Clinical trial NCT03815162: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Primary Raynaud Phenomenon
Keywords: cocoa flavanols
Lead sponsor: University of Nottingham
Sponsor class: OTHER
First posted: 2019-01-24
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded, placebo controlled study. Block randomised with equal allocation of participants between groups.
Primary purpose: PREVENTION

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).

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

Primary outcomes:
measure: Vasospasm
timeFrame: 3 months
Secondary outcomes:
measure: Severity of vasospasm symptoms
timeFrame: 3 months
measure: Duration of vasospasm symptoms
timeFrame: 3 months
measure: Raynaud's Condition score
timeFrame: 3 months
measure: Blood pressure
timeFrame: pre-intervention
measure: Blood pressure
timeFrame: 4 weeks after starting intervention
measure: Blood pressure
timeFrame: 8 weeks after starting intervention
measure: Blood pressure
timeFrame: 12 weeks after starting the intervention
measure: Dietary polyphenol intake
timeFrame: pre-intervention
measure: Dietary polyphenol intake
timeFrame: 4 weeks after starting intervention
measure: Dietary polyphenol intake
timeFrame: 8 weeks after starting intervention
measure: Dietary polyphenol intake
timeFrame: 12 weeks after starting the intervention
measure: Ambient skin temperature
timeFrame: pre-intervention
measure: Ambient skin temperature
timeFrame: 12 weeks after starting the intervention
measure: Ambient skin blood flow
timeFrame: pre-intervention
measure: Ambient skin blood flow
timeFrame: 12 weeks after starting the intervention
measure: Skin temperature response to acute cooling
timeFrame: pre-intervention
measure: Skin temperature response to acute cooling
timeFrame: 12 weeks after starting the intervention
measure: Skin blood flow response to acute cooling
timeFrame: pre-intervention
measure: Skin blood flow response to acute cooling
timeFrame: 12 weeks after starting the intervention
measure: Skin temperature response to re-warming
timeFrame: pre-intervention
measure: Skin temperature response to re-warming
timeFrame: 12 weeks after starting the intervention
measure: Skin temperature after re-warming
timeFrame: pre-intervention
measure: Skin temperature after re-warming
timeFrame: 12 weeks after starting the intervention
measure: Quality of life score
timeFrame: pre-intervention
measure: Quality of life score
timeFrame: 4 weeks after starting intervention
measure: Quality of life score
timeFrame: 8 weeks after starting intervention
measure: Quality of life score
timeFrame: 12 weeks after starting the intervention
measure: Attrition rate
timeFrame: 2 years
measure: Adverse events
timeFrame: 3 months
measure: Recruitment rate
timeFrame: 2 years
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: David Greenfield Human Physiology Laboratories
state: Notts
Study officials:
affiliation: University of Nottingham
name: Ian A Macdonald, PhD
role: STUDY_DIRECTOR
References:
citation: Herrick A. Raynaud's phenomenon. Curr Treat Options Cardiovasc Med. 2008 Apr;10(2):146-55. doi: 10.1007/s11936-008-0016-y.
citation: 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.