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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01355159




Registration number
NCT01355159
Ethics application status
Date submitted
11/05/2011
Date registered
17/05/2011
Date last updated
7/07/2020

Titles & IDs
Public title
High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention
Scientific title
Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)
Secondary ID [1] 0 0
ISRCTN23781770
Secondary ID [2] 0 0
2009-107
Universal Trial Number (UTN)
Trial acronym
FACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pregnancy Complications 0 0
Preeclampsia 0 0
Condition category
Condition code
Reproductive Health and Childbirth 0 0 0 0
Fetal medicine and complications of pregnancy
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Folic Acid 4 mg
Treatment: Drugs - Placebo

Experimental: Folic Acid 4 mg - 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 Comparator: Placebo - Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo


Treatment: Drugs: Folic Acid 4 mg
Folic Acid 1.0 mg or placebo 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

Treatment: Drugs: Placebo
Placebo x 4 tablets will be taken daily by oral administration.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Preeclampsia - PE is defined as diastolic blood pressure =90 mmHg on two occasions =4 hours apart and proteinuria developed in women greater than 20+0 weeks of gestation. Proteinuria is defined as: urinary protein =300mg in 24 hour urine collection OR in the absence of 24 hour collection, =2+ dipstick proteinuria, OR random protein-creatinine ratio =30mg protein/mmol.
OR HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome defined as: Haemolysis (characteristic peripheral blood smear), Serum LDH = 600U/L, Serum AST = 70U/L, and Platelet count <100 x109/L
OR Superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20+0 weeks' gestation) with new proteinuria.
Timepoint [1] 0 0
Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
Secondary outcome [1] 0 0
Maternal Death - According to the World Health Organization, "A maternal death is defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.
Timepoint [1] 0 0
Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery)
Secondary outcome [2] 0 0
Spontaneous Abortion - Spontaneous abortion or miscarriage defined as death of a fetus <500g or <20 weeks of gestation
Timepoint [2] 0 0
Participants will be followed from randomization until 20+0 weeks of gestation
Secondary outcome [3] 0 0
Placenta Abruption - Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus.
Timepoint [3] 0 0
Participants will be followed from 20+0 weeks of gestation until delivery
Secondary outcome [4] 0 0
Premature Rupture of Membranes - Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.
Timepoint [4] 0 0
Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor
Secondary outcome [5] 0 0
Preterm Birth - Birth that occur earlier than 37+0 weeks of gestational age.
Timepoint [5] 0 0
Participants will be followed from 20+0 weeks to 36+6 weeks of gestation
Secondary outcome [6] 0 0
HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count) - Haemolysis (characteristic peripheral blood smear), Serum LDH >=600U/L, Serum AST >=70U/L, Platelet count <100 x109/L
Timepoint [6] 0 0
Participants will be followed from 20+0 weeks of gestation until delivery
Secondary outcome [7] 0 0
Severe Preeclampsia - Severe PE: Defined as PE with convulsion or HELLP or delivery <34 weeks.
Timepoint [7] 0 0
Participants will be followed from 20+0 weeks of gestation until delivery.
Secondary outcome [8] 0 0
Antenatal Inpatient Length of Stay - Length of inpatient stay before admission for delivery in days
Timepoint [8] 0 0
Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery
Secondary outcome [9] 0 0
Stillbirth - Fetal death defined as death of fetus of at least 500 grams birth weight or, if birth weight is unavailable, a gestational age of at least 20+0 weeks of gestation.
Timepoint [9] 0 0
Participants will be followed from 20+0 weeks of gestation up to delivery.
Secondary outcome [10] 0 0
Intrauterine Growth Restriction (<3rd Percentile) - Intrauterine growth restriction is defined as a birth weight less than the 3rd percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard.
Timepoint [10] 0 0
Participants will be followed from 20+0 weeks of gestation until delivery
Secondary outcome [11] 0 0
Intrauterine Growth Restriction (<10th Percentile) - Intrauterine growth restriction is defined as a birth weight less than the 10th percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard.
Timepoint [11] 0 0
Participants will be followed from 20+0 weeks of gestation until delivery
Secondary outcome [12] 0 0
Neonatal Death - Neonatal death defined as death of a baby that occurred during first 28 days of life.
Timepoint [12] 0 0
Participants will be followed from birth until 28 days of life
Secondary outcome [13] 0 0
Perinatal Mortality - The perinatal mortality is defined as the number of deaths (fetal deaths and neonatal deaths) of babies = 500 grams birth weight or, if birth weight is unavailable, a gestational age = 20+0 weeks, up to 28 completed days after birth.
Timepoint [13] 0 0
Participants will be followed from 20+0 weeks of gestation until 28 days of life.
Secondary outcome [14] 0 0
Retinopathy of Prematurity - Retinopathy of prematurity a retinopathy typically occurring in premature infants treated with high concentrations of oxygen, characterized by vascular dilatation, proliferation, tortuosity, edema, retinal detachment, and fibrous tissue behind the lens confirmed by retinal examination according to an International Committee for the Classification of Retinopathy of Prematurity.
Timepoint [14] 0 0
Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks
Secondary outcome [15] 0 0
Early Onset Sepsis - Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
Timepoint [15] 0 0
Infants born to the participants will be followed first 48 hours of life.
Secondary outcome [16] 0 0
Necrotising Enterocolitis - Necrotizing enterocolitis (NEC) according to modified Bell's criteria stage 2 or higher (grossly bloody stool, plus absent bowel sounds with or without abdominal tenderness and radiographic findings such as intestinal dilation, ileus, pneumatosis intestinalis), excluding isolated spontaneous intestinal perforations.
Timepoint [16] 0 0
Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary outcome [17] 0 0
Intraventricular Hemorrhage (IVH) - IVH Grade 1(Blood in germinal matrix)
IVH Grade 2 (Blood in germinal matrix and extending into the ventricles)
IVH Grade 3 (Ventricular enlargement)
IVH Grade 4 (Intraparenchymal lesion)
Timepoint [17] 0 0
Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks
Secondary outcome [18] 0 0
Ventilation - Ventilatory support after initial resuscitation, with/without intubation.
Timepoint [18] 0 0
Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary outcome [19] 0 0
Need for Oxygen at 28 Days
Timepoint [19] 0 0
Infants to the participants will be followed for 28 days after birth.
Secondary outcome [20] 0 0
Composite Severe Adverse Fetal/Neonatal Outcome - Composite outcome included any of retinopathy of prematurity, periventricular leukomacia, early onset sepsis, necrotizing enterocolitis, intraventricular haemorrhage, ventilation. Need for O2at 28 days, NICU admission
Timepoint [20] 0 0
Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth
Secondary outcome [21] 0 0
Length of Stay in 'High Level' Neonatal Care Unit
Timepoint [21] 0 0
Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary outcome [22] 0 0
Neonatal Death - Neonatal death defined as death of the infant occurred before 28 days of life
Timepoint [22] 0 0
Infants to the participants will be followed for 28 days after birth.
Secondary outcome [23] 0 0
Periventricular Leukomalacia - One of the two outcomes used to measure neonatal morbidity.
Timepoint [23] 0 0
Infants to the participants were followed for 28 days after birth.
Secondary outcome [24] 0 0
Neonatal Intensive Care Unit (NICU) Admission - This outcome measured whether or not the infant was admitted into the NICU.
Timepoint [24] 0 0
Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key 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

6. Known hypersensitivity to folic acid

7. Multiple Pregnancy (triplets or more)

8. Participation in this study in a previous pregnancy

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Nepean - Penrith
Recruitment hospital [2] 0 0
Townsville - Douglas
Recruitment hospital [3] 0 0
Ipswich - Ipswich
Recruitment hospital [4] 0 0
Adelaide - North Adelaide
Recruitment hospital [5] 0 0
Royal Women's Hospital - Parkville
Recruitment hospital [6] 0 0
Sunshine - St Albans
Recruitment postcode(s) [1] 0 0
2750 - Penrith
Recruitment postcode(s) [2] 0 0
4814 - Douglas
Recruitment postcode(s) [3] 0 0
4305 - Ipswich
Recruitment postcode(s) [4] 0 0
5006 - North Adelaide
Recruitment postcode(s) [5] 0 0
3052 - Parkville
Recruitment postcode(s) [6] 0 0
3021 - St Albans
Recruitment outside Australia
Country [1] 0 0
Argentina
State/province [1] 0 0
Santa Fe
Country [2] 0 0
Argentina
State/province [2] 0 0
Buenos Aires
Country [3] 0 0
Canada
State/province [3] 0 0
Alberta
Country [4] 0 0
Canada
State/province [4] 0 0
British Columbia
Country [5] 0 0
Canada
State/province [5] 0 0
New Brunswick
Country [6] 0 0
Canada
State/province [6] 0 0
Newfoundland and Labrador
Country [7] 0 0
Canada
State/province [7] 0 0
Ontario
Country [8] 0 0
Canada
State/province [8] 0 0
Quebec
Country [9] 0 0
Canada
State/province [9] 0 0
Saskatchewan
Country [10] 0 0
Jamaica
State/province [10] 0 0
Kingston 7
Country [11] 0 0
Jamaica
State/province [11] 0 0
Kingston
Country [12] 0 0
United Kingdom
State/province [12] 0 0
Cambridgeshire
Country [13] 0 0
United Kingdom
State/province [13] 0 0
Cheshire
Country [14] 0 0
United Kingdom
State/province [14] 0 0
County Durham
Country [15] 0 0
United Kingdom
State/province [15] 0 0
Cumbria
Country [16] 0 0
United Kingdom
State/province [16] 0 0
Lancashire
Country [17] 0 0
United Kingdom
State/province [17] 0 0
Lincolnshire
Country [18] 0 0
United Kingdom
State/province [18] 0 0
Merseyside
Country [19] 0 0
United Kingdom
State/province [19] 0 0
Middlesex
Country [20] 0 0
United Kingdom
State/province [20] 0 0
Newcastle Upon Tyne
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Northumberland
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Tooting
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Tyne And Wear
Country [24] 0 0
United Kingdom
State/province [24] 0 0
West Midlands
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Blackburn
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Burnley
Country [27] 0 0
United Kingdom
State/province [27] 0 0
Crumpsall
Country [28] 0 0
United Kingdom
State/province [28] 0 0
London
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Middlesbrough
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Newcastle upon Tyne
Country [31] 0 0
United Kingdom
State/province [31] 0 0
North Shields
Country [32] 0 0
United Kingdom
State/province [32] 0 0
Norwich
Country [33] 0 0
United Kingdom
State/province [33] 0 0
Nottingham
Country [34] 0 0
United Kingdom
State/province [34] 0 0
Oldham
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Stockton
Country [36] 0 0
United Kingdom
State/province [36] 0 0
Sunderland
Country [37] 0 0
United Kingdom
State/province [37] 0 0
Uxbridge

Funding & Sponsors
Primary sponsor type
Other
Name
Ottawa Hospital Research Institute
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Canadian Institutes of Health Research (CIHR)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
To determine the efficacy of high dose folic acid supplementation for prevention of
preeclampsia in women with at least one risk factor: pre-existing hypertension, pre-pregnancy
diabetes (type 1 or 2), twin pregnancy, preeclampsia in a previous pregnancy, or body mass
index =35. It was hypothesized that high dose (4.0 mg per day) supplementation starting in
early pregnancy and continued throughout the entire pregnancy will lower the incidence of
preeclampsia in pregnant women at high risk of developing preeclampsia.
Trial website
https://clinicaltrials.gov/show/NCT01355159
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Shi Wu Wen, PhD
Address 0 0
Ottawa Hospital Research Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications