Clinical trial NCT01050556: Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic
Official title: Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: High Blood Arsenic Due to Chronic Arsenic Exposure
Keywords: arsenic
folate
folic acid
creatine
arsenicosis
nutrition
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-01-15
Enrollment: 600
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether folic acid, alone or together with creatine supplementation, can lower blood arsenic concentrations and improve the ability to detoxify arsenic.

Detailed description: Approximately 140 million people in over 70 countries are chronically exposed to arsenic (As)-contaminated drinking water at concentrations far exceeding the World Health Organization standard of 10 µg/L. As is a carcinogen known to cause cancers of the skin, bladder, and lung, as well as ischemic heart disease and neurologic impairments. Methylation of ingested inorganic arsenic (InAs) to methylarsonic-(MMA) and dimethylarsinic acids (DMA) relies on folate-dependent one carbon metabolism, utilizing S-adenosylmethionine (SAM) as the methyl donor, and facilitates urinary As elimination. The results from our Nutritional Influences on Arsenic Toxicity (NIAT) study indicate that folate deficiency and hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate arsenic and are risk factors for arsenic-induced skin lesions. Furthermore, folic acid (FA) supplementation does indeed facilitate As elimination and significantly lowers blood As concentrations in individuals who are folate deficient. We have also determined that blood As is a good biomarker of As exposure and is directly associated with the risk for As-induced skin lesions. Collectively, the implication of these findings is that FA has enormous therapeutic potential for ameliorating the long-term health consequences of arsenic exposure for the many populations at risk. However, several fundamental questions remain and will be addressed in this study. This trial is designed to determine 1) whether FA supplementation lowers blood As concentrations in the general Bangladeshi population, 2) at what time point a nadir in blood As is achieved, and 3) whether creatine supplementation, alone or in addition to 400 µg/d FA, will spare methyl groups, resulting in lower blood As, lower homocysteine (Hcys) concentrations, and increased methylation of As. The creatine arms are based on multiple studies that show that urinary creatinine concentrations are a very strong predictor of As methylation. The final step in creatine biosynthesis is the methylation of guanidinoacetate to creatine; this process consumes 50-75% of all SAM-derived methyl groups and is also responsible for 50-75% of all Hcys biosynthesis. Thus, this trial will test the hypothesis that creatine supplementation, which shuts down endogenous creatine biosynthesis, will spare methyl groups, lower Hcys, and increase As methylation.

Eligibility criteria: Inclusion Criteria:

* Currently exposed to arsenic via contaminated drinking water
* Well water arsenic concentration \> 10 ug/L
* Between the ages of 20 and 65

Exclusion Criteria:

* Women who are currently pregnant or plan to become pregnant within the next 6 months
* Currently taking nutritional supplements
* Known renal disease
* Participation in any other clinical trial

Primary outcomes:
measure: blood arsenic concentrations
timeFrame: 24 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: Columbia University Arsenic Research Project
Study officials:
affiliation: Columbia University, Department of Environmental Health Sciences
name: Mary V Gamble, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bae S, Kamynina E, Guetterman HM, Farinola AF, Caudill MA, Berry RJ, Cassano PA, Stover PJ. Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults. Cochrane Database Syst Rev. 2021 Oct 18;10(10):CD012649. doi: 10.1002/14651858.CD012649.pub2.
citation: Bozack AK, Howe CG, Hall MN, Liu X, Slavkovich V, Ilievski V, Lomax-Luu AM, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Gamble MV. Betaine and choline status modify the effects of folic acid and creatine supplementation on arsenic methylation in a randomized controlled trial of Bangladeshi adults. Eur J Nutr. 2021 Jun;60(4):1921-1934. doi: 10.1007/s00394-020-02377-z. Epub 2020 Sep 11.
citation: Bozack AK, Hall MN, Liu X, Ilievski V, Lomax-Luu AM, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Gamble MV. Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh. Am J Clin Nutr. 2019 Feb 1;109(2):380-391. doi: 10.1093/ajcn/nqy148.
citation: Hall MN, Howe CG, Liu X, Caudill MA, Malysheva O, Ilievski V, Lomax-Luu AM, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Gamble MV. Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults. J Nutr. 2016 May;146(5):1062-7. doi: 10.3945/jn.115.227132. Epub 2016 Apr 6.
citation: Peters BA, Hall MN, Liu X, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Ilievski V, Graziano JH, Gamble MV. Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. J Nutr. 2015 Oct;145(10):2245-52. doi: 10.3945/jn.115.216739. Epub 2015 Aug 26.