Clinical trial NCT04889274: Investigation of the Effects of Dietary Nitrate and Sex on COVID-19 Vaccine Induced Vascular Dysfunction in Healthy Men and Women (DiNOVasc-COVID-19)
Official title: A Double-blind, Randomised, Placebo-controlled Parallel Study to Investigate the Effect of Dietary Nitrate and Sex on COVID-19 Vaccine Induced Vascular Dysfunction in Healthy Men and Women
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Cardiovascular Diseases
Endothelial Dysfunction
Keywords: COVID-19, endothelial dysfunction, nitrate, nitrite, sex
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
First posted: 2021-05-17
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Inorganic nitrate can protect blood vessels from the damage that occurs during cardiovascular disease. Early experimental work suggests that nitrate-induced improvements in vascular function relate to the suppression of inflammatory pathways. Whether this protection against inflammation-induced damage to the blood vessel wall might also be functional in the setting of COVID-19 vaccination will be investigated.

Vascular function will be assessed before and after the healthy participant has received their COVID-19-vaccination. Whether there might be differences in the response to the vaccine between the sexes and whether a dietary nitrate intervention impacts upon the effects of vaccination will be investigated.

The study is in two parts:

Part A: To assess sex differences in the vascular response to COVID-19 vaccination.

Part B: To assess whether inorganic nitrate, in the form of dietary inorganic nitrate supplementation compared to placebo control, can raise circulating plasma nitrite levels and thereby prevent the systemic inflammation that causes vascular dysfunction.

Detailed description: Whether the COVID-19 vaccine can be used to study endothelial dysfunction and whether inorganic nitrate might be useful in restoring the function of the endothelium in a scenario simulating the COVID-19 infection setting will be investigated.

Furthermore, sex differences in the vascular response to the COVID-19 vaccination will be investigated.

Design: A prospective randomised, double-blind, placebo-controlled trial.

Target population: A total of 98 healthy participants will be recruited. Part A: 30 participants (15 male, 15 female.) Part B: 68 participants (34 intervention, 34 placebo). Participants will be recruited prior to receiving the COVID-19 vaccination, via Barts Health NHS Trust approved vaccination hubs.

Setting: Equal numbers of healthy male and female volunteers, aged between 18 and 60 years of age, will be recruited. Following recruitment, participants will undergo baseline measurements of vascular function of flow mediated dilatation (FMD) and pulse wave analysis/velocity (PWA, PWV), in addition to haematological and clinical biochemical analyses. Volunteers will then be randomised into one of the 2 study Parts (Part A: sex differences in vascular response to COVID-19 vaccine, Part B: influence of dietary nitrate upon vascular responses to COVID-19 vaccine). If randomised to Part B, volunteers will be treated with 3 days of either 4-5mmol nitrate-containing beetroot juice or placebo. If randomised to Part A, the volunteers will not receive an intervention. On day 3, all participants will receive their COVID-19 vaccine. At 8±2hours after the vaccine, the participants will undergo repeat measurements of vascular function. A quality of life questionnaire will be obtained 28 days after the vaccine has been administered.

Intervention: All volunteers will receive COVID-19 vaccination in Part A and Part B. In Part B of the study, volunteers will be randomised in a 1:1 fashion to receive either nitrate-containing beetroot juice (4-5mmol nitrate) or nitrate-deplete placebo.

The study will take place in the Clinical Research Centre at The William Harvey Research Institute.

Analysis: For the analysis of Part A linear regression will be used to compare change in vascular dysfunction from pre- to post-vaccination between the sexes, unadjusted and adjusted for important risk factors including age, BMI and baseline vessel diameter. For Part B analysis of covariance (ANCOVA) will be used to compare change in vascular dysfunction from pre- to post-vaccination between dietary nitrate and placebo control groups adjusting for pre-vaccination level, and to compare change in plasma nitrite between dietary nitrate and placebo control groups adjusting for baseline nitrite level.

Eligibility criteria: Inclusion Criteria:

1. Healthy volunteers with a booking for COVID-19 vaccination slot as per government guidelines
2. Aged 18-60
3. Volunteers who are willing to sign the consent form

Exclusion Criteria:

1. Aged \<18 or \>60 years
2. Healthy subjects unwilling to consent
3. Pregnant, or any possibility that a subject may be pregnant
4. History of any serious illnesses, including recent infections or trauma
5. Subjects taking systemic medication (other than the oral contraceptive pill)
6. Subjects with self-reported use of mouthwash or tongue scrapes
7. Subjects with recent (2 weeks) or current antibiotic use
8. Subjects with a history, or recent treatment of (within last 3 months) any oral condition (excluding caries), including gingivitis, periodontitis and halitosis
9. Subjects with a history of COVID-19 vaccination
10. Subjects with any history of a blood-borne infectious

Primary outcomes:
measure: Comparison of change in FMD from baseline between the sexes after COVID-19 vaccination
timeFrame: Up to 28 days
measure: Comparison of change in FMD from baseline after COVID-19 vaccination following inorganic nitrate versus placebo supplementation
timeFrame: Up to 28 days
measure: Comparison of change in plasma [NO2-] following inorganic nitrate versus placebo supplementation
timeFrame: Up to 28 days
Secondary outcomes:
measure: Comparison between the sexes in the systemic inflammatory response to COVID-19 vaccination
timeFrame: Up to 28 days
measure: Comparison between nitrate and placebo with respect to inflammatory cell activation state
timeFrame: Up to 28 days
measure: Comparison between nitrate and placebo with respect to circulating inflammatory mediators
timeFrame: Up to 28 days
measure: Comparison between nitrate and placebo with respect to platelet function during systemic inflammation
timeFrame: Up to 28 days
measure: Comparison between nitrate and placebo with respect to endothelium independent vasodilation of the brachial artery
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: The William Harvey Research Institute
Study officials:
References:
citation: 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.
citation: Kapil V, Khambata RS, Jones DA, Rathod K, Primus C, Massimo G, Fukuto JM, Ahluwalia A. The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway. Pharmacol Rev. 2020 Jul;72(3):692-766. doi: 10.1124/pr.120.019240.
citation: Shabbir A, Rathod KS, Khambata RS, Ahluwalia A. Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease. Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:333-359. doi: 10.1146/annurev-pharmtox-010919-023229. Epub 2020 Oct 9.