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Influence of Dietary Nitrate on Skin Inflammation

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ClinicalTrials.gov Identifier: NCT03183830
Recruitment Status : Unknown
Verified June 2018 by Queen Mary University of London.
Recruitment status was:  Recruiting
First Posted : June 12, 2017
Last Update Posted : June 18, 2018
Sponsor:
Information provided by (Responsible Party):
Queen Mary University of London

Study Description
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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.


Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Inflammation Inflammation; Skin Inflammatory Response Nitric Oxide Dietary Supplement: Nitrate-rich Beetroot Juice Dietary Supplement: Nitrate-deplete Beetroot Juice Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind randomised-control parallel two-limb study
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: All members of the study team and volunteer participants will be blinded to treatment versus placebo arm
Primary Purpose: Basic Science
Official Title: A Double-blind, Randomised, Placebo-controlled Parallel Study to Investigate the Influence of Dietary Nitrate on Skin Inflammation in Healthy Volunteers
Actual Study Start Date : February 2, 2017
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: Placebo


Outcome Measures
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Primary Outcome Measures :
  1. Change in plasma nitrate levels [ Time Frame: 2 weeks ]
    Comparison of change in plasma nitrite following dietary nitrate or placebo supplementation

  2. 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


Secondary Outcome Measures :
  1. 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. 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

  3. Change in non-invasive blood pressure measurement [ Time Frame: 2 weeks ]
    Comparison of change in blood pressure following dietary nitrate or placebo supplementation


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03183830


Contacts
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Contact: Prof Amrita Ahluwalia, BSc PhD 020 7882 8377 a.ahluwalia@qmul.ac.uk
Contact: Dr Christopher P Primus, MBBS BSc MRCP 020 7882 5720 c.primus@qmul.ac.uk

Locations
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United Kingdom
Queen Mary University of London Recruiting
London, United Kingdom, EC1M 6BQ
Contact: Prof Amrita Ahluwalia, BSc PhD    020 7882 8377    a.ahluwalia@qmul.ac.uk   
Contact: Dr Christopher P Primus, MBBS BSc MRCP    020 7882 5720    c.primus@qmul.ac.uk   
Principal Investigator: Prof Amrita Ahluwalia, BSc PhD         
Sub-Investigator: Dr Christopher P Primus, MBBS BSc MRCP         
Sub-Investigator: Dr Krishnaraj Rathod, MBBS BMedSci MRCP         
Sub-Investigator: Ms Sarah Duggan, MSc         
Sub-Investigator: Dr Clement Lau, MBChB BMedSci MRCP         
Sub-Investigator: Dr Vikas Kapil, MBBS PhD MRCP         
Sponsors and Collaborators
Queen Mary University of London
Investigators
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Principal Investigator: Prof Amrita Ahluwalia, BSc PhD Queen Mary University of London
More Information
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Publications:

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Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT03183830    
Other Study ID Numbers: 16/LO/0160
First Posted: June 12, 2017    Key Record Dates
Last Update Posted: June 18, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: N/A - no plan to make IPD available to others

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Queen Mary University of London:
Cardiovascular Disease
Inorganic nitrate
Nitric Oxide
Inflammation
Additional relevant MeSH terms:
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Cardiovascular Diseases
Dermatitis
Inflammation
Pathologic Processes
Skin Diseases