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FACT Biomarker Subgroup Analysis

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ClinicalTrials.gov Identifier: NCT03981029
Recruitment Status : Completed
First Posted : June 10, 2019
Last Update Posted : June 10, 2019
Sponsor:
Information provided by (Responsible Party):
Ottawa Hospital Research Institute

Tracking Information
First Submitted Date June 3, 2019
First Posted Date June 10, 2019
Last Update Posted Date June 10, 2019
Actual Study Start Date December 19, 2011
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 7, 2019)
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. ]
The primary outcome measure is maternal folate status. Folate status will be determined by:
  1. Red blood cell (RBC) folate concentrations.
  2. Total serum folate concentrations.
  3. 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).
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: June 7, 2019)
  • 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. ]
    Maternal homocysteine concentrations will be determined.
  • Status of modifiers of folate metabolism [ Time Frame: Taken at one time point between 24 and 26 completed weeks gestation. ]
    Status of modifiers of folate metabolism will be determined by:
    1. Vitamin B6 and B12 concentrations
    2. Frequency of single nucleotide polymorphisms (SNPs) in key folate metabolic enzymes (MTHFR, MTHFD1, MTR)
  • 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. ]
    Angiogenic potential will be determined from measurement of maternal circulating s-FLT-1, s-ENG-1 and placental growth factor concentrations.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 7, 2019)
Pre-eclampsia [ Time Frame: As in FACT: from 20+0 weeks of gestational age until 42 days postpartum (after delivery) ]
The association between all biomarkers analyzed in this study and risk of pre-eclampsia as determined though completion of FACT will be considered.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title FACT Biomarker Subgroup Analysis
Official Title Folic Acid Clinical Trial (FACT): Biomarker Subgroup Analysis
Brief 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.
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 Observational
Study Design Observational Model: Cohort
Time Perspective: Cross-Sectional
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Peripheral Whole Blood, Plasma, Serum
Sampling Method Probability Sample
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.

Condition 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

  • Other: 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.

Study Groups/Cohorts
  • 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.
    Intervention: Other: 4.0mg Folic Acid received through participation in FACT (NCT01355159)
  • FACT Placebo treatment group
    Consenting study participants who, through their participation in FACT (NCT01355159) are randomized to receive daily placebo supplementation during pregnancy.
    Intervention: Other: Placebo received through participation in FACT
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: June 7, 2019)
51
Original Actual Enrollment Same as current
Actual Study Completion Date September 2016
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria

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
Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Canada
Removed Location Countries  
 
Administrative Information
NCT Number NCT03981029
Other Study ID Numbers 2011649-01H
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Ottawa Hospital Research Institute
Study Sponsor Ottawa Hospital Research Institute
Collaborators Not Provided
Investigators Not Provided
PRS Account Ottawa Hospital Research Institute
Verification Date June 2019