Intake-dependent Effect of Cocoa Flavanol Absorption, Metabolism and Excretion in Humans

Study Overview
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Brief Summary
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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
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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.

Official Title
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Intake-dependent Effect of Cocoa Flavanol Absorption, Metabolism and Excretion in Humans

Conditions
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Healthy

Intervention / Treatment
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* Other: 100 mg of Cocoa Flavanols/70 kg BW
* Other: 200 mg of Cocoa Flavanols/70 kg BW
* Other: 400 mg of Cocoa Flavanols/70 kg BW
* Other: 1000 mg of Cocoa Flavanols/70 kg BW


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double-masked and cross-over dietary intervention study in healthy young adult males
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg of Cocoa Flavanols/70 kg BW<br>Fruit flavored non-dairy drink containing 100 cocoa flavanol/70 kg BW | Other: 100 mg of Cocoa Flavanols/70 kg BW<br>* Fruit-flavored non-dairy drink containing 100 cocoa flavanols/70kg BW.<br>|
| Experimental: 200 mg of Cocoa Flavanols/70 kg BW<br>Fruit flavored non-dairy drink containing 200 cocoa flavanol/70 kg BW | Other: 200 mg of Cocoa Flavanols/70 kg BW<br>* Fruit-flavored non-dairy drink containing 200 cocoa flavanols/70kg BW.<br>|
| Experimental: 400 mg of Cocoa Flavanols/70 kg BW<br>Fruit flavored non-dairy drink containing 400 cocoa flavanol/70 kg BW | Other: 400 mg of Cocoa Flavanols/70 kg BW<br>* Fruit-flavored non-dairy drink containing 400 cocoa flavanols/70kg BW.<br>|
| Experimental: 1000 mg of Cocoa Flavanols/70 kg BW<br>Fruit flavored non-dairy drink containing 1000 cocoa flavanol/70 kg BW | Other: 1000 mg of Cocoa Flavanols/70 kg BW<br>* Fruit-flavored non-dairy drink containing 1000 cocoa flavanols/70kg BW.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in levels of gut microbiome derived metabolites in urine | Gut microbiome derived metabolites include conjugates of 5-(3',4'-dihydroxyphenyl)-g-valerolatone metabolites | Urine collected 12h previous to intervention and up to 24 h after intervention | 
| Change in levels of gut microbiome derived metabolites in plasma | Gut microbiome derived metabolites include conjugates of 5-(3',4'-dihydroxyphenyl)-g-valerolatone | Plasma collected before (0h) and up to 6h post intervention | 
| Change in levels of structurally related epicatechin metabolites in urine | Structurally related epicatechin metabolites include sulfated, glucuronidated and/or methylated metabolites of epicatechin | Urine collected 12h previous to intervention and up to 24 h after intervention | 
| Change in levels of structurally related epicatechin metabolites in plasma | Structurally related epicatechin metabolites include sulfated, glucuronidated and/or methylated metabolites of epicatechin | Plasma collected before (0h) and up to 6h post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetic (PK) parameters of metabolites Maximum Plasma Concentration (CMax) | PK parameters: Cmax: maximum observed concentration in plasma; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Time to Maximum Plasma Concentration | tmax: time to maximum concentration in plasma; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Area Under the Curve | AUC0-t: area under the plasma concentration-time curve from hour 0 to the last measurable concentration in plasma; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Area Under the Curve extrapolated to infinity | AUC0-∞: area under the plasma concentration-time curve extrapolated to infinity; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Elimination Rate Constant | λZ: apparent terminal elimination rate constant in plasma; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Elimination Half-Life | t1/2: apparent terminal elimination half-life in plasma; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Systemic Clearance | CL/F: systemic clearance; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Renal Clearance | CLR: renal clearance;sampling interval and the total interval examined; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites cumulative Amount Excreted in Feces | Aef(0-t): Cumulative amount excreted in the feces over each sampling interval and the total interval examined. | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites Volume of Distribution | Vd/F: apparent volume of distribution; | Before intervention (0h) and up to 24 h after intervention | 
| Composite of pharmacokinetic (PK) parameters of metabolites cumulative Amount Excreted in Urine | Aeu(0-t): cumulative amount excreted in the urine over each | Before intervention (0h) and up to 24 h after intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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flavanol, ADME, cocoa flavanols, polyphenols