- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01244347
Folic Acid Dosage and Malformations Reduction
Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations
In 1991 the Medical Research Council Vitamin Study Group and in 1992 the Hungarian randomised clinical trial have shown conclusively that the risk of neural tube defects can be reduced substantially by taking folic acid during the peri-conceptional period. At present there is enough evidence to support the hypothesis that folic acid supplementation can reduce the risk of all congenital malformations or of a specific and selected group of them, namely: neural tube defects, oral clefts, cardiac defects, urinary tract anomalies except hypospadias, limb reduction defects, omphalocele, anal atresia and trisomy 21.
The hypothesis that a higher intake of folic acid is related to an higher risk reduction of neural tube defects and of other congenital malformations is the main rationale for the present study.
The present study is a randomized, double-blind, controlled trial evaluating whether supplementation with folic acid at high dose (4 mg/day) reduces the overall risk of major congenital malformations in the population more than the standard recommended dose (0.4 mg/day). At the enrolment visit all the eligible women will be interviewed to assess sociodemographic, life style and health status. After randomization, women will be interviewed every 4 months to evaluate pregnancy status. Women who have a pregnancy diagnosis during the study period will be interviewed by telephone at the expected 16, 24 and 40 weeks of gestation to evaluate the pregnancy outcome. The health status of live births will be evaluated at the child's age of 1 month, 3 months and 1 year.
The primary aim of this project is conducting a study to assess the effect of folic acid periconceptional supplementation of 4 mg/day compared to the 0.4 mg/day standard dose on reducing the occurrence of all congenital malformations. Secondary aims of this study include comparing severity of CMs in offspring of trial mothers, rates of "selected congenital malformations", rates of twinning, miscarriages, recurrent abortions, small-for-gestational age, preeclampsia and abruptio placentae. The sample size is not easy to be computed because lacking robust estimate of the size effect of the treatment. Three hypotheses of a size effect of 45%, 26% and 13% were considered. A sample size of outcomes (and women) respectively of 2,006 (5,015), 8,510 (21,275) and 30,126 (75,315) is needed. Since the sample size needed to evaluate different scenarios is large, the present study is also the pilot study to promote an international prospective meta-analysis.
Study Overview
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Locations
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-
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Milan, Italy, 20100
- Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
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Padova, Italy, 35100
- Azienda Ospedaliera di Padova
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Padova, Italy, 35132
- Family Health Centre
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Verona, Italy, 37134
- Policlinico G.B. Rossi
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Verona, Italy, 37126
- Ospedale Civile Maggiore
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Verona, Italy, 37122
- Family Health Centre
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Verona, Italy, 37126
- General Practice
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Verona, Italy, 37129
- General Practice
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Verona, Italy, 37131
- Family Health Centre
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Rovigo
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Adria, Rovigo, Italy, 45011
- Ospedale di Adria
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Trecenta, Rovigo, Italy, 45027
- Ospedale San Luca
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Treviso
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Conegliano, Treviso, Italy, 31015
- Ospedale di Conegliano
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Montebelluna, Treviso, Italy, 31044
- Family Health Centre
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Oderzo, Treviso, Italy, 31046
- Family Health Practice
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Villorba, Treviso, Italy, 31020
- Family Health Practice
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VI
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Vicenza, VI, Italy, 36100
- Ospedale di Vicenza
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Varese
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Gallarate, Varese, Italy, 21013
- Ospedale Sant'Antonio Abate
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Venezia
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Camponogara, Venezia, Italy, 30010
- Family Health Practice
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Martellago, Venezia, Italy, 30030
- Family Health Centre
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Mira, Venezia, Italy, 30034
- Family Health Practice
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Noale, Venezia, Italy, 30033
- Family Health Centre
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San Pietro di Stra, Venezia, Italy, 30031
- Family Health Centre
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Vogonovo, Venezia, Italy, 30030
- Family Health Centre
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Verona
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Bussolengo, Verona, Italy, 37012
- Ospedale di Bussolengo
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Legnago, Verona, Italy, 37045
- Ospedale di Legnago
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San Bonifacio, Verona, Italy, 37047
- Ospedale di San Bonifacio
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Vicenza
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Bassano, Vicenza, Italy, 36061
- Family Health Centre
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Bassano, Vicenza, Italy, 36061
- Ospedale San Bassiano
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Dueville, Vicenza, Italy, 36031
- General Practice
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Malo, Vicenza, Italy, 36034
- General Practice
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Schio, Vicenza, Italy, 36014
- General Practice
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Sovizzo, Vicenza, Italy, 36050
- General Practice
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Thiene, Vicenza, Italy, 36016
- Ospedale Boldrini
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Valdagno, Vicenza, Italy, 36078
- Ospedale di Valdagno
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- age between 18 and 44 years
- women who intend to become pregnant (not excluded women
Exclusion Criteria:
- pregnant women
- women planning to move to an area where the study is not ongoing
- women who do not understand and speak Italian
- women who do not have a phone
- women affected by epilepsy, even not assuming anticonvulsivant drugs
- women affected by diabetes
- women who previously had a tumour or a disease relevant for the study (Crohn disease, rheumatoid arthritis, ulcerative colitis)
- women who recently assumed antifolates, like methotrexate
- women who currently abuse or previously abused alcohol
- obese women
- vegetarian women
- women who had a previous pregnancy with neural tube defect (NTD) or any other congenital structural defect
- women or partners with NTD, or one of their relatives with an NTD
- women with positive family history for breast or colorectal cancer
- women with positive family or personal history of hereditary syndrome like adenomatous polyposis, or hereditary nonpolyposis colorectal cancer
- women allergic to folic acid
- women presenting contraindications to folic acid
- women affected by megaloblastic anaemia
- assuming folic acid at defined doses for conditions other than those already mentioned
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: folic acid 4 mg
|
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Active Comparator: folic acid 0.4 mg
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
number of congenital malformations
Time Frame: 112 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 28 weeks to all possible outcomes, plus 52 weeks of baby observation.
|
112 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
rate of selected congenital malformations
Time Frame: 112 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 28 weeks to all possible outcomes, plus 52 weeks of baby observation.
|
112 weeks
|
Miscarriages and recurrent abortions
Time Frame: 47 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 15 weeks as a mean of time from conception to different clinical conditions related to miscarriage.
|
47 weeks
|
pre-eclampsia
Time Frame: 60 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 28 weeks to the occurrence of pre-eclampsia.
|
60 weeks
|
abruptio placentae
Time Frame: 34 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 34 weeks to the occurrence of abruptio placentae.
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34 weeks
|
intrauterine growth restriction
Time Frame: 31 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 31 weeks to the occurrence of intrauterine growth restriction.
|
31 weeks
|
pre-term delivery
Time Frame: 30 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 30 weeks to the occurrence of pre-term delivery.
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30 weeks
|
multiple births
Time Frame: 24 weeks
|
The time frame was computed as an average of 32 weeks before conception, plus an average of 24 weeks to the possible diagnosis of twinnings or delivery.
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24 weeks
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Renata Bortolus, MD, Azienda Ospedaliera Universitaria integrata Verona
Publications and helpful links
General Publications
- Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832-5. doi: 10.1056/NEJM199212243272602.
- Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131-7.
- Badovinac RL, Werler MM, Williams PL, Kelsey KT, Hayes C. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2007 Jan;79(1):8-15. doi: 10.1002/bdra.20315.
- Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Correa A. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. 1999 Nov 11;341(20):1485-90. doi: 10.1056/NEJM199911113412001. Erratum In: N Engl J Med. 1999 Dec 9;341(24):1864.
- Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet C Semin Med Genet. 2004 Feb 15;125C(1):12-21. doi: 10.1002/ajmg.c.30004.
- Catov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Association of periconceptional multivitamin use and risk of preterm or small-for-gestational-age births. Am J Epidemiol. 2007 Aug 1;166(3):296-303. doi: 10.1093/aje/kwm071. Epub 2007 May 11.
- Ingrid Goh Y, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-689. doi: 10.1016/S1701-2163(16)32227-7.
- Bortolus R, Blom F, Filippini F, van Poppel MN, Leoncini E, de Smit DJ, Benetollo PP, Cornel MC, de Walle HE, Mastroiacovo P; Italian and Dutch folic acid trial study groups. Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands. BMC Pregnancy Childbirth. 2014 May 13;14:166. doi: 10.1186/1471-2393-14-166.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- FARM 6KWTCT
- 2008-004334-25 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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