Influence of Dietary Nitrate on Skin Inflammation

NCT03183830 | Completed Phase 1 DMC

• 1 other identifier: 16/LO/0160
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study evaluates the potential anti-inflammatory effects of inorganic dietary nitrate in a model of acute inflammation relevant to cardiovascular disease (CVD). Green leafy vegetables contain large amounts of inorganic nitrate, and research suggests that this nitrate has beneficial effects on the heart and blood vessels. The Ahluwalia Group have shown anti-inflammatory benefits of inorganic nitrate in pre-clinical models of CVD, early mechanistic studies in healthy volunteers, and in patients with hypertension, hypercholesterolaemia and those suffering acute heart attacks that translate to cardiovascular benefits. Understanding the mechanism of how this is achieved may open new therapeutic options in CVD. The Investigators therefore wish to explore whether inorganic nitrate might alter inflammatory responses using a blister-model of acute skin inflammation. This study is a randomised control trial with parallel limbs where half of patients receive nitrate-rich beetroot juice, and the other half a nitrate-deplete placebo beetroot juice.

Conditions

Cardiovascular Diseases; Inflammation; Inflammation; Skin; Inflammatory Response; Nitric Oxide

Keywords

Cardiovascular Disease; Inorganic nitrate; Nitric Oxide; Inflammation

Outcome Measures

Primary Outcomes (2)

• Change in plasma nitrate levels

  Comparison of change in plasma nitrite following dietary nitrate or placebo supplementation

  2 weeks

• Change in blister fluid leucocytes

  Comparison of change in blister fluid total and differential leucocyte numbers following dietary nitrate or placebo supplementation

  2 weeks

Secondary Outcomes (3)

• Change in blister fluid cytokine composition

  2 weeks

• Change in peripheral markers of inflammation

  2 weeks

• Change in non-invasive blood pressure measurement

  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

See description of placebo juice in "Arms" for comparative information. 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 - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteers
• Caucasian
• Willing to provide informed consent

You may not qualify if:

• Healthy subjects unwilling to consent
• Non-caucasian volunteers
• History of any serious illnesses, including recent infections or trauma
• Subjects taking systemic medication (other than the oral contraceptive pill)
• Subjects with self-reported use of mouthwash or tongue scrapers
• Subjects with recent or current antibiotic use
• Subjects with a history, or recent treatment of (within last 3 months) any oral condition (excluding caries), including gingivitis, periodontitis and halitosis
• Subjects with a history of skin conditions
• Subjects with and history of allergic reaction to any topical application
• Subjects with any history of a bloodborne infectious disease such Hepatitis B or C virus, or HIV
• We have excluded non-caucasian volunteers due to a small incidence of prolonged skin hyperpigmentation in non-caucasians in previous studies.
• We have excluded subjects using mouthwash/tongue scrapers and oral conditions as we know that the nitrate ingested from the diet (i.e. beetroot juice) is converted to nitrite by the commensal bacteria in the back of the mouth. Subjects who have oral conditions or use mouthwash/tongue scrapers would have differences in oral bacterial populations, both in number and species. Therefore, by excluding these subjects, we will try and keep this variable as similar as possible in both groups.

Sponsors & Collaborators

• Queen Mary University of London: lead

Study Sites (1)

Queen Mary University of London

London, EC1M 6BQ, United Kingdom

Location

Related Publications (7)

• 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

• Rathod KS, Kapil V, Velmurugan S, Khambata RS, Siddique U, Khan S, Van Eijl S, Gee LC, Bansal J, Pitrola K, Shaw C, D'Acquisto F, Colas RA, Marelli-Berg F, Dalli J, Ahluwalia A. Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans. J Clin Invest. 2017 Jan 3;127(1):169-182. doi: 10.1172/JCI89429. Epub 2016 Nov 28.

  PMID: 27893465 BACKGROUND

• 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

• Day RM, Harbord M, Forbes A, Segal AW. Cantharidin blisters: a technique for investigating leukocyte trafficking and cytokine production at sites of inflammation in humans. J Immunol Methods. 2001 Nov 1;257(1-2):213-20. doi: 10.1016/s0022-1759(01)00467-7.

  PMID: 11687254 BACKGROUND

• Lau C, Primus CP, Shabbir A, Chhetri I, Ono M, Masucci M, Bin Noorany Aubdool MA, Amarin J, Hamers AJ, Khan Z, Kumar NA, Montalvo Moreira SA, Nuredini G, Osman M, Whitear C, Godec T, Kapil V, Massimo G, Khambata RS, Rathod KS, Ahluwalia A. Accelerating inflammatory resolution in humans to improve endothelial function and vascular health: Targeting the non-canonical pathway for NO. Redox Biol. 2025 May;82:103592. doi: 10.1016/j.redox.2025.103592. Epub 2025 Mar 28.

  PMID: 40209616 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Inflammation; Dermatitis

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Prof Amrita Ahluwalia, BSc PhD

  Queen Mary University of London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All members of the study team and volunteer participants will be blinded to treatment versus placebo arm
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Double-blind randomised-control parallel two-limb study

Study Record Dates

• First Submitted: June 8, 2017
• First Posted: June 12, 2017
• Study Start: February 2, 2017
• Primary Completion: September 1, 2018
• Study Completion: November 1, 2020
• Last Updated: September 27, 2022

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)