FACT Biomarker Subgroup Analysis

Pre-Eclampsia Clinical Trial

Official title:

Folic Acid Clinical Trial (FACT): Biomarker Subgroup Analysis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03981029
• Other study ID #: 2011649-01H
• Status: Completed
• Start date: December 19, 2011
• Est. completion date: September 2016

Study information

• Verified date: June 2019
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The FACT Biomarker Subgroup Analysis is a pilot study of mothers who participated in the Folic Acid Clinical Trial (FACT, NCT01355159). This subgroup analysis aims to determine the effect of high-dose folic acid supplementation in pregnancy on maternal folate status and subsequent impact on risk for pre-eclampsia.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: September 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

Individuals participating in FACT (NCT01355159) will be eligible to participate. FACT eligibility criteria are as follows:

INCLUSION criteria

1. Capability of subject to comprehend and comply with study requirements

2. = 18 years of age at time of consent

3. Subject is taking =1.1 mg of folic acid daily at the time of randomization

4. Live fetus (documented positive fetal heart prior to randomization)

5. 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)

6. Subject plans to give birth in a participating hospital site

7. 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:

1. 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

2. Known major fetal anomaly or fetal demise

3. History of medical complications, including: renal disease with altered renal function, epilepsy, cancer, or use of folic acid antagonists such as valproic acid

4. 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)

5. 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

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia

Intervention

Other:
• 4.0mg Folic Acid received through participation in FACT (NCT01355159)
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
• Placebo received through participation in FACT
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.

Locations

Country	Name	City	State
Canada	Kingston General Hospital	Kingston	Ontario
Canada	The Moncton Hospital	Moncton	New Brunswick
Canada	Health Canada	Ottawa	Ontario
Canada	The Ottawa Hospital	Ottawa	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (29)

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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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Folate Status	The primary outcome measure is maternal folate status. Folate status will be determined by: Red blood cell (RBC) folate concentrations.; Total serum folate concentrations.; The relative contribution of folate vitamers to total serum folate concentrations (unmetabolized folic acid, tetrahydrofolic acid, 5,10-methenylTHF, 5-formylTHF, 5-methylTHF and MeFox).	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.
Secondary	Homocysteine Status	Maternal homocysteine concentrations will be determined.	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.
Secondary	Status of Modifiers of Folate metabolism_vitamin B-12	Status of modifiers of folate metabolism will be determined by Vitamin B6 and B12 concentrations	Taken at one time point between 24 and 26 completed weeks gestation.
Secondary	Angiogenic Potential	Angiogenic potential will be determined from measurement of maternal circulating s-FLT-1, s-ENG-1 and placental growth factor concentrations.	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.
Secondary	Status of Modifiers of Folate metabolism_MTHFR Genotype (C677T)	Status of modifiers of folate metabolism will be determined by frequency of single nucleotide polymorphisms (SNPs) in the key folate metabolic enzyme MTHFR	Taken at one time point between 24 and 26 completed weeks gestation.
Secondary	Status of Modifiers of Folate metabolism_ Vitamin B6 (Pyridoxal 5-phosphate)	Status of modifiers of folate metabolism will be determined by Vitamin B6 and B12 concentrations	Taken at one time point between 24 and 26 completed weeks gestation.

External Links

•   High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention (FACT) ClinicalTrials.gov registration