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Trial record 56 of 164 for:    PEMT

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 7, 2018
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

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.

Condition or disease Intervention/treatment Phase
Healthy Other: 25% Cho diet Other: 50% Cho diet Other: 100% Cho diet Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
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)
Masking Description: 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
Official Title: Choline Nutritional Status: Development of a Biomarker Panel
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 25%Cho, 50%Cho, 100%Cho
Diets containing 137.5mg (25% Cho diet), 275mg (50% Cho diet), and 550mg (100% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day

Experimental: 25% Cho, 100% Cho, 50% Cho
Diets containing 137.5mg (25% Cho diet) , 550mg (100% Cho diet), and 275mg Cho (50% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day

Experimental: 50% Cho, 25% Cho, 100% Cho
Diets containing 275mg (50% Cho diet), 137.5mg (25% Cho diet), and 550mg Cho (100% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day

Experimental: 50% Cho, 100% Cho, 25% Cho
Diets containing 275mg (50% Cho diet), 550mg (100% Cho diet), and 137.5mg Cho (25% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day

Experimental: 100% Cho, 25% Cho, 50% Cho
Diets containing 550mg (100% Cho diet), 137.5mg (25% Cho diet), and 275mg Cho (50% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day

Experimental: 100% Cho, 50% Cho, 25% Cho
Diets containing 550mg (100% Cho diet), 275mg (50% Cho diet), and 137.5mg Cho (25% Cho diet) will be given in that order for two weeks each with 2 weeks of washout between.
Other: 25% Cho diet
Subjects will consume meals containing 25% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 137.5mg Choline/day

Other: 50% Cho diet
Subjects will consume meals containing 50% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 275mg Choline/day

Other: 100% Cho diet
Subjects will consume meals containing 100% of recommended intake of Choline for 2 weeks. On day 12 of the diet period, subjects will consume 250 mg of Cho in the form of Cho chloride-(trimethyl-d9, 9%, Cambridge Isotope Laboratories, Tewksbury, Massachusetts, (USA), as a bolus
Other Name: 550mg Choline/day




Primary Outcome Measures :
  1. Change in Liver Choline Pool Size by Isotope Dilution [ Time Frame: 24h following administration of choline-d9 on day 12 of each dietary intervention ]
    The liver choline pool will be determined by the dilution of the deuterated choline metabolites formed in liver and released to plasma. The fraction of plasma phosphatidylcholine-d9 (PCd9) derived from liver is expressed as the tracer to tracee ratio (TTR), and is millimoles PCd9 (tracer) divided by millimoles of unlabeled PC (tracee): TTR = PCd9/PC. The liver choline pool size is the dose of Chod9 given (2.2 mmoles) divided by the TTR. Choline pool sizes at the end of each intervention will be compared.

  2. Biomarkers of Choline Status in Humans [ Time Frame: At the end of 2 weeks of 100% or 50% or 25% Cho diet ]
    Plasma choline metabolites (micromolar): choline, dimethylglycine, betaine, phosphatidylcholine, sphingomyelin, trimethylamine-oxide, and homocysteine will be measured by targeted metabolomic profiling. The levels of these metabolites at the end of each intervention will be compared. The association between choline metabolites and choline pool size will be investigated.

  3. Untargeted Metabolomics to Validate Choline Status Measured by Isotope Dilution [ Time Frame: At the end of 2 weeks of 100% or 50% or 25% Cho diet ]
    Changes in metabolites measured by untargeted metabolomics methods: carnitine, butyrylcarnitine, isobutyrylcarnitine, isovaleryl-L-carnitine, propionylcarnitine, hippurate, 3-indolepropionic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, creatinine, myo-inositol, pyridoxylate, erythronic acid, urate, pseudouridine, glutamine, pyroglutamate, valine, glutamyl-valine, glycine, leucine, trans-4-hydroxyproline, and stachydrine, will be studied. Differences in peak sizes at the end of each dietary intervention will be compared using linear mixed model. Peak sizes for an additional ~10,000 plasma and urine metabolites will also be assessed for changes associated with the interventions. Supervised Orthogonal Partial Least Squares Regression will be used to identify a panel of metabolites associated with choline pool size, and assign weight to each metabolite. The selected metabolites will be used to calculate a composite choline status score to predict choline pool size.

  4. Phosphatidylethanolamine-N-methyltransferase (PEMT) Single Nucleotide Polymorphisms (SNPs) and their associations with choline pool size [ Time Frame: At the end of 2 weeks of 100% or 50% or 25% Cho diet ]
    DNA will be collected and evaluated for the presence of the various PEMT SNPs. Genotypes will be measured by RT-PCR (real time polymerase chain reaction) and a custom Illumina Expanded Multi-Ethnic genotyping array (Mega-Ex). The magnitude of changes in choline pool size at the end of each dietary intervention will be compared among subjects with different genotypes in PEMT SNPs. Linear mixed model with repeated measures will be performed for each group (healthy men, pre- and postmenopausal women) separately to study the genotype effect and genotype*intervention interaction effect on choline pool size (or choline status score). The P values from this analysis will be adjusted for multiple testing correction.

  5. Validation of Fibroscan Method by Magnetic Resonance Imaging (MRI) to Assess Liver Fat Content [ Time Frame: At the end of 2 weeks of 100% or 50% or 25% Cho diet ]
    Controlled attenuation parameter (CAP) as measured by Fibroscan is an ultrasound-based technique to measure liver fat. This method will be validated by MRI where liver fat is normalized to spleen fat.


Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   17 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • Male or female, aged 17-70 years
  • In good general health as evidenced by medical history, clinical chemistries, physical exam, and BMI≤ 30
  • Women who are included in the study and are of pregnancy potential will have a urine pregnancy test at the beginning and end of each dietary intervention arm and must be using birth control during the study.

Exclusion Criteria:

  • using drugs or medication known to be damaging to liver or muscle at typically prescribed doses or that have the potential to alter Cho metabolism (e.g., methotrexate);
  • history of hepatic, renal, or other chronic systemic disease.
  • subjects with liver abnormalities (e.g.cysts) as determined by ultrasound
  • current smokers
  • consume >2 alcoholic beverages/d or >14/wk
  • substance abusers or drug addicted
  • eating unusual diet that would interfere with the study
  • food allergies, (e.g., soy) or any problems with eating all foods on required study diet
  • using Cho-containing dietary supplements
  • women who are breastfeeding, pregnant, or plan to become pregnant due to potential risk to fetus/child of low choline diet
  • performing intense exercise of more than 1 hour a day or other intense muscle building exercise (such as weightlifting beyond low weight repetitions)
  • Actively participating in other research study where required to exercise or ingest any food, medicine, or supplement in any manner
  • claustrophobia
  • has a cardiac pacemaker, artificial heart valve, metal plate, pin, or other metallic implant, intrauterine device, insulin or other drug pump, aneurysm clips, previous gunshot wound, cochlear implant or other implantable hearing device, employment history as a metalworker, or permanent cosmetic tattoos (eyeliner, eyebrow)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03726671


Contacts
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Contact: Julie M. Stegall, MSW 704-250-5048 julie_stegall@unc.edu
Contact: Isis Trujillo, PhD 704-250-5041 isis_trujillo@unc.edu

Locations
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United States, North Carolina
UNC Chapel Hill Nutrition Research Institute Recruiting
Kannapolis, North Carolina, United States, 28081
Contact: Julie Stegall, MSW    704-250-5048    julie_stegall@unc.edu   
Principal Investigator: Steven H Zeisel, MD, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Steven H. Zeisel, MD, PhD UNC Chapel Hill - Nutrition Research Institute

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT03726671     History of Changes
Other Study ID Numbers: 17-1982
1R01DK115380-01 ( U.S. NIH Grant/Contract )
First Posted: October 31, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Choline
Lipotropic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Lipid Regulating Agents
Nootropic Agents