Clinical trial NCT03201822: Intake-dependent Effect of Cocoa Flavanol Absorption, Metabolism and Excretion in Humans
Official title: Intake-dependent Effect of Cocoa Flavanol Absorption, Metabolism and Excretion in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: flavanol
ADME
cocoa flavanols
polyphenols
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Mars, Inc.
First posted: 2017-06-28
Enrollment: 14
Sex: MALE
Minimum age (years): 25
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double-masked and cross-over dietary intervention study in healthy young adult males
Primary purpose: BASIC_SCIENCE

Brief summary: A randomized, double-masked and cross-over dietary intervention study in healthy young adult males to evaluate the concentration of F-derived metabolites in plasma and urine after single acute intakes of F-containing drinks on four different test days.

Detailed description: Flavanols (F) are plant-derived compounds commonly present in the human diet. Examples of F-containing foods and beverages are apples, chocolate, tea, wine, berries, pomegranate and nuts. The consumption of F-containing foods and beverages has been associated with improvements in cardiovascular health. In this context, there exists a great interest in describing the absorption, metabolism and excretion of F in humans, as it is thought that F-derived metabolites present in circulation are the mediators of F-beneficial effects in humans. Recently, we described a series of F-derived metabolites in circulation that are present after the consumption of a single acute intake amount of F in humans. A key question, however, is if the metabolites we observed after a single acute feeding are the same as those that occur in individuals who consume F-rich diets on a regular basis. Studies investigating the metabolism of numerous other xenobiotics have shown that the profile of metabolites can greatly vary over time, as well as with the amount of xenobiotic ingested. In this context, and considering that i) the amount of F-consumed from diet greatly varies among individuals, ii) recent epidemiology studies indicate that the vascular protective effects of F diets primarily occur when daily intake of F are relatively high; and iii) there is evidence of an intake amount-dependency on the vascular effects of F in dietary intervention studies; we submit it is important to assess whether or not there are F intake amount-dependent effects on the levels and profile of F-derived metabolites in humans. This study will provide new information concerning the F-derived metabolites that may be responsible for mediating F-beneficial effects in humans. We suggest the information that will be obtained from the outlined work will be particularly timely given ongoing discussion concerning the possible generation of dietary recommendations for F-rich foods.

Eligibility criteria: Inclusion Criteria:

* No prescription medications
* BMI 18.5 - 29.9 kg/m2
* Weight ≥ 110 pounds
* previously consumed cocoa and peanut products, with no adverse reactions

Exclusion Criteria:

* Adults unable to consent
* Prisoners
* Non-English speaking\*
* BMI ≥ 30 kg/m2
* Allergies to nuts, cocoa and chocolate products
* Active avoidance of coffee and caffeinated soft drinks
* Under current medical supervision
* A history of cardiovascular disease, stroke, renal, hepatic, or thyroid disease
* History of clinically significant depression, anxiety or other psychiatric condition
* History of Raynaud's disease
* History of difficult blood draws
* Indications of substance or alcohol abuse within the last 3 years
* Current use of herbal, plant or botanical supplements (multi-vitamin/mineral supplements are allowed)
* Blood Pressure \> 140/90 mm Hg
* GI tract disorders, previous GI surgery (except appendectomy)
* Self-reported malabsorption (e.g. difficulty digesting or absorbing nutrients from food, potentially leading to bloating, cramping or gas)
* Diarrhea within the last month, or antibiotic intake within the last month
* Vegetarian, Vegan, food faddists, individuals using non-traditional diets, on a weight loss diet or individual following diets with significant deviations from the average diet
* Metabolic panel results or complete blood counts that are outside of the normal reference range and are considered clinically relevant by the study physician
* Screening LDL ≥ 190 mg/dl for those who have 0-1 major risk factors apart from LDL cholesterol (i.e. family history of premature coronary artery disease (male first degree relative \< 55 years; CHD in female first degree relative \< 65 years), cigarette smoker, HDL-C ≤ 40 mg/dL)
* Screening LDL ≥ 160 mg/dl for those who have 2 major risk factors apart from LDL cholesterol (i.e. family history of premature coronary artery disease (male first degree relative \< 55 years; CHD in female first degree relative \< 65 years), cigarette smoker, HDL-C ≤ 40 mg/dL).

(using NCEP calculator http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof)

* Screening LDL ≥ 130 mg/dl for those who have 2 major risk factors apart from LDL cholesterol (i.e. family history of premature coronary artery disease (male first degree relative \< 55 years; CHD in female first degree relative \< 65 years), cigarette smoker, HDL-C ≤ 40 mg/dL), and a Framingham 10-year Risk Score 10-20% (Framingham risk calculated using NCEP calculator http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof)
* Cold, flu, or upper respiratory condition at screening
* Currently participating in a clinical or dietary intervention study

Primary outcomes:
measure: Change in levels of gut microbiome derived metabolites in urine
timeFrame: Urine collected 12h previous to intervention and up to 24 h after intervention
measure: Change in levels of gut microbiome derived metabolites in plasma
timeFrame: Plasma collected before (0h) and up to 6h post intervention
measure: Change in levels of structurally related epicatechin metabolites in urine
timeFrame: Urine collected 12h previous to intervention and up to 24 h after intervention
measure: Change in levels of structurally related epicatechin metabolites in plasma
timeFrame: Plasma collected before (0h) and up to 6h post intervention
Secondary outcomes:
measure: Composite of pharmacokinetic (PK) parameters of metabolites Maximum Plasma Concentration (CMax)
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Time to Maximum Plasma Concentration
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Area Under the Curve
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Area Under the Curve extrapolated to infinity
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Elimination Rate Constant
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Elimination Half-Life
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Systemic Clearance
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Renal Clearance
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites cumulative Amount Excreted in Feces
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites Volume of Distribution
timeFrame: Before intervention (0h) and up to 24 h after intervention
measure: Composite of pharmacokinetic (PK) parameters of metabolites cumulative Amount Excreted in Urine
timeFrame: Before intervention (0h) and up to 24 h after intervention
Other outcomes:
Locations:
city: Davis
country: United States
facility: UC Davis
state: California
Study officials:
affiliation: UC Davis
name: Carl L Keen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mars, Inc.
name: Javier I Ottaviani, PhD
role: STUDY_DIRECTOR
References:
citation: Schroeter H, Heiss C, Spencer JP, Keen CL, Lupton JR, Schmitz HH. Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. Mol Aspects Med. 2010 Dec;31(6):546-57. doi: 10.1016/j.mam.2010.09.008. Epub 2010 Sep 18.
citation: Ottaviani JI, Momma TY, Kuhnle GK, Keen CL, Schroeter H. Structurally related (-)-epicatechin metabolites in humans: assessment using de novo chemically synthesized authentic standards. Free Radic Biol Med. 2012 Apr 15;52(8):1403-12. doi: 10.1016/j.freeradbiomed.2011.12.010. Epub 2011 Dec 23.
citation: Koster H, Halsema I, Scholtens E, Knippers M, Mulder GJ. Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes. The role of saturation of phenolsulfotransferase. Biochem Pharmacol. 1981 Sep 15;30(18):2569-75. doi: 10.1016/0006-2952(81)90584-0. No abstract available.
citation: McCullough ML, Chevaux K, Jackson L, Preston M, Martinez G, Schmitz HH, Coletti C, Campos H, Hollenberg NK. Hypertension, the Kuna, and the epidemiology of flavanols. J Cardiovasc Pharmacol. 2006;47 Suppl 2:S103-9; discussion 119-21. doi: 10.1097/00005344-200606001-00003.
citation: Heiss C, Kleinbongard P, Dejam A, Perre S, Schroeter H, Sies H, Kelm M. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol. 2005 Oct 4;46(7):1276-83. doi: 10.1016/j.jacc.2005.06.055.