Intra-individual Real Life Effects of Cocoa Flavanols on Blood Pressure and Arterial Stiffness

Intra-individual Real Life Effects of Cocoa Flavanols on Blood Pressure and Arterial Stiffness Using Personal Devices in Healthy Humans: Series of Repeated Cross-over Randomized Controlled Double-blind N-of-1 Pilot Studies

Very controlled dietary intervention studies support that individual polyphenol rich foods and isolated polyphenols can increase endothelial function and HDL cholesterol and decrease blood pressure, arterial stiffness, and LDL cholesterol even in healthy subjects. The intake of (-)-epicatechin, the major polyphenol in cocoa, was previously mechanistically linked with acute improvements in endothelial function and nitric oxide availability. A profound understanding of inter- and intra-individual variability of responses in real life are an important area of research in a world that aims at personalized nutrition and medicine. N-of-1 trials are a powerful tool allowing to study small effects even in fewer subjects and help account for intra-individual variations in responses. The overall aim of the present pilot study is to evaluate intra-and inter-individual variability of responses to cocoa flavanols in everyday life using the N-of-1 paradigm. In this pilot study, young healthy humans will monitor blood pressure, pulse wave velocity, heart rate, diet, and physical activity on 8 days using a personal and wearable devices. Each subject will undergo the 8 study days; 4 days with cocoa flavanol capsules (CF; containing 750 mg (1500 mg per day)) and 4 days with calorically matched placebo capsules (P; 0 mg cocoa flavanols) taken at the same time in the morning with breakfast and at night before going to bed. The subjects will be randomized to different treatment allocation sequences to allow blinding of volunteers and investigator; either CF-P-CF-P-CF-P-CF-P or P-CF-P-CF-P-CF-P-CF.

Study Overview

• Status: Completed
• Conditions: Sleep; Blood Pressure; Stiffness, Vascular
• Intervention / Treatment: Dietary supplement: Cocoa flavanol (CF); Other: Placebo (P)

Detailed Description

Background: Very controlled dietary intervention studies support that individual polyphenol rich foods and isolated polyphenols can increase endothelial function and HDL cholesterol and decrease blood pressure, arterial stiffness, and LDL cholesterol even in healthy subjects. The intake of (-)-epicatechin, the major polyphenol in cocoa, was previously mechanistically linked with acute improvements in endothelial function and nitric oxide availability. However, the clinical intervention studies were performed in tightly controlled experimental settings and variability of individual responses were not investigated. A profound understanding of inter- and intra-individual variability of responses in real life are an important area of research in a world that aims at personalized nutrition and medicine. N-of-1 trials are a powerful tool allowing to study small effects even in fewer subjects and help account for intra-individual variations in responses. N-of-1 trials in clinical medicine are multiple crossover trials, usually randomized and often blinded, conducted in a single patient.

Aim, hypothesis, objectives: The overall aim of the present pilot study is to evaluate intra-and inter-individual variability of responses to cocoa flavanols in everyday life using the N-of-1 paradigm. It is the hypothesis that cocoa flavanols decrease blood pressure and arterial stiffness in everyday life of healthy individuals. The objectives to investigate the aim are (1) to test the effect of CF using wearable devices repeatedly measuring blood pressure, arterial stiffness, and heart rate in healthy individuals participating in in every days life, (2) to explore intra-and inter-individual variability in responses by repeatedly testing responses in the same individuals, and (3) to test different statistical models taking repeated measurements in the same subject into account.

Methods: In this pilot study, young healthy humans will monitor blood pressure, pulse wave velocity, heart rate, diet, and physical activity on 8 days using a personal and wearable devices. Each subject will undergo the 8 study days; 4 days with cocoa flavanol capsules (CF; containing 750 mg (1500 mg per day)) and 4 days with calorically matched placebo capsules (P; 0 mg cocoa flavanols) taken at the same time in the morning with breakfast and at night before going to bed. The subjects will be randomized to different treatment allocation sequences to allow blinding of volunteers and investigator; either CF-P-CF-P-CF-P-CF-P or P-CF-P-CF-P-CF-P-CF. Blood pressure and heart rate will be measured by a standard upper arm blood pressure cuff and estimated by a fitness wristband and pulse wave velocity via a finger device in 30 min intervals for 3 h starting after morning treatment ingestion followed by hourly intervals until going to bed.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Guildford, United Kingdom, GU2 7XH
    • University of Surrey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy
• Body mass index <30 kg/m2
• Age <45 years

Exclusion Criteria:

• Diabetes mellitus
• Symptoms of acute infection
• Cardiac arrhythmia
• Active malignancy

• Clinical signs or symptoms of cardiovascular disease including:

  1. Angina pectoris
  2. Shortness of breath
  3. Palpitations
  4. Syncopes
  5. Claudication
• Active vasoactive medication
• Vitamin supplements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Flavanol first; Subjects will receive over 8 days both cocoa flavanols (CF) and placebo (P) capsules on alternating days. Sequence of this arm is: CF-P-CF-P-CF-P-CF-P	Dietary supplement: Cocoa flavanol (CF); 2 times per day 750 mg cocoa flavanols (each delivered in 6 CocoaVia capsules); Other: Placebo (P); 2 times per day 0 mg cocoa flavanols calorically matched control (delivered in 6 identical capsules)
ACTIVE_COMPARATOR: Placebo first; Subjects will receive over 8 days both cocoa flavanols (CF) and placebo (P) capsules on alternating days. Sequence of this arm is: P-CF-P-CF-P-CF-P-CF	Dietary supplement: Cocoa flavanol (CF); 2 times per day 750 mg cocoa flavanols (each delivered in 6 CocoaVia capsules); Other: Placebo (P); 2 times per day 0 mg cocoa flavanols calorically matched control (delivered in 6 identical capsules)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in systolic and diastolic blood pressure	Standard upper arm cuff (day) and wrist band (day and night)	Measurements over 24 hours
Change in arterial stiffness	Pulse wave velocity by finger clip (iHeart)	Measurements over 24 hours
Change in heart rate	Fitness bracelet	Measurements over 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical activity	Steps measured on fitness bracelet	Assessed over 24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dietary composition	Dietary assessment based on food diary	Assessed over 24 hours

Collaborators and Investigators

• Sponsor: University of Surrey
• Investigators: Principal Investigator: Christian Heiss, MD, University of Surrey

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2019
• Primary Completion (ACTUAL): February 1, 2021
• Study Completion (ACTUAL): February 1, 2021

Study Registration Dates

• First Submitted: April 26, 2019
• First Submitted That Met QC Criteria: July 4, 2022
• First Posted (ACTUAL): July 7, 2022

Study Record Updates

• Last Update Posted (ACTUAL): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 4, 2022
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: FER-1819-040

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No