Choline Nutritional Status: Development of a Biomarker Panel
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|ClinicalTrials.gov Identifier: NCT03726671|
Recruitment Status : Recruiting
First Posted : October 31, 2018
Last Update Posted : December 13, 2019
|First Submitted Date ICMJE||October 25, 2018|
|First Posted Date ICMJE||October 31, 2018|
|Last Update Posted Date||December 13, 2019|
|Actual Study Start Date ICMJE||November 1, 2018|
|Estimated Primary Completion Date||March 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03726671 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Validation of Isotope Dilution Method to Assess Choline Pool Size by Magnetic Resonance Spectroscopy (MRS) [ Time Frame: At the end of 2 weeks of 100% or 50% or 25% Cho diet ]
MRS is a direct measurement of liver choline content. Changes in liver choline by MRS should correlate with changes in liver choline measured by isotope dilution. Pearson correlation coefficient or non-parametric correlation analyses, such as Spearman correlation and Kendall correlation, will be used to study the correlation between data generated from the two types of measurements.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures
||SNPs that create inefficiencies in choline metabolism associated with change in choline pool size and choline biomarkers [ Time Frame: At baseline visit ]
Exploratory analysis of >2 million SNPs measured on a custom Illumina Expanded Multi-Ethnic genotyping array (Mega-Ex). The same analysis described for Outcome 4 will be applied for Outcome 7. Benjamini-Hochberg method for False Discovery Rate (FDR) correction will be used for multiple testing correction.
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Choline Nutritional Status: Development of a Biomarker Panel|
|Official Title ICMJE||Choline Nutritional Status: Development of a Biomarker Panel|
|Brief Summary||People who eat diets low in choline should deplete their choline (Cho) stores, and measurements of Cho pool size using isotope dilution should reflect this depletion. Investigators will identify a biomarker panel that correlates well with measured Cho pool size across the range of different degrees of depletion.The investigators propose that, as body stores of Cho diminish, cells and organs will reach the point when metabolism/function in the cell is altered, and that this will result in a progression of changes in biomarkers that reflect Cho status.|
Choline (Cho) is an essential nutrient and most Americans' diets do not achieve the recommended intake. Diets low in Cho are associated with liver and muscle disease and with suboptimal fetal development, while diets too high in choline may be associated with increased risk for heart disease. Cho is a required nutrient and in 1998, an Adequate Intake (AI) and a Tolerable Upper Limit (UL) for Cho was established In 2016, the US Food and Drug Administration (FDA) set a Recommended Daily Intake (RDI) for Cho based on the AIs as part of the new Nutrition Facts label for packaged foods (published in the Federal Register on May 27, 2016; FDA-2012-N-1210-0875, Federal Register Number:2016-11867). The AI/RDI varies by age and gender, but is 550 mg/d in adolescent and adult men and 425 mg/d in adult women (more in pregnant and lactating women) and 400 mg/day for adolescent women.
There is no validated biomarker for choline status (the availability of the various forms of Cho needed to sustain optimal cellular function). Measurement of plasma Cho concentrations is not adequate as plasma choline is homeostatically regulated. Based on extensive preliminary and published data this group identified a panel of potential biomarkers that could be used to assess Cho status, and now the investigators propose to validate this biomarker panel against measures of Cho pool size using isotope dilution. The largest stores of Cho are located in the liver, and mass resonance spectroscopy (MRS) of liver has been used in the past to assess Cho status in humans. This method is not practical for use as a biomarker in clinical or public health practice as it is expensive and the availability of the instrumentation is limited. However, the MRS can be utilized to confirm correlations between the biomarker panel and the isotope dilution method. Liver biopsy is risky and not practical, making measurement of hepatic Cho and Cho metabolites concentrations a poor choice for assessing Cho status.
Perhaps there is a panel of biomarkers that together will more accurately and reliably reflect Cho status. By making measurements in people fed 3 different dietary amounts of Cho for two weeks at a time, and comparing the biomarker measures to body total Cho pool size assessed using isotope dilution (a proxy for the availability of the various forms of Cho), investigators will be able to identify the combination of biomarkers and algorithm for calculating a Cho status score that best predicts total Cho pool size, and therefore predicts choline nutritional status (the availability of the various forms of Cho needed to sustain cellular function). People who eat diets low in choline should deplete their choline (Cho) stores, and measurement of Cho pool size using isotope dilution should reflect this depletion. The investigators will identify a biomarker panel that correlates well with measured Cho pool size across the range of different degrees of depletion. This study tests a method for using stable isotope dilution to measure body choline stores, and then asks how this measure correlates with a panel of biomarkers in plasma and with liver fat measured using Fibroscan®. Using isotope dilution can provide an estimate of the size of the body pool of Cho. The investigators' proposed method is conceptually similar to the method for measuring total body water from a bolus dose of labeled water. Similar methodology was used recently in studies of metabolic flux of Cho in pregnant women. Isotope dilution is a well-established method used to estimate pool size for other nutrients, such as vitamin A. Similar to vitamin A, the major storage pools for Cho are in the liver, and ingested Cho is rapidly absorbed and accumulated by liver. MRS/MRI scans will also be performed to investigate correlation between these "gold standard" measures and the other methods described above.
Participants will consume meals provided in two week dietary intervals with 3 different levels of choline with a 2 week washout periods between those dietary intervals. Participants will receive 100% of the recommended intake (RDI) of Cho (550mg Cho/day); 50% of the RDI of Cho (275mg/day); and 25% of the RDI of Cho (137.5mg/day). The meal order will be randomly assigned and all participants will receive all diets at some point in the study. There will be a minimum of a two week washout between diet intervals. Both participants and researchers will be blinded to the diet order.
Participants will have brief exercise challenges (Biodex) to assess muscle function as an additional predictor of choline status.
To validate the isotope dilution and Fibroscan measures participants will also complete MRI/MRS scans.
Saliva, stool, and urine samples will be collected.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Healthy volunteers will consume meals, provided by the investigator, in two week intervals with 3 different levels of choline (Cho). Participants will receive 100% of the recommended daily intake (RDI) of Cho (550 mg Cho/day); 50% of the RDI of Cho (275mg/day); and 25% of the RDI of Cho (137.5 mg/day). The meal order will be randomly assigned and all participants will receive all diets at some point in the study. There will be a minimum of a two week washout between diet intervals where participants return to their regular diets. Both participants and researchers will be blinded to the diet order.Masking: Triple (Participant, Investigator, Outcomes Assessor)
Participant dietary arm assignment is randomized by a randomization plan created by the study coordinator at www.randomization.com. Each of the 3 hormonal related demographic groups (male, premenopausal females, and postmenopausal females) will have a list of the same order of diets created by the randomizer. Each participant will be assigned upon entry into the study into the next open diet for their group as ordered by the randomizer. No one collecting or processing data will be informed of the choline levels the participant is experiencing in their dietary arms at any given time to attempt to eliminate bias and ensure appropriate data collection. All staff who interact with participants or who are handling samples/data, will not be informed of the code linking dietary choline levels to diet order.Primary Purpose: Screening
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||March 2021|
|Estimated Primary Completion Date||March 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||17 Years to 70 Years (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03726671|
|Other Study ID Numbers ICMJE||17-1982
1R01DK115380-01 ( U.S. NIH Grant/Contract )
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||University of North Carolina, Chapel Hill|
|Study Sponsor ICMJE||University of North Carolina, Chapel Hill|
|Collaborators ICMJE||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|
|PRS Account||University of North Carolina, Chapel Hill|
|Verification Date||December 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP