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The investigators are interested in learning more about choline, a nutrient required by the body. The body does make some choline, but it does not make enough to support health and the rest must be acquired through diet. Eggs, and especially egg yolks, are a major dietary source of choline. Choline can also be given as a dietary supplement. Ingestion of choline supplements has been linked to an increased concentration of a compound called TMAO (trimethylamine N-oxide). Elevated TMAO levels have been linked to higher heart disease risk. With this study, the investigators hope to learn whether there is a difference in the way your body responds to the ingestion of a choline supplement versus the choline found within eggs.
The principal goal for the study is to examine whether there is a difference between the ingestion of choline through supplements versus choline found within eggs on plasma TMAO levels. The investigators have previously shown that dietary intake of trimethylamines, including the choline group of phosphatidylcholine (PC), is mechanistically linked to cardiovascular disease risk and that the metabolism of these trimethylamine nutrients in humans is modulated by the intestinal microbes (gut microbes). Additionally, extensive animal studies link an essential role of gut microbiota to the metabolism of choline and the production of metabolites that promote / accelerate atherosclerotic processes. The investigators have also recently shown a 10-fold increase in plasma TMAO levels following supplementation with choline bitartrate supplements. However, another pilot study by a collaborator (unpublished) did not show the same increase in plasma TMAO levels following the ingestion of whole eggs, a major dietary source of choline. Therefore, with this study the investigators wish to examine the differences, if any, between the ingestion of an equivalent mass of total choline in the free form (as bitartrate salt) as a supplement vs. within whole eggs.
Eggs, and specifically the egg yolk, contain a large amount of total choline. However, egg white contains potential anti-microbial peptides that could influence gut microbial composition and function, and therefore impact conversion of choline into TMA and TMAO observed in subjects. Therefore, the investigators hypothesize that the consumption of whole eggs (hardboiled) will not elevate plasma TMAO levels to the same extent as a comparable amount of total choline ingested in capsule form as the choline bitartrate salt. The investigators further hypothesize that the consumption of egg white with choline bitartrate tablets may result in less of a rise in TMAO levels than ingestion of the choline bitartrate supplement alone.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Whole Hardboiled Eggs | Experimental | Subjects will consume four (4) pre-cooked, pre-peeled whole hardboiled eggs per day for 28 days. |
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| Choline Bitartrate Tablets | Experimental | Subjects will consume two (2) 500mg choline bitartrate tablets per day for 28 days. |
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| Hardboiled Eggs + Choline Bitartrate Tablets | Experimental | Subjects will consume both four (4) whole, pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. |
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| Egg Whites + Choline Bitartrate Tablets | Experimental | Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. |
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| Phosphatidylcholine Capsules | Experimental | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Choline Bitartrate | Dietary Supplement | 500mg choline bitartrate tablets |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Plasma Levels of Fasting Trimethylamine-N-oxide (TMAO), a Choline Metabolite | Changes in levels of non-labeled TMAO from baseline to end-of-study (day 28) as measured by established techniques by mass spectrometry. | Baseline, 28 days |
| Changes in Platelet Function With Increased Choline Intake | The activation and functioning of platelets within a single subject will be compared before and after increased choline intake. | Baseline, Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Levels of Fasting Trimethylamine-N-oxide (TMAO) in 24-hour Urine Collections | Changes in levels of non-labeled TMAO from baseline to Day 28 measured by established mass spectrometry techniques. | Baseline, Day 28 |
| Changes in Plasma Levels of Fasting Choline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| W. H. Wilson Tang, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic Foundation | Cleveland | Ohio | 44195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21475195 | Background | Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922. | |
| 2007906 |
| Label | URL |
|---|---|
| Patterson K, Bhagwat S, Williams J, Howe J, and Holden J. USDA Database for the Choline Content of Common Foods, Release Two. January 2008. | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Whole Hardboiled Eggs | Subjects will consume four (4) pre-cooked, pre-peeled whole hardboiled eggs per day for 28 days. Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. |
| FG001 | Choline Bitartrate Tablets |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 2, 2017 |
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| Pre-cooked, pre-peeled whole hardboiled eggs | Other | Obtained from a commercial source. |
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| Egg whites from pre-cooked, pre-peeled hardboiled eggs | Other | Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded. |
|
| Phosphatidylcholine capsules | Dietary Supplement | 420 mg phosphatidylcholine capsules obtained from a commercial source. |
|
Fasting plasma levels of choline from samples obtained at baseline and at day 28 were compared. |
| Baseline, Day 28 |
| Changes in Plasma Levels of Fasting Carnitine. | Fasting plasma levels of carnitine from samples obtained at baseline and at day 28 were compared. | Baseline, Day 28 |
| Changes in Plasma Levels of Fasting Betaine. | Fasting plasma levels of betaine from samples obtained at baseline and at day 28 were compared. | Baseline, Day 28 |
| Changes in Lipid Profile, Total Cholesterol | Changes in total cholesterol levels between baseline and Day 28 | Baseline, Day 28 |
| Changes in Lipid Profile, HDL | Changes in measured HDL levels between baseline and Day 28 | Baseline, Day 28 |
| Changes in Lipid Profile, LDL | Changes in measured LDL levels between baseline and Day 28 | Baseline, Day 28 |
| Changes in Lipid Profile, Triglycerides | Changes in measured triglyceride levels between baseline and Day 28 | Baseline, Day 28 |
| Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr. 1991 Apr;121(4):539-46. doi: 10.1093/jn/121.4.539. |
| 19232103 | Background | Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study. Nutr J. 2009 Feb 20;8:14. doi: 10.1186/1475-2891-8-14. |
| 33872583 | Derived | Wilcox J, Skye SM, Graham B, Zabell A, Li XS, Li L, Shelkay S, Fu X, Neale S, O'Laughlin C, Peterson K, Hazen SL, Tang WHW. Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial. Am J Med. 2021 Sep;134(9):1160-1169.e3. doi: 10.1016/j.amjmed.2021.03.016. Epub 2021 Apr 17. |
Subjects will consume two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets |
| FG002 | Hardboiled Eggs + Choline Bitartrate Tablets | Subjects will consume both four (4) whole, pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. |
| FG003 | Egg Whites + Choline Bitartrate Tablets | Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Egg whites from pre-cooked, pre-peeled hardboiled eggs: Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded. |
| FG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Whole Hardboiled Eggs | Subjects will consume four (4) pre-cooked, pre-peeled whole hardboiled eggs per day for 28 days. Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. |
| BG001 | Choline Bitartrate Tablets | Subjects will consume two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets |
| BG002 | Hardboiled Eggs + Choline Bitartrate Tablets | Subjects will consume both four (4) whole, pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. |
| BG003 | Egg Whites + Choline Bitartrate Tablets | Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Egg whites from pre-cooked, pre-peeled hardboiled eggs: Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded. |
| BG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
| BG005 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
| ||||||||||||||||
| TMAO at Baseline | Median | Inter-Quartile Range | uM |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Plasma Levels of Fasting Trimethylamine-N-oxide (TMAO), a Choline Metabolite | Changes in levels of non-labeled TMAO from baseline to end-of-study (day 28) as measured by established techniques by mass spectrometry. | All participants with TMAO measured at baseline and Day 28. | Posted | Median | Inter-Quartile Range | uM | Baseline, 28 days |
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| Primary | Changes in Platelet Function With Increased Choline Intake | The activation and functioning of platelets within a single subject will be compared before and after increased choline intake. | Posted | Median | Inter-Quartile Range | aggregation percentage | Baseline, Day 28 |
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| Secondary | Changes in Levels of Fasting Trimethylamine-N-oxide (TMAO) in 24-hour Urine Collections | Changes in levels of non-labeled TMAO from baseline to Day 28 measured by established mass spectrometry techniques. | Posted | Median | Inter-Quartile Range | mg in 24 hours | Baseline, Day 28 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Changes in Plasma Levels of Fasting Choline | Fasting plasma levels of choline from samples obtained at baseline and at day 28 were compared. | Posted | Median | Inter-Quartile Range | uM | Baseline, Day 28 |
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| Secondary | Changes in Plasma Levels of Fasting Carnitine. | Fasting plasma levels of carnitine from samples obtained at baseline and at day 28 were compared. | Posted | Median | Inter-Quartile Range | uM | Baseline, Day 28 |
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| Secondary | Changes in Plasma Levels of Fasting Betaine. | Fasting plasma levels of betaine from samples obtained at baseline and at day 28 were compared. | Posted | Median | Inter-Quartile Range | uM | Baseline, Day 28 |
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| Secondary | Changes in Lipid Profile, Total Cholesterol | Changes in total cholesterol levels between baseline and Day 28 | Posted | Median | Inter-Quartile Range | mg/dL | Baseline, Day 28 |
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| Secondary | Changes in Lipid Profile, HDL | Changes in measured HDL levels between baseline and Day 28 | Posted | Median | Inter-Quartile Range | mg/dL | Baseline, Day 28 |
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| Secondary | Changes in Lipid Profile, LDL | Changes in measured LDL levels between baseline and Day 28 | Posted | Median | Inter-Quartile Range | mg/dL | Baseline, Day 28 |
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| Secondary | Changes in Lipid Profile, Triglycerides | Changes in measured triglyceride levels between baseline and Day 28 | Posted | Median | Inter-Quartile Range | mg/dL | Baseline, Day 28 |
|
Adverse event data were collected during study participation, up to 30 days from enrollment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Whole Hardboiled Eggs | Subjects will consume four (4) pre-cooked, pre-peeled whole hardboiled eggs per day for 28 days. Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. | 0 | 19 | 0 | 19 | 0 | 19 |
| EG001 | Choline Bitartrate Tablets | Subjects will consume two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets | 0 | 20 | 0 | 20 | 0 | 20 |
| EG002 | Hardboiled Eggs + Choline Bitartrate Tablets | Subjects will consume both four (4) whole, pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Pre-cooked, pre-peeled whole hardboiled eggs: Obtained from a commercial source. | 0 | 17 | 0 | 17 | 0 | 17 |
| EG003 | Egg Whites + Choline Bitartrate Tablets | Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Egg whites from pre-cooked, pre-peeled hardboiled eggs: Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded. | 0 | 20 | 0 | 20 | 0 | 20 |
| EG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. 420 mg phosphatidylcholine capsules obtained from a commercial source. | 0 | 10 | 0 | 10 | 0 | 10 |
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Small sample sizes within each group created uneven distributions of some baseline characteristics; participants' dietary intake beyond the assigned interventions was not controlled during the study period; using only healthy controls makes the translatability of the results to other patient populations, like those with impaired renal function, unclear.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jennifer Wilcox | Cleveland Clinic Foundation | 216-636-6153 | kirsopj@ccf.org |
| Apr 21, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D002794 | Choline |
| D010713 | Phosphatidylcholines |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D000588 | Amines |
| D050337 | Trimethyl Ammonium Compounds |
| D000644 | Quaternary Ammonium Compounds |
| D009861 | Onium Compounds |
| D020404 | Glycerophospholipids |
| D010712 | Phosphatidic Acids |
| D005994 | Glycerophosphates |
| D010743 | Phospholipids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Day 28 |
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| <0.0001 |
A p-value <0.05 was considered significant. |
| Equivalence |
For equivalence testing, the difference was assumed to be 0. |
| Wilcoxon Signed Rank test | <0.0001 | A p-value <0.05 was considered significant. | Equivalence | For equivalence testing, the difference was assumed to be 0. |
| Wilcoxon Signed Rank test | <0.0001 | A p-value <0.05 was considered significant. | Equivalence | For equivalence testing, the difference was assumed to be 0. |
| Wilcoxon Signed Rank test | 0.27 | A p-value <0.05 was considered significant. | Equivalence | For equivalence testing, the difference was assumed to be 0. |
Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days.
Choline Bitartrate: 500mg choline bitartrate tablets
Egg whites from pre-cooked, pre-peeled hardboiled eggs: Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded.
| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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Subjects will consume both the egg whites (no yolks) of four (4) pre-cooked, pre-peeled hardboiled eggs and two (2) 500mg choline bitartrate tablets per day for 28 days. Choline Bitartrate: 500mg choline bitartrate tablets Egg whites from pre-cooked, pre-peeled hardboiled eggs: Egg whites from pre-cooked, pre-peeled hardboiled eggs. The yolks are removed and discarded. |
| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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| OG004 | Phosphatidylcholine Capsules | Subjects will consume six (6) 420 mg phosphatidylcholine capsules by mouth per day for 28 days. Phosphatidylcholine capsules: 420 mg phosphatidylcholine capsules obtained from a commercial source. |
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