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Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic

NCT ID: NCT01050556

Last Updated: 2012-08-01

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

600 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-09-30

Study Completion Date

2011-06-30

Brief Summary

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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

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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.

Conditions

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High Blood Arsenic Due to Chronic Arsenic Exposure

Keywords

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arsenic folate folic acid creatine arsenicosis nutrition

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Placebo

Placebo daily

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

daily, 24 weeks

Folic Acid 400 ug

400 µg folic acid daily

Group Type EXPERIMENTAL

folic acid

Intervention Type DIETARY_SUPPLEMENT

400 ug/d for 12 or 24 weeks

Folic Acid 800 ug

800 µg folic acid daily

Group Type EXPERIMENTAL

folic acid

Intervention Type DIETARY_SUPPLEMENT

800 µg/d for 12 or 24 weeks

Creatine

creatine daily

Group Type EXPERIMENTAL

creatine

Intervention Type DIETARY_SUPPLEMENT

3 mg/d for 12 weeks

Creatine + Folic Acid

creatine + folic acid daily

Group Type EXPERIMENTAL

creatine + folic acid

Intervention Type DIETARY_SUPPLEMENT

3 mg creatine/d + 400 µg folic acid/d for 12 weeks

Interventions

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Placebo

daily, 24 weeks

Intervention Type OTHER

folic acid

400 ug/d for 12 or 24 weeks

Intervention Type DIETARY_SUPPLEMENT

folic acid

800 µg/d for 12 or 24 weeks

Intervention Type DIETARY_SUPPLEMENT

creatine

3 mg/d for 12 weeks

Intervention Type DIETARY_SUPPLEMENT

creatine + folic acid

3 mg creatine/d + 400 µg folic acid/d for 12 weeks

Intervention Type DIETARY_SUPPLEMENT

Eligibility Criteria

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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
Minimum Eligible Age

20 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Cancer Institute (NCI)

NIH

Sponsor Role collaborator

Columbia University

OTHER

Sponsor Role lead

Responsible Party

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Mary Gamble

Associate Professor of Environmental Health Sciences

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Mary V Gamble, PhD

Role: PRINCIPAL_INVESTIGATOR

Columbia University, Department of Environmental Health Sciences

Locations

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Columbia University Arsenic Research Project

Dhaka, , Bangladesh

Site Status

Countries

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Bangladesh

References

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Li W, Wu H, Goldsmith J, Glabonjat RA, Ilievski V, Balac O, Slavkovich V, Pinto-Pacheco B, Lin X, Parvez F, Jackson GL, Siddique AB, Uddin MN, Islam T, Martinez-Morata I, Navas-Acien A, Niedzwiecki MM, Kioumourtzoglou MA, Pierce BL, Graziano JH, Bottiglieri T, Walker DI, Gamble MV. Metabolic Signature of Arsenic Exposure and Metabolism: The Folic Acid and Creatine Trial. Environ Sci Technol. 2025 Jul 29;59(29):14905-14916. doi: 10.1021/acs.est.5c01597. Epub 2025 Jul 16.

Reference Type DERIVED
PMID: 40668877 (View on PubMed)

Martinez-Morata I, Wu H, Galvez-Fernandez M, Ilievski V, Bottiglieri T, Niedzwiecki MM, Goldsmith J, Jones DP, Kioumourtzoglou MA, Pierce B, Walker DI, Gamble MV. Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT Trial. J Nutr. 2024 Feb;154(2):670-679. doi: 10.1016/j.tjnut.2023.12.010. Epub 2023 Dec 12.

Reference Type DERIVED
PMID: 38092151 (View on PubMed)

Abuawad AK, Bozack AK, Navas-Acien A, Goldsmith J, Liu X, Hall MN, Ilievski V, Lomax-Luu AM, Parvez F, Shahriar H, Uddin MN, Islam T, Graziano JH, Gamble MV. The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population. Environ Health Perspect. 2023 Mar;131(3):37015. doi: 10.1289/EHP11270. Epub 2023 Mar 28.

Reference Type DERIVED
PMID: 36976258 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34661903 (View on PubMed)

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.

Reference Type DERIVED
PMID: 32918135 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30590411 (View on PubMed)

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.

Reference Type DERIVED
PMID: 27052531 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26311810 (View on PubMed)

Other Identifiers

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R01CA133595

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AAAC8618

Identifier Type: -

Identifier Source: org_study_id