We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified October 2017 by Ant Shepherd, University of Portsmouth
Sponsor:
ClinicalTrials.gov Identifier:
NCT03129178
First Posted: April 26, 2017
Last Update Posted: October 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Loughborough University
University of Exeter
Information provided by (Responsible Party):
Ant Shepherd, University of Portsmouth
  Purpose

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.


Condition Intervention
Raynaud Phenomenon Dietary Supplement: Concentrated beetroot juice

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Double blind, randomised control trial. Supplements will be dispensed by nurses or a member of the research team.
Primary Purpose: Other
Official Title: 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

Further study details as provided by Ant Shepherd, University of Portsmouth:

Primary Outcome Measures:
  • Change in peripheral blood flow [ Time Frame: Baseline (day 1), visit 2 (day 2), 3 (day 16), 4 (day 23) and (day 36). ]
    Laser doppler

  • Change in skin temperature [ Time Frame: Baseline (day 1), visit 2 (day 2), 3 (day 16), 4 (day 23) and (day 36). ]
    Thermal imaging


Secondary Outcome Measures:
  • Change in perceived discomfort [ Time Frame: Baseline (day 1), visit 2 (day 2), 3 (day 16), 4 (day 23) and (day 36). ]
    Scale

  • Acceptability to participants [ Time Frame: During qualitative interviews after the intervention has ended (post day 36). ]
    Interview

  • Establish recruitment rates [ Time Frame: From start of study recruitment until the last participant is randomised. Estimated assesment period 6 - 52 weeks ]
    Descriptive statistics

  • Change in perceived pain [ Time Frame: Baseline (day 1), visit 2 (day 2), 3 (day 16), 4 (day 23) and (day 36). ]
    Scale

  • Feasible to participants [ Time Frame: During qualitative interviews after the intervention has ended (post day 36). ]
    Interview

  • Establish retention rates [ Time Frame: From date of randomization until the end of the last study visit. Estimated assesment period 6 - 52 weeks ]
    Descriptive statistics


Estimated Enrollment: 30
Actual Study Start Date: July 1, 2017
Estimated Study Completion Date: March 1, 2019
Estimated Primary Completion Date: August 1, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Concentrated 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.
Placebo Comparator: Nitrate depleted 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.

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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): NCT03129178


Contacts
Contact: Anthony I Shepherd, PhD 0239284 ext 5289 ant.shepherd@port.ac.uk
Contact: Clare Eglin, PhD 0239284 ext 5299 clare.eglin@port.ac.uk

Locations
United Kingdom
Department of Sport and Exercise Science Recruiting
Portsmouth, Hampshire, United Kingdom, PO1 2ER
Contact: Anthony I Shepherd, PhD    +44 (0)23 9284 5289    ant.shepherd@port.ac.uk   
Sponsors and Collaborators
University of Portsmouth
Loughborough University
University of Exeter
  More Information

Responsible Party: Ant Shepherd, Lecturer, University of Portsmouth
ClinicalTrials.gov Identifier: NCT03129178     History of Changes
Other Study ID Numbers: 001
First Submitted: March 30, 2017
First Posted: April 26, 2017
Last Update Posted: October 25, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to release IPD, until all avenues of further funding have been exhausted.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ant Shepherd, University of Portsmouth:
Nitrate
Nitric oxide
Microvascular

Additional relevant MeSH terms:
Raynaud Disease
Peripheral Vascular Diseases
Vascular Diseases
Cardiovascular Diseases