Folic Acid Dosage and Malformations Reduction

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Azienda Ospedaliera Universitaria Integrata Verona
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: October 7, 2013
Last verified: September 2013
  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

Contacts
Contact: Renata Bortolus, MD 00390458126898 renata.bortolus@ospedaleuniverona.it
Contact: Pierpaolo Mastroiacovo, Prof 0039063701905 mc8682@mclink.it

Locations
Italy
Ospedale di Adria Not yet recruiting
Adria, Rovigo, Italy, 45011
Contact: Enrico Di Mambro, MD    00390426940111    enricodimambro@gmail.com   
Principal Investigator: Enrico Di Mambro, MD         
Ospedale San Luca Not yet recruiting
Trecenta, Rovigo, Italy, 45027
Contact: Cristina Dibello, MD    00390425725631    drdibello@gmail.com   
Principal Investigator: Cristina Dibello, MD         
Ospedale di Conegliano Recruiting
Conegliano, Treviso, Italy, 31015
Contact: Andrea Baffoni, MD    00390438663295    andrea.baffoni@ulss7.it   
Principal Investigator: Andrea Baffoni, MD         
Family Health Centre Recruiting
Montebelluna, Treviso, Italy, 31044
Contact: Carlo Failli, MD    00390423614977    c.failli@libero.it   
Principal Investigator: Carlo Failli, MD         
Family Health Practice Recruiting
Oderzo, Treviso, Italy, 31046
Contact: Maurizia Marzolini, MD    00390422715620    mmarzolini@ulss.tv.it   
Principal Investigator: Maurizia Marzolini, MD         
Family Health Practice Recruiting
Villorba, Treviso, Italy, 31020
Contact: Nedelia Minisci, MD       nminisci@ulss.tv.it   
Principal Investigator: Nedelia Minisci, MD         
Ospedale Sant'Antonio Abate Recruiting
Gallarate, Varese, Italy, 21013
Contact: Elena Cesari, MD    00390331751259    elenacesari@gmail.com   
Principal Investigator: elena cesari, MD         
Family Health Practice Not yet recruiting
Camponogara, Venezia, Italy, 30010
Contact: Daniela Licori, MD    00390415798453    danielalicori@libero.it   
Principal Investigator: Daniela Licori, MD         
Family Health Centre Recruiting
Martellago, Venezia, Italy, 30030
Contact: Maria Grazia Salviato, MD    0039041431289    samagrazia@yahoo.it   
Principal Investigator: Maria Grazia Salviato, MD         
Family Health Practice Recruiting
Mira, Venezia, Italy, 30034
Contact: Marina Matterazzo, MD    0039041421979    carlopellarin@virgilio.it   
Principal Investigator: Marina Matterazzo, MD         
Family Health Centre Not yet recruiting
Noale, Venezia, Italy, 30033
Contact: Gerardo Guida, MD       gerrygin@libero.it   
Principal Investigator: Gerardo Guida, MD         
Family Health Centre Recruiting
San Pietro di Stra, Venezia, Italy, 30031
Contact: Francesco L Giorgino, MD       francescolgiorgino@libero.it   
Principal Investigator: Francesco L Giorgino, MD         
Family Health Centre Recruiting
Vogonovo, Venezia, Italy, 30030
Contact: Anna Sandri, MD       annasandri@abilene.it   
Principal Investigator: Anna Sandri, MD         
Ospedale di Bussolengo Recruiting
Bussolengo, Verona, Italy, 37012
Contact: Giorgia Negrini, MD       giorgianegrini@yahoo.it   
Sub-Investigator: Giorgia Negrini, MD         
Ospedale di Legnago Recruiting
Legnago, Verona, Italy, 37045
Contact: Elisa Caloi, MD       elisacaloi79@gmai.com   
Principal Investigator: Elisa Caloi, MD         
Ospedale di San Bonifacio Recruiting
San Bonifacio, Verona, Italy, 37047
Contact: Debora Balestreri, MD    00390456138111    dbalestreri@ulss20.verona.it   
Principal Investigator: Debora Balestreri, MD         
Family Health Centre Recruiting
Bassano, Vicenza, Italy, 36061
Contact: Simonetta Marinangeli, MD    00390424885421    simonetta.marinangeli@aslbassano.it   
Principal Investigator: Simonetta Marinangeli, MD         
Ospedale San Bassiano Recruiting
Bassano, Vicenza, Italy, 36061
Contact: Paola Lanza, MD    00390424888508    paola@battistella.eu   
Principal Investigator: Paola Lanza, MD         
General Practice Recruiting
Dueville, Vicenza, Italy, 36031
Contact: Enrico Ioverno, MD       enricoioverno@alice.it   
Principal Investigator: Enrico Ioverno, MD         
General Practice Recruiting
Malo, Vicenza, Italy, 36034
Contact: Chiara Tresso, MD    00390445589140    chiara.tresso@ulss4.veneto.it   
Principal Investigator: Chiara Tresso, MD         
General Practice Recruiting
Schio, Vicenza, Italy, 36014
Contact: Gianpiero Piazza, MD       gianpietro.piazza@gmail.com   
Principal Investigator: Gianpietro Piazza, MD         
General Practice Recruiting
Sovizzo, Vicenza, Italy, 36050
Contact: Renato Ruffini, MD    003904441802160    r.ruffini@medicisovizzo.org   
Principal Investigator: Renato Ruffini, MD         
Ospedale Boldrini Recruiting
Thiene, Vicenza, Italy, 36016
Contact: Gianfranco Jorizzo, MD    00390445388805    gjorizzo@ulss4.veneto.it   
Sub-Investigator: Gaetana Cirelli, MD         
Ospedale di Valdagno Recruiting
Valdagno, Vicenza, Italy, 36078
Contact: Claudia Guaraldi, MD    00390445484108    claudia.guaraldi@ulss5.it   
Principal Investigator: Claudia Guaraldi, MD         
Ospedale di Vicenza Recruiting
Vicenza, VI, Italy, 36100
Contact: Giuliano Zanni, MD       giuliano.zanni@ulssvicenza.it   
Sub-Investigator: Chiara Vernier, MD         
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Recruiting
Milan, Italy, 20100
Contact: Claudia Scarduelli, MD    00390255034309    centrosterilita@policlinico.mi.it   
Principal Investigator: Claudia Scarduelli, MD         
Family Health Centre Recruiting
Padova, Italy, 35132
Contact: Anna Casaro, MD    00390498876550    annacasaro@libero.it   
Principal Investigator: Anna Casaro, MD         
Azienda Ospedaliera di Padova Recruiting
Padova, Italy, 35100
Contact: Erich Cosmi, MD    00390498213410    ecosmi@hotmail.com   
Principal Investigator: Erich Cosmi, MD         
Family Health Centre Recruiting
Verona, Italy, 37131
Contact: Graziella Mortaro, MD    00390458787797    mortarog@yahoo.it   
Principal Investigator: Graziella Mortaro, MD         
Family Health Centre Recruiting
Verona, Italy, 37122
Contact: Patrizia Rosi, MD    0039045576059    rosi.patrizia11@libero.it   
Principal Investigator: Patrizia Rosi, MD         
General Practice Active, not recruiting
Verona, Italy, 37126
General Practice Recruiting
Verona, Italy, 37129
Contact: Laura Valotto, MD    0458032053    lavalott@libero.it   
Principal Investigator: Laura Valotto, MD         
General Practice Recruiting
Verona, Italy, 37126
Contact: Angelo Guido, MD    00390458344044    angeloguido@libero.it   
Principal Investigator: Angelo Guido, MD         
Policlinico G.B. Rossi Recruiting
Verona, Italy, 37134
Contact: Giovanni Zanconato, Prof    00390458124409    giovanni.zanconato@univr.it   
Principal Investigator: Giovanni Zanconato, Prof         
Ospedale Civile Maggiore Recruiting
Verona, Italy, 37126
Contact: Vittorio Travagliati, MD    00390458122720    vittorio.travagliati@ospedaleuniverona.it   
Principal Investigator: Vittorio Travagliati, MD         
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: October 7, 2013
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
Hematinics
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 16, 2014