghosh SM, Rathod KS, Thevathasan T, Filomena F, Xiao Q, Ahluwalia A. Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E550-E559. doi: 10.1073/pnas.1613063114. Epub 2017 Jan 5.

  PMID: 28057862 BACKGROUND

MeSH Terms

Conditions

Heart Failure; Heart Failure, Systolic

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Dr Simon Woldman, MD FRCP FESC

  Fellow of the Royal College of Physicians and Fellow of the European Society of Cardiology

  PRINCIPAL INVESTIGATOR

• Dr Ceri Davies, MD FRCP FESC

  Fellow of the Royal College of Physicians and Fellow of the European Society of Cardiology

  PRINCIPAL INVESTIGATOR

• Prof Amrita Ahluwalia, BSc PhD

  William Harvey Research Institute, Queen Mary University of London

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind study, with randomisation undertaken by Barts Cardiovascular Clinical Trials Unit
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised double-blind placebo-controlled parallel two-limb study

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: April 27, 2018
• Study Start: June 1, 2018
• Primary Completion: January 7, 2025
• Study Completion: January 7, 2025
• Last Updated: August 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)