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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/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
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Scientific title
Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)
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Secondary ID [1]
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ISRCTN23781770
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Secondary ID [2]
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2009-107
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Universal Trial Number (UTN)
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Trial acronym
FACT
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pregnancy Complications
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Preeclampsia
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Condition category
Condition code
Reproductive Health and Childbirth
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Fetal medicine and complications of pregnancy
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Cardiovascular
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0
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Hypertension
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Preeclampsia
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Assessment method [1]
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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.
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Timepoint [1]
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Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
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Secondary outcome [1]
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Maternal Death
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Assessment method [1]
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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.
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Timepoint [1]
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Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery)
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Secondary outcome [2]
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Spontaneous Abortion
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Assessment method [2]
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Spontaneous abortion or miscarriage defined as death of a fetus \<500g or \<20 weeks of gestation
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Timepoint [2]
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Participants will be followed from randomization until 20+0 weeks of gestation
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Secondary outcome [3]
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Placenta Abruption
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Assessment method [3]
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Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus.
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Timepoint [3]
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Participants will be followed from 20+0 weeks of gestation until delivery
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Secondary outcome [4]
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Premature Rupture of Membranes
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Assessment method [4]
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Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.
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Timepoint [4]
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Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor
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Secondary outcome [5]
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Preterm Birth
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Assessment method [5]
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Birth that occur earlier than 37+0 weeks of gestational age.
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Timepoint [5]
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Participants will be followed from 20+0 weeks to 36+6 weeks of gestation
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Secondary outcome [6]
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HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count)
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Assessment method [6]
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Haemolysis (characteristic peripheral blood smear), Serum LDH \>=600U/L, Serum AST \>=70U/L, Platelet count \<100 x109/L
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Timepoint [6]
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Participants will be followed from 20+0 weeks of gestation until delivery
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Secondary outcome [7]
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Severe Preeclampsia
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Assessment method [7]
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Severe PE: Defined as PE with convulsion or HELLP or delivery \<34 weeks.
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Timepoint [7]
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Participants will be followed from 20+0 weeks of gestation until delivery.
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Secondary outcome [8]
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Antenatal Inpatient Length of Stay
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Assessment method [8]
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Length of inpatient stay before admission for delivery in days
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Timepoint [8]
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Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery
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Secondary outcome [9]
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Stillbirth
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Assessment method [9]
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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.
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Timepoint [9]
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Participants will be followed from 20+0 weeks of gestation up to delivery.
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Secondary outcome [10]
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Intrauterine Growth Restriction (<3rd Percentile)
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Assessment method [10]
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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.
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Timepoint [10]
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Participants will be followed from 20+0 weeks of gestation until delivery
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Secondary outcome [11]
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Intrauterine Growth Restriction (<10th Percentile)
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Assessment method [11]
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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.
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Timepoint [11]
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Participants will be followed from 20+0 weeks of gestation until delivery
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Secondary outcome [12]
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Neonatal Death
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Assessment method [12]
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Neonatal death defined as death of a baby that occurred during first 28 days of life.
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Timepoint [12]
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Participants will be followed from birth until 28 days of life
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Secondary outcome [13]
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Perinatal Mortality
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Assessment method [13]
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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.
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Timepoint [13]
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Participants will be followed from 20+0 weeks of gestation until 28 days of life.
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Secondary outcome [14]
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Retinopathy of Prematurity
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Assessment method [14]
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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.
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Timepoint [14]
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Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks
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Secondary outcome [15]
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Early Onset Sepsis
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Assessment method [15]
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Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
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Timepoint [15]
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Infants born to the participants will be followed first 48 hours of life.
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Secondary outcome [16]
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Necrotising Enterocolitis
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Assessment method [16]
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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.
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Timepoint [16]
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Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
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Secondary outcome [17]
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Intraventricular Hemorrhage (IVH)
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Assessment method [17]
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* 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)
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Timepoint [17]
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Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks
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Secondary outcome [18]
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Ventilation
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Assessment method [18]
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Ventilatory support after initial resuscitation, with/without intubation.
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Timepoint [18]
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Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
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Secondary outcome [19]
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Need for Oxygen at 28 Days
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Assessment method [19]
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Timepoint [19]
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Infants to the participants will be followed for 28 days after birth.
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Secondary outcome [20]
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Composite Severe Adverse Fetal/Neonatal Outcome
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Assessment method [20]
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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
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Timepoint [20]
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Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth
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Secondary outcome [21]
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Length of Stay in 'High Level' Neonatal Care Unit
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Assessment method [21]
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Timepoint [21]
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Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
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Secondary outcome [22]
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Neonatal Death
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Assessment method [22]
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Neonatal death defined as death of the infant occurred before 28 days of life
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Timepoint [22]
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Infants to the participants will be followed for 28 days after birth.
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Secondary outcome [23]
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Periventricular Leukomalacia
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Assessment method [23]
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One of the two outcomes used to measure neonatal morbidity.
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Timepoint [23]
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Infants to the participants were followed for 28 days after birth.
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Secondary outcome [24]
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Neonatal Intensive Care Unit (NICU) Admission
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Assessment method [24]
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This outcome measured whether or not the infant was admitted into the NICU.
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Timepoint [24]
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Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
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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)
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/04/2011
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/09/2016
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Sample size
Target
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Accrual to date
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Final
2464
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
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Recruitment hospital [1]
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Nepean - Penrith
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Recruitment hospital [2]
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Townsville - Douglas
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Recruitment hospital [3]
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Ipswich - Ipswich
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Recruitment hospital [4]
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Adelaide - North Adelaide
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Recruitment hospital [5]
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Royal Women's Hospital - Parkville
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Recruitment hospital [6]
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Sunshine - St Albans
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Recruitment postcode(s) [1]
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2750 - Penrith
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Recruitment postcode(s) [2]
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4814 - Douglas
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Recruitment postcode(s) [3]
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4305 - Ipswich
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Recruitment postcode(s) [4]
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5006 - North Adelaide
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Recruitment postcode(s) [5]
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3052 - Parkville
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Recruitment postcode(s) [6]
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3021 - St Albans
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Recruitment outside Australia
Country [1]
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Argentina
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Santa Fe
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Argentina
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Buenos Aires
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Canada
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Alberta
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Canada
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British Columbia
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Canada
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New Brunswick
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Canada
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Newfoundland and Labrador
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Country [7]
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Canada
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Ontario
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Canada
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Quebec
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Canada
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Saskatchewan
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Jamaica
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Kingston 7
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Jamaica
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Kingston
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United Kingdom
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Cambridgeshire
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United Kingdom
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Cheshire
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United Kingdom
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County Durham
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United Kingdom
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Cumbria
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United Kingdom
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Lancashire
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United Kingdom
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Lincolnshire
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United Kingdom
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Merseyside
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United Kingdom
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Middlesex
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United Kingdom
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Newcastle Upon Tyne
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United Kingdom
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Northumberland
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United Kingdom
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Tooting
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United Kingdom
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Tyne And Wear
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United Kingdom
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West Midlands
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United Kingdom
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Blackburn
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United Kingdom
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Burnley
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United Kingdom
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Crumpsall
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United Kingdom
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London
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United Kingdom
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Middlesbrough
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United Kingdom
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Newcastle upon Tyne
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United Kingdom
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North Shields
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United Kingdom
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Norwich
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United Kingdom
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Nottingham
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United Kingdom
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Oldham
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United Kingdom
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Stockton
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United Kingdom
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Sunderland
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United Kingdom
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State/province [37]
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Uxbridge
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Funding & Sponsors
Primary sponsor type
Other
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Name
Ottawa Hospital Research Institute
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Address
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Other collaborator category [1]
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Government body
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Name [1]
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Canadian Institutes of Health Research (CIHR)
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Address [1]
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Ethics approval
Ethics application status
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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.
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Trial website
https://clinicaltrials.gov/study/NCT01355159
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Trial related presentations / publications
Rose EG, Murphy MSQ, Erwin E, Muldoon KA, Harvey ALJ, Rennicks White R, MacFarlane AJ, Wen SW, Walker MC. Gestational Folate and Folic Acid Intake among Women in Canada at Higher Risk of Pre-Eclampsia. J Nutr. 2021 Jul 1;151(7):1976-1982. doi: 10.1093/jn/nxab063. Corsi DJ, Gaudet LM, El-Chaar D, White RR, Rybak N, Harvey A, Muldoon K, Wen SW, Walker M. Effect of high-dose folic acid supplementation on the prevention of preeclampsia in twin pregnancy. J Matern Fetal Neonatal Med. 2022 Feb;35(3):503-508. doi: 10.1080/14767058.2020.1725882. Epub 2020 Feb 18. 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, 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. Epub 2013 Nov 18.
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Public notes
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Contacts
Principal investigator
Name
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Shi Wu Wen, PhD
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Address
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Ottawa Hospital Research Institute
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT01355159
Download to PDF