Condition category
Pregnancy and Childbirth
Date applied
14/01/2010
Date assigned
31/03/2010
Last edited
08/12/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Pre-eclampsia (PE) is a complication of pregnancy that affects at least 5% of all pregnancies worldwide. Early signs of pre-eclampsia include having high blood pressure and protein in your urine. It has profound health implications to women and infants in both the short and long term, and has significant economic consequences on society. Recent research has shown that women who have PE during pregnancy are more likely to be at risk for future cardiovascular events later in life. Presently, the only effective treatment for PE is for a woman to deliver her unborn baby. Because delivery may be required earlier than the expected date, PE is also one of the leading causes of preterm birth, which puts these babies at increased risk of serious health problems. A successful preventative therapy, such as folic acid supplementation, could have a significant impact on the disease burden in this population. Studies on folic acid supplementation suggest that a high dose of folic acid may be needed for the prevention of PE. The aim of this study is to find out whether high-dose supplementation of folic acid throughout pregnancy is an effective preventative strategy in women who are at high risk of developing PE.

Who can participate?
Pregnant women (8 0/7 and 16 6/7 weeks of gestation) aged 18 or over, taking 1.1 mg or less of folic acid supplementation who fulfil at least one of the following risk factors for PE:
1. Pre-existing high blood pressure
2. Pre-pregnancy diabetes
3. Twin pregnancy
4. History of PE in a previous pregnancy
5. BMI 35 kg/m2 or over within 3 months prior to current pregnancy or up to joining the study

What does the study involve?
Eligible women will be randomly allocated to take four tablets of folic acid daily or to take placebo (dummy) tablets. There are four visits during the study and one telephone call 6 weeks after delivery.

What are the possible benefits and risks of participating?
Folic acid is relatively nontoxic in humans; however, in rare instances it can cause allergic reactions or hypersensitivity including redness of the skin, skin rash and itching. While there is no guarantee that women will benefit from the study, the knowledge gained from this study may help other pregnant women at high risk for developing PE in the future.

Where is the study run from?
The study is run from Ottawa Hospital Research Institute (Canada) and is recruiting women from Canada, Australia, Argentina, Jamaica and the United Kingdom.

When is the study starting and how long is it expected to run for?
The study started in March 2011 and will run until December 2015.

Who is funding the study?
Canadian Institute of Health Research (CIHR).

Who is the main contact?
Dr Shi Wu Wen
swwen@ohri.ca

Trial website

Contact information

Type

Scientific

Primary contact

Dr Shi Wu Wen

ORCID ID

Contact details

501 Smyth Road
Ottawa
K1H 8L6
Canada
+1 613 739-6655
swwen@ohri.ca

Additional identifiers

EudraCT number

ClinicalTrials.gov number

NCT01355159

Protocol/serial number

MCT-98030

Study information

Scientific title

Effect of folic acid supplementation in pregnancy on preeclampsia - Folic Acid Clinical Trial

Acronym

FACT

Study hypothesis

High dose (4.0 mg per day) supplementation for pregnant women at high risk of developing preeclampsia starting in early pregnancy and continued throughout the entire pregnancy lower the incidence of preeclampsia.

Ethics approval

Ottawa Hospital Research Ethics Board, 14/10/2010

Study design

Randomised double-blind placebo-controlled phase III international multicentre trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Prevention of pre-eclampsia

Intervention

Current interventions as of 13/03/2012:
Drug name: Folic Acid /Placebo
Dosage form: Tablet
Dosage: 4 mg
Frequency: 4 tablets of 1 mg folic acid daily

Study Treatment will be administered from randomization until delivery.

Follow up visits:
Visit 2 at 24 0/7 - 26 6/7 weeks in pregnancy
Visit 3 at 34 0/7 - 36 6/7 weeks in pregnancy
Visit 4 Postpartum
Visit 5 Telephone interview at 42 days (±3 days) post-partum

Secondary investigator:
Dr. Mark Walker
(Same address as Dr. Shi Wu Wen in contact details below)


Previous interventions:
Drug name: Folic Acid /Placebo
Dosage form: Tablet
Dosage: 4 mg
Frequency: 4 tablets of 1 mg folic acid daily

Study Treatment will be administered from randomization until delivery.

Follow up visits:
Visit 2 at 24 0/7 - 26 6/7 weeks in pregnancy
Visit 3 at 34 0/7 - 36 6/7 weeks in pregnancy
Visit 4 Postpartum (within 8 - 24 hours post-partum)
Visit 5 Telephone interview at 42 days (±3 days) post-partum

Secondary investigator:
Dr. Mark Walker
(Same address as Dr. Shi Wu Wen in contact details below)

Intervention type

Drug

Phase

Phase III

Drug names

Folic acid

Primary outcome measures

Preeclampsia

Secondary outcome measures

Current secondary outcome measures:
1. Maternal death
2. Severe preeclampsia
3. Placenta abruptio
4. Preterm delivery
5. Premature rupture of membranes
6. Antenatal inpatient length of stay
7. Intrauterine growth restriction
8. Spontaneous abortion

9. Perinatal mortality:
9.1. Stillbirth
9.2 Neonatal death

10. Neonatal morbidity such as:
10.1Retinopathy of prematurity
10.2 Periventricular leukomalacia
10.3 Early onset sepsis
10.4 Necrotising enterocolitis
10.5 Intraventricular haemorrhage
10.6 Ventilation
10.7 Need for O2 at 28 days

11. Length of stay in neonatal Intensive Care Unit (NICU)

Previous secondary outcome measures:
1. Maternal death
2. Severe PE (PE with convulsion or haemolytic anaemia, elevated liver enzymes and low platelet count [HELLP] or delivery less than 32 weeks)
3. Preterm delivery, premature rupture of membranes, antenatal inpatient days, intrauterine growth restriction (less than 3rd centile)
4. Perinatal mortality, spontaneous abortion, neonatal morbidity, retinopathy of prematurity, leukomalacia, thrombocytopenia, neutropenia, early onset sepsis, necrotising enterocolitis, intraventricular haemorrhage, ventilation, need for O2 at 28 days, length of stay in neonatal Intensive Care Unit (NICU)

Overall trial start date

31/03/2011

Overall trial end date

30/07/2016

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 28/04/2014:
1. Capability of subject to comprehend and comply with study requirements
2. At least 18 years of age at time of consent
3. Subject is taking less than or equal to 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 0/7 and 16 6/7 weeks of pregnancy
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):
7.1 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)
7.2 Pre-pregnancy diabetes (documented evidence of Type I or Type II DM)
7.3 Twin pregnancy
7.4 Documented evidence of history of PE in a previous pregnancy
7.5 BMI > 35 kg/m2 within 3 months prior to this pregnancy or up to randomization of this pregnancy (documented evidence of height and weight to calculate BMI is required)

Inclusion criteria from 13/03/2012 to 28/04/2014:
1. Capability of subject to comprehend and comply with study requirements
2. At least 18 years of age at time of consent
3. Subject is taking less than or equal to 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 0/7 and 16 6/7 weeks of pregnancy
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):
7.1 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)
7.2 Pre-pregnancy diabetes (documented evidence of Type I or Type II DM)
7.3 Twin pregnancy
7.4 Documented evidence of history of PE in a previous pregnancy
7.5 BMI > 35 kg/m2 within 3 months prior to this pregnancy or during the first trimester of this pregnancy (documented evidence of height and weight to calculate BMI is required)

Inclusion criteria from 14/07/2011 to 13/03/2012:
1. Capability of subject to comprehend and comply with study requirements
2. At least 18 years of age at time of consent
3. Subject is taking less than or equal to 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 0/7 and 16 6/7 weeks of pregnancy
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):
7.1 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)
7.2 Pre-pregnancy diabetes (documented evidence of Type I or Type II DM)
7.3 Twin pregnancy
7.4 Documented evidence of history of PE in a previous pregnancy
7.5 BMI > 35 kg/m2 within 3 months prior to this pregnancy or during the first trimester of this pregnancy (documented evidence of height and weight to calculate BMI is required)

Original inclusion criteria until 14/07/2011:
1. Women at least 18 years of age at time of consent
2. Taking less than or equal to 1 mg of folic acid at the time of randomisation
3. Between 8 and 16 weeks of pregnancy. Gestational age of patients will be based on the first day of the last menstrual period and confirmed by ultrasound examination completed between 80/7 and 166/7 weeks of pregnancy.
4. Pregnant women with body mass index (BMI) less than 40 kg/m^2 prior to her pregnancy or prior to her first trimester. Previous BMI (height and weight) record or measurement is required.
5. Pregnant subjects (nulliparous, primaparous or multiparous) must fulfill at least one of the following identified risk factors for pre-eclampsia (PE)
6. Pre-pregnancy or current chronic hypertension (or diastolic blood pressure greater than or equal to 90 mmHg before 20 gestational weeks or use of antihypertensive medication)
7. Pre-pregnancy or current diabetes (insulin-dependent or use of hypoglycaemic agents)
8. History of PE in the previous pregnancy

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

3,656

Participant exclusion criteria

Current exclusion criteria as of 14/07/2011:
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:
3.1 Renal disease with altered renal function
3.2 Epilepsy
3.3 Cancer, or
3.4 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 history or presence of:
5.1 Alcohol abuse (≥ 2 drinks per day) or alcohol dependence
5.2 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

Previous exclusion criteria:
1. Known history or presence of any clinically significant disease or condition, as determine by the Principal Investigator which he/she believes would be a contraindication to folic acid supplementation of up to 5 mg daily for the pregnancy duration
2. Women who have known abnormalities (e.g. hydatidiform mole) or known foetal chromosomal or major malformations in the current pregnancy
3. Women who have a history of medical complications, including:
3.1. Untreated hypo/hyper thyroidism
3.2. Renal disease with altered renal function
3.3. Epilepsy
3.4. Any collagen disease such as lupus erythromatosus and scleroderma
3.5. Active and chronic liver disease (hepatitis)
3.6. Cancer
3.7. Use of folic acid antagonists such as valproic acid
4. Threatened abortion. Women with a previous bleeding in the first trimester, can be included if the site documents a viable foetus at the time of recruitment through ultrasound.
5. Women who are using illicit drug or alcohol abuse (greater than or equal to 2 drinks per day) during current pregnancy
6. Known history or presence of:
6.1. Alcoholism
6.2. Drug dependence and/or substance abuse
6.3. Hypersensitivity or idiosyncratic reaction to folic acid
7. Previously been enrolled in this study

Recruitment start date

31/03/2011

Recruitment end date

31/12/2015

Locations

Countries of recruitment

Argentina, Australia, Canada, Jamaica, United Kingdom

Trial participating centre

501 Smyth Road
Ottawa
K1H 8L6
Canada

Sponsor information

Organisation

Ottawa Hospital Research Institute (OHRI) (Canada)

Sponsor details

725 Parkdale Avenue
Ottawa
K1Y 4E9
Canada
+1 613 737-8899 ext. 71895
rhanlon@ohri.ca

Sponsor type

Research organisation

Website

http://www.ohri.ca

Funders

Funder type

Research organisation

Funder name

Canadian Institutes of Health Research (CIHR) (Canada) - http://www.cihr-irsc.gc.ca (ref: MCT-98030)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2013 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/24349782

Publication citations

  1. Protocol

    Wen SW, Champagne J, Rennicks White R, Coyle D, Fraser W, Smith G, Fergusson D, Walker MC, Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study., J Pregnancy, 2013, 2013, 294312, doi: 10.1155/2013/294312.

Additional files

Editorial Notes

08/12/2016: The overall trial end date has been updated from 31/12/2015 to 30/07/2016. 12/04/2010: This record was updated to reflect the new acronym given to this trial for ease of identification. The previous acronym, 'FACTOH10-01', has been removed. 14/07/2011: Various updates have been made to this trial. These can be found under this date in the relevant fields below: 1. The public and scientific titles have been updated. The previous titles were 'Effect of folic acid supplementation in pregnancy on pre-eclampsia - Folic Acid Clinical Trial (FACT)' and 'Randomised, double-blind, placebo-controlled, phase III, international multicentre study in 3,656 pregnant subjects with a dose of 4.0 mg folic acid daily' respectively. 2. The start date has been updated from 02/08/2010 to 31/03/2011. 29/04/2014: The following changes were made to the trial record: 1. Countries of recruitment: Israel, Netherlands and New Zealand were removed and Jamaica was added 2. The anticipated end date was changed from 31/12/2014 to 31/12/2015