Folic Acid Dosage and Malformations Reduction

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
International Centre of Birth Defects
Information provided by:
Azienda Ospedaliera Universitaria Integrata Verona
ClinicalTrials.gov Identifier:
NCT01244347
First received: October 11, 2010
Last updated: January 13, 2015
Last verified: January 2015
  Purpose

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.


Condition Intervention Phase
Congenital Malformations
Drug: folic acid
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations

Resource links provided by NLM:


Further study details as provided by Azienda Ospedaliera Universitaria Integrata Verona:

Primary Outcome Measures:
  • number of congenital malformations [ Time Frame: 112 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • rate of selected congenital malformations [ Time Frame: 112 weeks ] [ Designated as safety issue: No ]
    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.

  • Miscarriages and recurrent abortions [ Time Frame: 47 weeks ] [ Designated as safety issue: No ]
    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.

  • pre-eclampsia [ Time Frame: 60 weeks ] [ Designated as safety issue: No ]
    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.

  • abruptio placentae [ Time Frame: 34 weeks ] [ Designated as safety issue: No ]
    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.

  • intrauterine growth restriction [ Time Frame: 31 weeks ] [ Designated as safety issue: No ]
    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.

  • pre-term delivery [ Time Frame: 30 weeks ] [ Designated as safety issue: No ]
    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.

  • multiple births [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 5000
Study Start Date: July 2009
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: folic acid 4 mg Drug: folic acid
Active Comparator: folic acid 0.4 mg Drug: folic acid

  Eligibility

Ages Eligible for Study:   18 Years to 44 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01244347

Locations
Italy
Ospedale di Adria
Adria, Rovigo, Italy, 45011
Ospedale San Luca
Trecenta, Rovigo, Italy, 45027
Ospedale di Conegliano
Conegliano, Treviso, Italy, 31015
Family Health Centre
Montebelluna, Treviso, Italy, 31044
Family Health Practice
Oderzo, Treviso, Italy, 31046
Family Health Practice
Villorba, Treviso, Italy, 31020
Ospedale Sant'Antonio Abate
Gallarate, Varese, Italy, 21013
Family Health Practice
Camponogara, Venezia, Italy, 30010
Family Health Centre
Martellago, Venezia, Italy, 30030
Family Health Practice
Mira, Venezia, Italy, 30034
Family Health Centre
Noale, Venezia, Italy, 30033
Family Health Centre
San Pietro di Stra, Venezia, Italy, 30031
Family Health Centre
Vogonovo, Venezia, Italy, 30030
Ospedale di Bussolengo
Bussolengo, Verona, Italy, 37012
Ospedale di Legnago
Legnago, Verona, Italy, 37045
Ospedale di San Bonifacio
San Bonifacio, Verona, Italy, 37047
Family Health Centre
Bassano, Vicenza, Italy, 36061
Ospedale San Bassiano
Bassano, Vicenza, Italy, 36061
General Practice
Dueville, Vicenza, Italy, 36031
General Practice
Malo, Vicenza, Italy, 36034
General Practice
Schio, Vicenza, Italy, 36014
General Practice
Sovizzo, Vicenza, Italy, 36050
Ospedale Boldrini
Thiene, Vicenza, Italy, 36016
Ospedale di Valdagno
Valdagno, Vicenza, Italy, 36078
Ospedale di Vicenza
Vicenza, VI, Italy, 36100
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, Italy, 20100
Azienda Ospedaliera di Padova
Padova, Italy, 35100
Family Health Centre
Padova, Italy, 35132
Family Health Centre
Verona, Italy, 37131
Family Health Centre
Verona, Italy, 37122
General Practice
Verona, Italy, 37126
General Practice
Verona, Italy, 37129
Ospedale Civile Maggiore
Verona, Italy, 37126
Policlinico G.B. Rossi
Verona, Italy, 37134
Sponsors and Collaborators
Azienda Ospedaliera Universitaria Integrata Verona
International Centre of Birth Defects
Investigators
Principal Investigator: Renata Bortolus, MD Azienda Ospedaliera Universitaria Integrata Verona
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT01244347     History of Changes
Other Study ID Numbers: FARM 6KWTCT, 2008-004334-25
Study First Received: October 11, 2010
Last Updated: January 13, 2015
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Azienda Ospedaliera Universitaria Integrata Verona:
folic acid
malformations
prevention

Additional relevant MeSH terms:
Congenital Abnormalities
Folic Acid
Vitamin B Complex
Growth Substances
Hematinics
Hematologic Agents
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vitamins

ClinicalTrials.gov processed this record on July 28, 2015