Beet the Cold: The Effect of Inorganic Nitrate Supplementation in Individuals With Raynaud's Phenomenon

February 4, 2020 updated by: Ant Shepherd, University of Portsmouth

Beet the Cold: The Effect of Inorganic Nitrate Supplementation on Peripheral Blood Flow and Pain in Individuals With Raynaud's Phenomenon. A Pilot, Double-blind, Placebo Controlled, Randomised Crossover Trial

Individuals with Raynaud's phenomenon often experience episodes of reduced blood flow to their fingers and toes during times of stress or cold exposure, causing significant discomfort and pain. Typically, treatment for these individuals involves using drugs like Glyceryl Trinitrate (GTN), which increases blood flow to the fingers and toes by increasing a substance called nitric oxide in the blood. Unfortunately, repeated use of these drugs increases tolerance to them, meaning higher doses are required to produce the same effect. However, increasing the dose can cause more side effects like headaches, and is therefore not considered an ideal long-term therapy.

Leafy green vegetables, especially beetroot, contain high amounts of nitrate and are beneficial to blood vessel health, since nitrate from the diet can also be turned into the important blood vessel relaxer, nitric oxide. Unlike GTN, people don't appear to develop a tolerance to dietary nitrate or experience negative side effects.

Therefore, this study aims to see if short and longer term beetroot juice supplementation can improve blood flow to the hands and feet in individuals with Raynaud's phenomenon, as well as reduce their pain. This study will tell us how many people are needed for a definitive trial investigating whether beetroot juice can help treat Raynaud's phenomenon.

Raynaud's phenomenon can cause significant discomfort and pain to individuals. Dietary nitrate appears to offer a simple, low cost means of improving blood flow to the hands and feet which should reduce both the discomfort and pain experienced characterising this condition. This study will advance our understanding of the causes of Raynaud's phenomenon, specifically the role that the nitrate-nitrite-nitric oxide pathway might play in changing Raynaud's phenomenon symptoms and identifying targets for intervention.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Raynaud's phenomenon (RP) is characterised by a recurrent transient vasospasm of the fingers or toes in response to a cold or stressful stimulus. Nitric oxide (NO•) is a known vasodilator and NO• donors, such as Glyceryl Trinitrate (GTN), improve blood flow in patients with RP and in cold sensitive individuals (Figure 1, see accompanying document). However, individuals develop a tolerance to GTN and show diminishing vasodilatory effects with chronic treatment. In addition, the deleterious side effects such as headaches means that organic nitrates (i.e. GTN and isosorbide mononitrate) are not optimal longterm therapies for RP. Alternative treatments therefore, warrant further investigation.

Diets rich in fruit and vegetables has been shown to be effective in reducing blood pressure. In addition, it lowers the risk of morbidity and mortality from cardiovascular disease and are thought to be beneficial to cardiovascular health due to their vasodilatory effects. As diet exhibits such tremendous intra- and inter-individual variation, elucidating which components of such a diet are responsible for this effect is difficult. There is a growing weight of evidence from both human and animal studies that nitrate and nitrite derived from the diet can serve as a source for nitric oxide (NO; please see below), particularly where it is deficient. Indeed, the greatest protective effect on cardiovascular disease is to be found in those diets with the greatest consumption of green leafy and or cruciferous vegetables which typically have high nitrate content.

NO is produced in the body in two ways. The first requires the availability the amino acid L-arginine, molecular oxygen, and families of enzymes, the nitric oxide synthases (NOS); that is the NOS pathway. The second pathway is independent of NOS pathway and involves the stepwise enzymatic and chemical reduction of inorganic nitrate to nitrite. A major source of nitrite in humans is the reduction of dietary nitrate by facultative anaerobic bacteria in the mouth. The remaining nitrite is then absorbed into the circulation where it acts as a storage pool for subsequent NO• production, which is expedited in hypoxaemia.

Localised hypoxemia such as that observed in the digital vasculature of individuals with RP is a potential therapeutic target for dietary nitrate supplementation. In contrast to organic nitrates (GTN), inorganic nitrate (in the form of beetroot juice) does not cause the same negative side effects or demonstrate tachyphylaxis whilst it does notable improve skin blood flow, microvascular function and lower blood pressure (BP) in healthy individuals and chronic conditions such as hypertension, peripheral arterial disease, heart failure and chronic obstructive pulmonary disease. Thus concentrated beetroot juice (CBJ) may offer an inexpensive, safe and potentially effective intervention to improve the pain and reduced peripheral blood flow characterising individuals with RP.

RP can cause significant discomfort and pain to individuals during a vasospasm. Dietary nitrate appears to offer a simple, low cost means of modifying blood flow to the peripheries and, ultimately, reducing both the discomfort and pain experienced by individuals with RP. This study will also advance our understanding of the aetiology and pathophysiology of RP, specifically the role that the nitrate-nitrite-nitric oxide pathway might play in modulating RP symptoms. An understanding of the effects of concentrated beetroot juice on microvascular blood flow and pain may lead to a range of simple, low cost and effective therapeutic interventions to prevent and treat episodes of RP.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
27

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

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
    • Hampshire
      • Portsmouth, Hampshire, United Kingdom, PO1 2ER
        • Department of Sport and Exercise Science

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male or Female, aged 18 years or above.
  • Diagnosed with Raynaud's Phenomenon.
  • Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

  • Patients with significant renal impairment (eGFR<30)
  • Uncontrolled hypertension,
  • Taking regular organic nitrates, nicorandil, or thiazolidinidiones,
  • or any medication which may interfere with data interpretation or safety,
  • who have had a myocardial infarction or cerebro-vascular event,
  • who smoke,
  • or any other serious medical condition which would interfere with data interpretation or safety will be excluded from participation.

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Beetroot juice then nitrate depleted beetroot juice
Participants will be asked to consume 140ml of beetroot juice prior to their first experimental visit. Participants will then be asked to consume 70ml a day for 2 weeks and final visit the investigators once more following another 140ml drink.
Dietary supplement: Concentrated beetroot juice
Acute and chronic supplementation of beetroot juice.
Experimental: Nitrate depleted beetroot juice then beetroot juice
Participants will be asked to consume 140ml of placebo prior to their first experimental visit. Participants will then be asked to consume 70ml a day for 2 weeks and final visit the investigators once more following another 140ml drink.
Dietary supplement: Concentrated beetroot juice
Acute and chronic supplementation of beetroot juice.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Peripheral Blood Flow
Time Frame: Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).
Peripheral blood flow (CVC = skin flux/MAP; flux.mmHg-1).
Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).
Skin Temperature.
Time Frame: Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).
Skin temperature (via thermal imaging).
Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Perceived Discomfort
Time Frame: Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).

Perceived discomfort.

Thermal discomfort were measured using a 20 cm scale (0 = very cold/uncomfortable; 10 = neutral; 20 = very hot/comfortable; modified from Zhang et al. (2004)) and recorded prior to immersion, during immersion and every 2 minutes of the rewarming period.
Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).
Acceptability to Participants
Time Frame: During qualitative interviews after the intervention has ended (post day 36).
Interview. Specifically, semi-structured interviews explored participants' experiences of the study procedures and consumption of beetroot juice. Interviews were conducted by a researcher with experience in qualitative research methods. Interviews were recorded, transcribed verbatim, and analysed through thematic analysis as outlined by Braun and Clarke (2006). Participants were asked about the testing procedures and their thoughts on the juice.
During qualitative interviews after the intervention has ended (post day 36).
Overall Number of Participants Recruited
Time Frame: From start of study recruitment until the last participant is randomised. Estimated assesment period 6 - 52 weeks
Number of participants who remained in the study
From start of study recruitment until the last participant is randomised. Estimated assesment period 6 - 52 weeks
Perceived Pain
Time Frame: Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).

Perceived pain.

Pain sensation was assessed using a numerical rating scale for pain (0 no pain, 10 unimaginable, unspeakable pain; (Ferreira-Valente et al., 2011)) at the same time points.
Baseline (day 1), Acute (2 or 23), Chronic (day 16 or 36).
Feasible to Participants
Time Frame: During qualitative interviews after the intervention has ended (post day 36).
Feasible to participants via interview. Specifically, semi-structured interviews explored participants' experiences of the study procedures and consumption of beetroot juice. Interviews were conducted by a researcher with experience in qualitative research methods. Interviews were recorded, transcribed verbatim, and analysed through thematic analysis as outlined by Braun and Clarke (2006).
During qualitative interviews after the intervention has ended (post day 36).
Establish Retention Rates
Time Frame: From date of randomization until the end of the last study visit. Estimated assesment period 6 - 52 weeks
Establish retention rates (Descriptive statistics)
From date of randomization until the end of the last study visit. Estimated assesment period 6 - 52 weeks

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Portsmouth

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Exeter
Loughborough University

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 30, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 25, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 26, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 10, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 4, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 001 (Buy Pharma Ecza Deposu San. Tic. Ltd.)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

There is no plan to release IPD, until all avenues of further funding have been exhausted.

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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