Influence of Dietary Nitrate on Skin Inflammation

September 26, 2022 updated by: Queen Mary University of London

A Double-blind, Randomised, Placebo-controlled Parallel Study to Investigate the Influence of Dietary Nitrate on Skin Inflammation in Healthy Volunteers

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Nitric oxide (NO) is an important substance produced continuously by all blood vessels. It is thought to maintain health, in part, by preventing and suppressing inflammatory responses. NO is normally generated at the endothelium by a group of important enzymes called nitric oxide synthases. However, in chronic inflammatory states such as those seen in cardiovascular disease (CVD), the endothelial isoform of the enzyme becomes dysfunctional and produces less NO, and the NO that is produced is scavenged by the products of oxidative stress.

Giving NO back to the blood vessel to mediate its beneficial effects is not straightforward. However, the Ahluwalia Group have shown that dietary inorganic nitrate, both as a capsule and a dietary intervention with nitrate-rich beetroot juice, has a number of beneficial effects in CVD states. This beneficial effect is mediated through it's endogenous conversion from nitrate to nitrite in the mouth, and then from nitrite to NO via nitrite reductases within the blood vessel. The Investigators have shown benefit of inorganic nitrate in pre-clinical models of CVD, early mechanistic studies in healthy volunteers, and anti-inflammatory benefits in patients with hypertension, hypercholesterolaemia and those suffering acute heart attacks.

The Investigators wish to prospectively investigate the anti-inflammatory effects of inorganic nitrate using a cantharidin-induced blister model of acute inflammation. This allows investigation of the innate immune system's response to an acute insult and characterise the inflammatory and resolution phases. Cantharidin is commonly used as a vesicant in the treatment of plantar verrucae and molluscum contagiosum, and experimentally to study the pharmacokinetics of drugs within the interstitial space.

This will be a double-blind placebo-controlled parallel limb study supplementing 24 healthy volunteers with dietary-rich beetroot juice versus nitrate-deplete placebo juice, to investigate blister formation, and inflammatory cell recruitment and activation.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • London, United Kingdom, EC1M 6BQ
        • Queen Mary University of London

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 43 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Healthy volunteers
  • Caucasian
  • Willing to provide informed consent

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nitrate-rich Beetroot Juice
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
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.
Placebo Comparator: Nitrate-deplete Beetroot Juice
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
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.
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in plasma nitrate levels
Time Frame: 2 weeks
Comparison of change in plasma nitrite following dietary nitrate or placebo supplementation
2 weeks
Change in blister fluid leucocytes
Time Frame: 2 weeks
Comparison of change in blister fluid total and differential leucocyte numbers following dietary nitrate or placebo supplementation
2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in blister fluid cytokine composition
Time Frame: 2 weeks
Comparison of change in blister fluid cytokine analysis following dietary nitrate or placebo supplementation
2 weeks
Change in peripheral markers of inflammation
Time Frame: 2 weeks
Comparison of change in peripheral markers of inflammation and leucocyte count following dietary nitrate or placebo supplementation
2 weeks
Change in non-invasive blood pressure measurement
Time Frame: 2 weeks
Comparison of change in blood pressure following dietary nitrate or placebo supplementation
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Queen Mary University of London

Investigators

  • Principal Investigator: Prof Amrita Ahluwalia, BSc PhD, Queen Mary University of London

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 2, 2017

Primary Completion (Actual)

September 1, 2018

Study Completion (Actual)

November 1, 2020

Study Registration Dates

First Submitted

June 8, 2017

First Submitted That Met QC Criteria

June 8, 2017

First Posted (Actual)

June 12, 2017

Study Record Updates

Last Update Posted (Actual)

September 27, 2022

Last Update Submitted That Met QC Criteria

September 26, 2022

Last Verified

June 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16/LO/0160

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

N/A - no plan to make IPD available to others

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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