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    Summary
    EudraCT Number:2011-003325-10
    Sponsor's Protocol Code Number:1.01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-08-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-003325-10
    A.3Full title of the trial
    A randomized controlled trail on the effects of periconceptional and prenatal folic acid supplementation on congenital anomalies and preterm birth
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of folic acid on birth defect and preterm birth
    A.3.2Name or abbreviated title of the trial where available
    Folic acid Extra
    A.4.1Sponsor's protocol code number1.01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVU University Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportZonMw
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMediClara Projects BV
    B.5.2Functional name of contact pointProjectleader
    B.5.3 Address:
    B.5.3.1Street AddressHollandse Kade 10a
    B.5.3.2Town/ cityAbcoude
    B.5.3.3Post code1391 JD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 294281173
    B.5.5Fax number+31294282956
    B.5.6E-maildjdesmit@mediclara.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name folic acid
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namefolic acid
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFOLIC ACID
    D.3.9.1CAS number 59-30-3
    D.3.9.4EV Substance CodeSUB07774MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    congenital anomalies
    E.1.1.1Medical condition in easily understood language
    birth defects
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10004953
    E.1.2Term Birth premature
    E.1.2System Organ Class 10036585 - Pregnancy, puerperium and perinatal conditions
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLT
    E.1.2Classification code 10007607
    E.1.2Term Cardiac septal defects congenital
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10041524
    E.1.2Term Spina bifida
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. What is the effect of a high (4.0 mg) versus low (0.4 mg) dose of folic acid supplementation from 4 weeks before conception to 12 weeks of gestation on the prevalence of folic acid related congenital anomalies?
    2. What is the effect of 0.8 mg folic acid supplementation versus 0,2 folic acid supplementation from 12 weeks of gestation to the end of pregnancy on the prevalence of preterm birth and preeclampsia?
    E.2.2Secondary objectives of the trial
    3. Which side effects of periconceptional and prenatal folic acid use are reported by trail participants?
    4. What associations between study groups and the incidence, severity and types of side effects reported, can be identified?
    a. During the first period (until 12 weeks of gestation);
    b. During the second period (from 12 weeks of gestation until the end of the pregnancy).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All women living in the Northern region of the Netherlands of 18 to 45 years old who want to become pregnant within 12 months are eligible for participation in the study.
    E.4Principal exclusion criteria
    When the participant appears to have a multiple pregnancy, she will be excluded for further participation, because these women are advised by midwifes to use 1 mg FA. Women who had previous offspring with NTD and other women who take high doses of FA for any other reason and women who use FA-antagonists will be excluded from the study.
    Further exclusion criteria are:
    a) no informed consent given
    b) not understanding Dutch
    c) already pregnant at time of inclusion or within 4 weeks after start intervention
    d) planning to move to an area where the study is not implemented
    e) recently or at present using folic acid antagonists or antifolates or other drugs influencing the folic acid metabolism (methotrexaat, pyrimethamine, trimethoprim)
    f) being affected by epilepsy, diabetes, megaloblastic anaemia and/or cancer (previous cancer or abnormal PAP smears)
    g) being allergic to folic acid or any other ingredient of the pills used in this study
    h) take defined dosages of folic acid for directions other than those listed in the above exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    FA related congenital anomalies and preterm birth.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at birth and during first year postpartum
    E.5.2Secondary end point(s)
    - Birth weight, obtained from medical records
    - preeclampsia (defined as a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg after 20 weeks of gestation among women with previously normal blood pressure, combined with proteinuria (≥ 300 mg/24 hours)), obtained from medical records
    - compliance with intervention: Women will be asked to return all pills they have not used within a 12 week period to the pharmacy, in order to check compliance with folic acid supplementation. Additionally, each time they pick up their supplements at the pharmacy, they will be asked to fill in a short questionnaire including questions on compliance with the intervention (MARS-5 questionnaire).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Compliance: when picking up new folic acid supplements at pharmacy (every 3 months)

    others: at birth.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    One year after last participant gave birth.

    Birth defects are registered during the first year after birth.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5000
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5000
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-08-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-10-08
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