Cocoa Flavanol Supplementation in Raynaud's Phenomenon

• ClinicalTrials.gov Identifier: NCT03815162
• Recruitment Status: Completed
• First Posted: January 24, 2019
• Last Update Posted: November 4, 2021
• Sponsor: University of Nottingham
• Information provided by (Responsible Party): Elizabeth Simpson, University of Nottingham

Tracking Information

• First Submitted Date: January 18, 2019
• First Posted Date: January 24, 2019
• Last Update Posted Date: November 4, 2021
• Actual Study Start Date: October 16, 2018
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 21, 2019)

Vasospasm [ Time Frame: 3 months ]

frequency of vasospasm

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 21, 2019)

• Severity of vasospasm symptoms [ Time Frame: 3 months ]
  visual analogue score for pain associated with each vasospasm occasion. Participants indicate pain intensity by placing a vertical line on a 100mm horizontal line where the start of the line (left-hand side; 0mm) represents 'no pain' and the end of the line (right-hand side; 100mm) represents 'most severe pain'. Distance of the vertical line from 0 provides the visual analogue score. A lower score indicates a more favourable outcome.
• Duration of vasospasm symptoms [ Time Frame: 3 months ]
  duration that symptoms persist for on each vasospasm occasion
• Raynaud's Condition score [ Time Frame: 3 months ]
  Assessment of Raynaud's symptoms using the validated Raynaud's Condition Score. This is a 1 to 10 Likert scale, with 0 representing 'no difficulty' and 10 indicating 'extreme difficulty' with symptoms; collected daily for 3 months, a lower score indicates a more favourable outcome.
• Blood pressure [ Time Frame: pre-intervention ]
  blood pressure measured by automated oscillometric blood pressure
• Blood pressure [ Time Frame: 4 weeks after starting intervention ]
  blood pressure measured by automated oscillometric blood pressure
• Blood pressure [ Time Frame: 8 weeks after starting intervention ]
  blood pressure measured by automated oscillometric blood pressure
• Blood pressure [ Time Frame: 12 weeks after starting the intervention ]
  blood pressure measured by automated oscillometric blood pressure
• Dietary polyphenol intake [ Time Frame: pre-intervention ]
  estimation of dietary polyphenols made by food frequency questionnaire
• Dietary polyphenol intake [ Time Frame: 4 weeks after starting intervention ]
  estimation of dietary polyphenols made by food frequency questionnaire
• Dietary polyphenol intake [ Time Frame: 8 weeks after starting intervention ]
  estimation of dietary polyphenols made by food frequency questionnaire
• Dietary polyphenol intake [ Time Frame: 12 weeks after starting the intervention ]
  estimation of dietary polyphenols made by food frequency questionnaire
• Ambient skin temperature [ Time Frame: pre-intervention ]
  skin temperature of a finger exposed to an environmental temperature of 25oC, before cooling
• Ambient skin temperature [ Time Frame: 12 weeks after starting the intervention ]
  skin temperature of a finger exposed to an environmental temperature of 25oC, before cooling
• Ambient skin blood flow [ Time Frame: pre-intervention ]
  finger blood flow (measured using laser Doppler flowmetry) when exposed to an environmental temperature of 25oC, before cooling
• Ambient skin blood flow [ Time Frame: 12 weeks after starting the intervention ]
  finger blood flow (measured using laser Doppler flowmetry) when exposed to an environmental temperature of 25oC, before cooling
• Skin temperature response to acute cooling [ Time Frame: pre-intervention ]
  The time taken for skin temperature of the finger to stabilise in response to localised cooling (in an air temperature of 0oC)
• Skin temperature response to acute cooling [ Time Frame: 12 weeks after starting the intervention ]
  The time taken for skin temperature of the finger to stabilise in response to localised cooling (in an air temperature of 0oC)
• Skin blood flow response to acute cooling [ Time Frame: pre-intervention ]
  Finger Skin blood flow; measurement (using laser Doppler flowmetry) made once finger skin temperature has stabilised in response to localised cooling (in an air temperature of 0oC)
• Skin blood flow response to acute cooling [ Time Frame: 12 weeks after starting the intervention ]
  Finger Skin blood flow; measurement (using laser Doppler flowmetry) made once finger skin temperature has stabilised in response to localised cooling (in an air temperature of 0oC)
• Skin temperature response to re-warming [ Time Frame: pre-intervention ]
  The time taken for skin temperature of finger to stabilise in an environmental temperature of 25oC following localised cooling (in an air temperature of 0oC)
• Skin temperature response to re-warming [ Time Frame: 12 weeks after starting the intervention ]
  The time taken for skin temperature of finger to stabilise in an environmental temperature of 25oC following localised cooling (in an air temperature of 0oC)
• Skin temperature after re-warming [ Time Frame: pre-intervention ]
  skin temperature that a finger exposed to an environmental temperature of 25oC stabilises to after localised cooling
• Skin temperature after re-warming [ Time Frame: 12 weeks after starting the intervention ]
  skin temperature that a finger exposed to an environmental temperature of 25oC stabilises to after localised cooling
• Quality of life score [ Time Frame: pre-intervention ]
  Assessed using SF-36 questionnaire. Responses are coded and normalised to the UK population, as per standard methods, and a score for mental and physical health calculated; a higher score indicating a more favourable outcome
• Quality of life score [ Time Frame: 4 weeks after starting intervention ]
  Assessed using SF-36 questionnaire. Responses are coded and normalised to the UK population, as per standard methods, and a score for mental and physical health calculated; a higher score indicating a more favourable outcome
• Quality of life score [ Time Frame: 8 weeks after starting intervention ]
  Assessed using SF-36 questionnaire. Responses are coded and normalised to the UK population, as per standard methods, and a score for mental and physical health calculated; a higher score indicating a more favourable outcome
• Quality of life score [ Time Frame: 12 weeks after starting the intervention ]
  Assessed using SF-36 questionnaire. Responses are coded and normalised to the UK population, as per standard methods, and a score for mental and physical health calculated; a higher score indicating a more favourable outcome
• Attrition rate [ Time Frame: 2 years ]
  Number of participants completing the protocol as a proportion of those who were randomised to the study
• Adverse events [ Time Frame: 3 months ]
  Any injury, accident or illness experienced over the intervention period will be documented
• Recruitment rate [ Time Frame: 2 years ]
  number of people volunteering to take part in the study as a proportion of those expressing initial interest

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cocoa Flavanol Supplementation in Raynaud's Phenomenon
• Official Title: Pilot Study to Investigate the Effect of Cocoa Flavanols on Symptoms in Primary Raynaud's Phenomenon
• Brief Summary: The study aims to investigate the effect that supplementing the diet with cocoa flavanols has on vasospasm symptoms and temperature regulation in women with primary Raynaud's phenomenon (PRP). Participants will be randomised to consume either high flavanol cocoa extract or low flavanol cocoa (placebo) daily for 3 months.

Detailed Description

Primary Raynaud's phenomenon (PRP) is characterised by periodic vasospasm of the fingers and toes precipitated by exposure to cold or emotional stimuli and stress. Previous studies have demonstrated that underlying this condition there can be vascular endothelium dysfunction. Pharmacological interventions used to relieve symptoms and complications in PRP include drugs targeted at increasing nitric oxide (NO; transdermal nitrates) levels. Cocoa derived products, rich in the phytonutrients 'flavanols', have been shown to increase the bioavailability of NO at the vascular endothelium and promote vasodilation, which may address an underlying cause of PRP and mitigate symptoms. Previous work carried out in the research group has indicated that the acute consumption of cocoa does not compromise the counter-regulatory responses to localised cold exposure in those with PRP.

30 individuals with PRP will be recruited. Those interested in taking part will attend a medical screening and consent visit. If recruited, a participant number will be assigned to them sequentially and they will be randomised to either experimental or control group, with neither the participants nor the research team knowing which group they have been allocated to. Participants will be asked to complete a diet diary before attending 4 further visits over a period of 3 months.

Visit 1 (pre-intervention) and 4 (end of intervention); immediately on arrival, participants will be asked to lie semi-supine on a hospital bed. Skin temperature (surface thermocouples) and 'core' temperature (infrared tympanic thermometer) will start to be recorded to identify when these parameters have stabilized in room temperature (set at 25oC). Blood pressure will be taken using an arm cuff. Then a Finometer cuff will be attached to the left middle finger to record cardiovascular parameters (Blood pressure /heart rate/ cardiac output) and a laser Doppler probe will be attached to the dorsum of both index fingers to assess skin blood flow. Once the finger skin temperature has remained stable for 6 minutes, baseline Finometer and laser Doppler measurements will be recorded and the skin and 'core' temperature will be noted. Then, the right hand will be placed in a temperature regulated box which is set at an air temperature of 0oC. The hand will be cooled to a finger skin temperature of 15oC, then the box temperature will be modified to maintain the skin temperature at 15oC. The time that it takes for the skin temperature on the fingers to reach 15oC will be recorded. With the finger skin temperature stable at 15oC, Finometer and laser Doppler measurements will be repeated and the 'core' temperature at this point noted. Then, the hand will be removed from the chamber, and allowed to equilibrate in room temperature. The time taken for the skin temperature to reach stability will be recorded, as will the absolute temperature that it stabilises to. Measures above will be repeated once hand temperature is stable. Once these measures have been made, all equipment will be removed and a 15ml blood sample will be taken (for epicatechin, glucose and insulin analysis). The participant will be asked to complete 3 questionnaires (SF-36, Raynaud's symptoms and a food frequency questionnaire). Participants will also return a 4-day diet diary at visits 1 and 4, and their symptom diary at visit 4.

Visits 2 (end of month 1) and 3 (end of month 2); participants will return a 4-day diet diary, symptom diary and any unused capsules. They will also have a resting blood pressure measurement made, weight measured and be asked to complete 3 questionnaires (SF-36, Raynaud's symptoms and a food frequency questionnaire).

At the end of Visits 1, 2 and 3, participants will be given a months' supply of capsules, a symptom diary and a diet diary (to be completed in the week prior to the next visit).

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Double-blinded, placebo controlled study. Block randomised with equal allocation of participants between groups.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Opaque capsules of equal size and appearance presented in similar bottles labelled only by a code. Code to product information is held by the manufacturer and un-blinding of the PI will only occur once the study analysis has been completed or in the event of a serious adverse event occurring.

Primary Purpose: Prevention

• Condition: Primary Raynaud Phenomenon

Intervention

• Dietary Supplement: High Flavanol Cocoa extract
  Experimental group
• Dietary Supplement: Alkalised cocoa
  Control group

Study Arms

• Experimental: High Flavanol Cocoa extract
  278mg total flavanols (38.3mg epicatechin) per opaque cellulose capsule 3 capsules consumed once per day (836 mg total flavanols; 115mg epicatechin) for 3 months
  Intervention: Dietary Supplement: High Flavanol Cocoa extract
• Placebo Comparator: Alkalised cocoa
  0mg total flavanols (0mg epicatechin) per opaque cellulose capsule 3 capsules consumed once per day (0mg total flavanols; 0mg epicatechin) for 3 months
  Intervention: Dietary Supplement: Alkalised cocoa

Publications *

• Herrick A. Raynaud's phenomenon. Curr Treat Options Cardiovasc Med. 2008 Apr;10(2):146-55. doi: 10.1007/s11936-008-0016-y.
• Chung L, Shapiro L, Fiorentino D, Baron M, Shanahan J, Sule S, Hsu V, Rothfield N, Steen V, Martin RW, Smith E, Mayes M, Simms R, Pope J, Kahaleh B, Csuka ME, Gruber B, Collier D, Sweiss N, Gilbert A, Dechow FJ, Gregory J, Wigley FM. MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: a randomized, controlled trial. Arthritis Rheum. 2009 Mar;60(3):870-7. doi: 10.1002/art.24351.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 3, 2021): 27
• Original Estimated Enrollment (submitted: January 21, 2019): 30
• Actual Study Completion Date: July 31, 2021
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Experience symptoms of Primary Raynaud's Phenomenon, with >1 attack / week through the winter months
• Daily consumption of caffeine containing foods/drinks.
• BMI <27kg/m2

Exclusion Criteria:

• pregnant or breast feeding (women only),
• clinically significant metabolic or endocrine abnormalities
• fasting glucose >6.5mmol/l,
• taking Bosentan, aspirin, dipyridamole, heparin or transdermal nitrates,
• herbal supplement use,
• food allergies related to the investigational product (cocoa, peanuts, milk),
• sensitivity to methylxanthines (e.g. caffeine, theobromine).
• Presence or history of digital ulceration,
• blood parameters suggesting secondary Raynaud's,
• history of migraines

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03815162
• Other Study ID Numbers: 112-1809
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual data will not be shared with other researchers

• Current Responsible Party: Elizabeth Simpson, University of Nottingham
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Nottingham
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ian A Macdonald, PhD; University of Nottingham

• PRS Account: University of Nottingham
• Verification Date: November 2021