- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03981029
FACT Biomarker Subgroup Analysis
Folic Acid Clinical Trial (FACT): Biomarker Subgroup Analysis
Study Overview
Status
Conditions
Detailed Description
The Folic Acid Clinical Trial (FACT) was developed to conclusively determine the effect of high dose folic acid supplementation in pregnancy on the prevention of preeclampsia (PE) in a randomized controlled trial (RCT) design.
The primary objective of the FACT Biomarker Subgroup Analysis is to determine the folate status and its impact on risk for PE in a subgroup of women participating in FACT. Our secondary objectives are to:
i) To determine serum vitamin B6 and B12 status, modifiers of folate metabolism, and their impact on risk for PE in women participating in the FACT
ii) To determine plasma homocysteine status, a folate-responsive biomarker for PE risk, and its relationship with risk for PE in women participating in the FACT
iii) To determine the modifying effect of single nucleotide polymorphisms (SNPs) in key folate metabolic enzymes (MTHFR, MTHFD1, MTR) on PE risk in women participating in the FACT
iv) To determine the effect of folic acid supplementation and folate status on biomarkers of PE (sFLT, sENG, PlGF) and their association with PE risk in women participating in the FACT
Folate biomarker analyses will provide key information to identify modifiers of the response to folic acid treatment and elucidate the mechanism(s) underlying the relationship between folic acid treatment and PE risk. Folate status will vary in response to folic acid treatment depending on a number of factors including compliance in taking the study supplement, folate intake from the diet (natural folate and folic acid used for enrichment), vitamin B12 status, and genetic polymorphisms in enzymes involved in folate metabolism that have been shown to effect placental development/function. As such, variation in the response to folic acid treatment may account for differences in observed PE risk.
Folic acid supplementation may also reduce homocysteine, its related endothelial dysfunction and consequently reduce PE risk. In addition, homocysteine metabolism is dependent on vitamins B12 and B6, the deficiency of which can result in hyperhomocysteinemia. Thus, homocysteine, B12 and B6 will each be evaluated.
Lastly, it will be useful to assess biomarkers of placental health and PE risk (sFlt-1, sEng, PlGF) that are found in maternal circulation and determine their association with folate intake and status.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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New Brunswick
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Moncton, New Brunswick, Canada, E1C 6Z8
- The Moncton Hospital
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Ontario
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Kingston, Ontario, Canada, K7L 2V7
- Kingston General Hospital
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Ottawa, Ontario, Canada, K1Y 4E9
- The Ottawa Hospital
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Ottawa, Ontario, Canada
- Health Canada
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
The FACT Biomarker Subgroup Analysis is a pilot study that aims to determine the folate status and its impact on risk for pre-eclampsia in a subgroup of women participating in FACT (NCT01355159).
Women participating in FACT (NCT01355159) will be eligible to participate.
Description
Individuals participating in FACT (NCT01355159) will be eligible to participate. FACT eligibility criteria are as follows:
INCLUSION criteria
- Capability of subject to comprehend and comply with study requirements
- ≥ 18 years of age at time of consent
- Subject is taking ≤1.1 mg of folic acid daily at the time of randomization
- Live fetus (documented positive fetal heart prior to randomization)
- Gestational age between 8+0 and 16+6 weeks of pregnancy (Gestational age (GA) of subjects will be calculated based on the first day of the last menstrual period (LMP) or ultrasound performed before 12+6. If early ultrasound and LMP dates differ by ≤ 7 days, base GA estimate on LMP date; if > 7 days, use early < 12+6 ultrasound)
- Subject plans to give birth in a participating hospital site
Pregnant subjects must fulfill at least one of the following identified risk factors for pre-eclampsia (PE):
- Pre-existing hypertension (documented evidence of diastolic blood pressure ≥ 90 mmHg on two separate occasions or at least 4 hours apart prior to randomization, or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to randomization)
- Pre-pregnancy diabetes (documented evidence of Type I or type II DM)
- Twin pregnancy
- Documented evidence of history of PE in a previous pregnancy
- BMI > 35 kg/m2 within 3 months prior to this pregnancy and up to randomization of this pregnancy (documented evidence of height and weight to calculate BMI is required)
EXCLUSION Criteria:
- Known history or presence of any clinically significant disease or condition which would be a contraindication to folic acid supplementation of up to 5 mg daily for the duration of pregnancy
- Known major fetal anomaly or fetal demise
- History of medical complications, including: renal disease with altered renal function, epilepsy, cancer, or use of folic acid antagonists such as valproic acid
- Individual who is currently enrolled or has participated in another clinical trial or who received an investigational drug within 3 months of the date of randomization (unless approved by the Trial Coordinating Centre)
- Known presence of: Alcohol abuse (≥ 2 drinks per day) or alcohol dependence, Illicit drug/substance use and/or dependence, Known hypersensitivity to folic acid, Multiple Pregnancy (triplets or more), Participation in this study in a previous pregnancy
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
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FACT High-dose folic acid treatment group
Consenting study participants who, through their participation in FACT (NCT01355159) are randomized to receive daily high-dose folic acid supplementation during pregnancy.
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Participants in this study received either daily high-dose folic acid supplementation during pregnancy OR placebo through their participation in FACT (NCT01355159). Details of the FACT Folic Acid intervention are provided below: Folic Acid 1.0 mg x 4 tablets will be taken daily by oral administration. The majority of women in the study will routinely take 1.0 mg folic acid in a prenatal vitamin supplement, as recommended by their primary obstetrical provider; the study requirements do not require that participants change their practice. Therefore the actual total daily dose may be up to 5.1 mg of folic acid |
FACT Placebo treatment group
Consenting study participants who, through their participation in FACT (NCT01355159) are randomized to receive daily placebo supplementation during pregnancy.
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Participants in this study received either daily high-dose folic acid supplementation during pregnancy OR placebo through their participation in FACT (NCT01355159). Details of the FACT Folic Acid placebo are provided below: Placebo x 4 tablets will be taken daily by oral administration. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Folate Status
Time Frame: From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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The primary outcome measure is maternal folate status. Folate status will be determined by:
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From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Homocysteine Status
Time Frame: From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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Maternal homocysteine concentrations will be determined.
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From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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Status of modifiers of folate metabolism
Time Frame: Taken at one time point between 24 and 26 completed weeks gestation.
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Status of modifiers of folate metabolism will be determined by:
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Taken at one time point between 24 and 26 completed weeks gestation.
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Angiogenic potential
Time Frame: From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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Angiogenic potential will be determined from measurement of maternal circulating s-FLT-1, s-ENG-1 and placental growth factor concentrations.
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From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pre-eclampsia
Time Frame: As in FACT: from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
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The association between all biomarkers analyzed in this study and risk of pre-eclampsia as determined though completion of FACT will be considered.
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As in FACT: from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
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Collaborators and Investigators
Publications and helpful links
General Publications
- Wen SW, White RR, Rybak N, Gaudet LM, Robson S, Hague W, Simms-Stewart D, Carroli G, Smith G, Fraser WD, Wells G, Davidge ST, Kingdom J, Coyle D, Fergusson D, Corsi DJ, Champagne J, Sabri E, Ramsay T, Mol BWJ, Oudijk MA, Walker MC; FACT Collaborating Group. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ. 2018 Sep 12;362:k3478. doi: 10.1136/bmj.k3478.
- Wen SW, Chen XK, Rodger M, White RR, Yang Q, Smith GN, Sigal RJ, Perkins SL, Walker MC. Folic acid supplementation in early second trimester and the risk of preeclampsia. Am J Obstet Gynecol. 2008 Jan;198(1):45.e1-7. doi: 10.1016/j.ajog.2007.06.067.
- Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115-41. doi: 10.1146/annurev.nu.05.070185.000555.
- Guven MA, Coskun A, Ertas IE, Aral M, Zencirci B, Oksuz H. Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens Pregnancy. 2009 May;28(2):190-200. doi: 10.1080/10641950802601179.
- Lindblad B, Zaman S, Malik A, Martin H, Ekstrom AM, Amu S, Holmgren A, Norman M. Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses. Acta Obstet Gynecol Scand. 2005 Nov;84(11):1055-61. doi: 10.1111/j.0001-6349.2005.00876.x.
- Dalery K, Lussier-Cacan S, Selhub J, Davignon J, Latour Y, Genest J Jr. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995 Jun 1;75(16):1107-11. doi: 10.1016/s0002-9149(99)80739-5.
- Powers RW, Evans RW, Majors AK, Ojimba JI, Ness RB, Crombleholme WR, Roberts JM. Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol. 1998 Dec;179(6 Pt 1):1605-11. doi: 10.1016/s0002-9378(98)70033-x.
- Stover PJ. Physiology of folate and vitamin B12 in health and disease. Nutr Rev. 2004 Jun;62(6 Pt 2):S3-12; discussion S13. doi: 10.1111/j.1753-4887.2004.tb00070.x.
- Hustad S, Midttun O, Schneede J, Vollset SE, Grotmol T, Ueland PM. The methylenetetrahydrofolate reductase 677C-->T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am J Hum Genet. 2007 May;80(5):846-55. doi: 10.1086/513520. Epub 2007 Mar 13.
- Parle-McDermott A, Kirke PN, Mills JL, Molloy AM, Cox C, O'Leary VB, Pangilinan F, Conley M, Cleary L, Brody LC, Scott JM. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet. 2006 Jun;14(6):768-72. doi: 10.1038/sj.ejhg.5201603.
- Parle-McDermott A, Mills JL, Kirke PN, Cox C, Signore CC, Kirke S, Molloy AM, O'Leary VB, Pangilinan FJ, O'Herlihy C, Brody LC, Scott JM. MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae. Am J Med Genet A. 2005 Feb 1;132A(4):365-8. doi: 10.1002/ajmg.a.30354.
- Parle-McDermott A, Pangilinan F, Mills JL, Signore CC, Molloy AM, Cotter A, Conley M, Cox C, Kirke PN, Scott JM, Brody LC. A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod. 2005 Jul;11(7):477-80. doi: 10.1093/molehr/gah204.
- Furness DL, Fenech MF, Khong YT, Romero R, Dekker GA. One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency. Am J Obstet Gynecol. 2008 Sep;199(3):276.e1-8. doi: 10.1016/j.ajog.2008.06.020.
- Tam LE, McDonald SD, Wen SW, Smith GN, Windrim RC, Walker MC. A survey of preconceptional folic acid use in a group of Canadian women. J Obstet Gynaecol Can. 2005 Mar;27(3):232-6. doi: 10.1016/s1701-2163(16)30515-1.
- Shakur YA, Garriguet D, Corey P, O'Connor DL. Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians. Am J Clin Nutr. 2010 Oct;92(4):818-25. doi: 10.3945/ajcn.2010.29696. Epub 2010 Aug 25.
- Czeizel AE, Tomcsik M. Acute toxicity of folic acid in pregnant women. Teratology. 1999 Jul;60(1):3-4. doi: 10.1002/(SICI)1096-9926(199907)60:13.0.CO;2-4. No abstract available.
- Czeizel AE, Dudas I, Metneki J. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report. Arch Gynecol Obstet. 1994;255(3):131-9. doi: 10.1007/BF02390940.
- Czeizel AE, Susanszky E. Diet intake and vitamin supplement use of Hungarian women during the preconceptional period. Int J Vitam Nutr Res. 1994;64(4):300-5.
- Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res. 2001 Apr;4(2):63-6. doi: 10.1375/1369052012155.
- Kirke PN, Daly LE, Elwood JH. A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group. Arch Dis Child. 1992 Dec;67(12):1442-6. doi: 10.1136/adc.67.12.1442.
- Stevens VL, McCullough ML, Sun J, Gapstur SM. Folate and other one-carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the Cancer Prevention Study II Nutrition Cohort. Am J Clin Nutr. 2010 Jun;91(6):1708-15. doi: 10.3945/ajcn.2009.28553. Epub 2010 Apr 21.
- Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J. A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev. 1999 Mar;8(3):209-17.
- Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA. 2008 Nov 5;300(17):2012-21. doi: 10.1001/jama.2008.555.
- Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst. 2003 Mar 5;95(5):373-80. doi: 10.1093/jnci/95.5.373.
- Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst. 2007 Jan 3;99(1):64-76. doi: 10.1093/jnci/djk006.
- Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ, Logan RF, Baron JA. Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials. Int J Cancer. 2011 Jul 1;129(1):192-203. doi: 10.1002/ijc.25872. Epub 2011 Apr 1.
- Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Harnack L, Jacobs EJ, Leitzmann M, Mannisto S, Miller AB, Potter JD, Rohan TE, Schatzkin A, Speizer FE, Stevens VL, Stolzenberg-Solomon R, Terry P, Toniolo P, Weijenberg MP, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. 2010 Nov;21(11):1919-30. doi: 10.1007/s10552-010-9620-8. Epub 2010 Sep 5.
- Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 2003 Jun;77(6):1474-7. doi: 10.1093/ajcn/77.6.1474.
- Wilson RD; GENETICS COMMITTEE; MOTHERISK. RETIRED: Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2007 Dec;29(12):1003-1013. doi: 10.1016/S1701-2163(16)32685-8. Erratum In: J Obstet Gynaecol Can. 2008 Mar;30(3):193. Goh, Ingrid [corrected to Goh, Y Ingrid]. English, French.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2011649-01H
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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