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Trial registered on ANZCTR


Registration number
ACTRN12619001511123
Ethics application status
Approved
Date submitted
21/10/2019
Date registered
1/11/2019
Date last updated
1/11/2019
Date data sharing statement initially provided
1/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does stopping folic acid at 12 weeks of pregnancy reduce the amount of unmetabolised folic acid in the blood of pregnant women - The Folic Acid in Pregnancy Study
Scientific title
Cessation of folic acid supplementation after 12 weeks gestation to investigate maternal late-gestation plasma unmetabolised folic acid levels.
Secondary ID [1] 299336 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Folic acid supplementation in late gestation 314483 0
Condition category
Condition code
Metabolic and Endocrine 312816 312816 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive either a prenatal micronutrient supplement containing 0.8 mg folic acid (Control) or an identical micronutrient supplement containing no folic acid (Intervention).

The composition of micronutrients within the intervention and control supplements are formulated to approximate the current leading brands of prenatal micronutrient supplements and both contain the following: calcium 250 mg, Iron 27 mg, thiamine 1.4 mg, riboflavin 1.4 mg, niacinamide 18 mg, vitamin B-6 1.9 mg, vitamin B-12 2.6 mcg, pantothenic acid 6 mg, biotin 30 mg, vitamin C 85 mg, vitamin E 13.5 IU, magnesium 50 mg, zinc 7.5 mg, manganese 2.0 mg, iodine 0.22 mg, copper 1 mg, chromium 30 mcg, selenium 30 mcg, Vitamin D3 10 mcg, b-carotene 2500 IU.

Intervention and control supplements will be in tablet form and are identical in size, shape, colour and packaging. They only differ in the removal of folic acid from the intervention supplement. Study supplements will be packaged and labelled in accordance with the Code of Good Manufacturing Practice (GMP) for Medicinal Products and Therapeutic Goods Administration (TGA) guidelines for clinical trial products, including; product identification number (Product ID), batch number, expiry date and include the statement “for clinical trial use only”. The intervention and control supplements will be manufactured and donated by Factors Group of Companies, Coquitlam, British Columbia, Canada.

Participants will be supplied with supplements for the duration of their pregnancy. The initial supply will be dispensed following randomisation and enough supplements will be given to last until the 36 week clinic visit as well as additional supplements as a compliance measure. At the 36 week clinic visit, participants will then be issued with supplements to last the reminder of their pregnancy. The study supplements are ready to administer requiring no preparation. Participants will be instructed to take one supplement per day, orally from randomisation (>12 to <16 weeks gestation) until delivery.

The Research Assistant will maintain regular contact with participating women by SMS/email or telephone (depending on participant preference) to monitor and encourage compliance. At each contact, women will be asked if they have missed any supplements in the last week and if so, how many have been missed. Women will be supplied with excess supplements and will be asked to return unused supplements at the 36 week clinic visit for a supplement count. The proportion of supplements returned will serve as an additional measure of adherence.
Intervention code [1] 315606 0
Prevention
Intervention code [2] 315893 0
Treatment: Other
Comparator / control treatment
The control group represents women following the common practice of taking folic acid containing supplements throughout pregnancy.

Control group supplements contain the identical micronutrients detailed in the intervention group with the addition of 0.8mg of folic acid.
Control group
Active

Outcomes
Primary outcome [1] 321439 0
Maternal plasma unmetabolised folic acid concentrations between groups
Timepoint [1] 321439 0
36 weeks gestation
Secondary outcome [1] 374948 0
Maternal plasma folate levels.
Timepoint [1] 374948 0
36 weeks gestation
Secondary outcome [2] 376178 0
Maternal red blood cell folate levels.
Timepoint [2] 376178 0
36 weeks gestation.

Eligibility
Key inclusion criteria
To be eligible for participation women must meet all of the following criteria;
1) a singleton pregnancy greater or equal to 12 weeks and less than 16 weeks gestation.
2) currently taking a folic acid containing supplement and planning to continue throughout pregnancy.
3) be able to give informed consent.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women will be ineligible for trial participation if they meet any the following criteria;

1) carrying a fetus with a confirmed or suspected fetal abnormality.
2) unwilling to cease current folic acid containing supplement/s
3) previous history of a NTD affected pregnancy
4) currently taking medication known to interfere with folate metabolism (i.e. anti-convulsant, anti-malaria medication or barbiturates).
5) Known haemolytic anaemia or haemoglobinopathy
6) Known malabsorption syndrome or MTHFR mutation
7) intolerance or allergy to prenatal vitamin and mineral supplements.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each study pack will contain either intervention or control supplements, pre-packed according to the randomisation schedule. Randomised Participants will be allocated product Id to identify which product should be dispensed. Participants and their family, care providers, outcome assessors and data analysts will be blinded to randomisation group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be assigned to the intervention or control group through a secure web-based randomisation service (REDCap). Allocation will follow a computer-generated randomisation schedule using balanced variable block sizes, prepared by an independent statistician.
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
Other design features
Stratification will be by gestational age at trial entry; greater or equal to 12 weeks and less than or equal to 14 weeks gestation and greater than 14 weeks and less than 16 weeks gestation.

Participants will be asked to cease their current prenatal supplements immediately and for the duration of the study.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan. For the primary outcome, we will assess whether there is a difference in mean unmetabolised folic acid levels at 36 weeks gestation between groups using analysis of covariance, with adjustment for baseline unmetabolised folic acid levels level and gestational age at trial entry (12 to = 14 weeks or > 14 weeks). The treatment effect will be described as a mean difference with 95% confidence interval. In a secondary analysis, we will also compare the percentage of women in each group who maintain serum folate levels > 905 nmol/L at 36 weeks gestation using a Fisher exact test (with an exact 95% confidence interval used to described uncertainty in the estimated percentage within each group). In all analyses, a two-sided p-value < 0.05 will be taken to indicate statistical significance.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/11/2019
Actual
Date of last participant enrolment
Anticipated
21/12/2020
Actual
Date of last data collection
Anticipated
30/07/2021
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 14812 0
Womens and Childrens Hospital - North Adelaide
Recruitment postcode(s) [1] 28062 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 303853 0
Charities/Societies/Foundations
Name [1] 303853 0
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG)
Country [1] 303853 0
Australia
Funding source category [2] 304162 0
Commercial sector/Industry
Name [2] 304162 0
Factors Group of Companies
Country [2] 304162 0
Canada
Primary sponsor type
Government body
Name
South Australian Health and Medical Research Institute (SAHMRI)
Address
SAHMRI Women and Kids Theme
Clarence Riedge Building Level 7
Women's and Children's Hospital
72 King William Rd, North Adelaide SA 5006
Country
Australia
Secondary sponsor category [1] 303987 0
None
Name [1] 303987 0
Address [1] 303987 0
Country [1] 303987 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304365 0
Women's and Children's Health Network Human Research Ethics Committee
Ethics committee address [1] 304365 0
Women's & Children's Hospital
Research Secretariat
Level 2, Samuel Way Building
72 King William Road
North Adelaide, SA 5006
Ethics committee country [1] 304365 0
Australia
Date submitted for ethics approval [1] 304365 0
01/02/2019
Approval date [1] 304365 0
23/05/2019
Ethics approval number [1] 304365 0
HREC/19/WCHN/18

Summary
Brief summary
Australian women receive 0.15-0.2 mg/d of folic acid from food containing fortified bread flour. In addition, >80% of Australian women take a multivitamin during pregnancy, with one of the most popular brands containing double the amount of folic acid recommended for pregnant women until 3 months gestation. (0.8 mg/d). There is no question that taking folic acid in early pregnancy is important to prevent neural tube defects. However, there is no proven benefit and potential harm from taking folic acid after neural tube closure at approximately 28 days post conception. We aim to determine if removing folic acid from prenatal supplements after 12 weeks of gestation results in lower blood concentrations of unmetabolised folic acid, a biomarker of excess folic acid, at 36 weeks’ gestation. We will also determine if removing folic acid from prenatal supplements after 12 weeks’ gestation allows women to maintain red blood cell folate concentrations >905 nmol/L at 36 weeks’ gestation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96698 0
Dr Karen Best
Address 96698 0
SAHMRI Women & Kids
Level 7, Clarence Building
Women's and Children's Hospital
72 King William Rd, North Adelaide SA 5006
Country 96698 0
Australia
Phone 96698 0
+610881284404
Fax 96698 0
Email 96698 0
[email protected]
Contact person for public queries
Name 96699 0
Karen Best
Address 96699 0
SAHMRI Women & Kids
Level 7, Clarence Building
Women's and Children's Hospital
72 King William Rd, North Adelaide SA 5006
Country 96699 0
Australia
Phone 96699 0
+61 08 81284404
Fax 96699 0
Email 96699 0
[email protected]
Contact person for scientific queries
Name 96700 0
Karen Best
Address 96700 0
SAHMRI Women & Kids
Level 7, Clarence Building
Women's and Children's Hospital
72 King William Rd, North Adelaide SA 5006
Country 96700 0
Australia
Phone 96700 0
+61 08 81284404
Fax 96700 0
Email 96700 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified, individual participant data that underlie the results reported in this article (text, tables, figures and appendices). Dataset(s) will be limited to those participants and variables that are necessary for completion of the approved research proposal.
When will data be available (start and end dates)?
Three months after publication of trial results, no end date.
Available to whom?
Researchers who provide a methodologically sound research proposal following review and approval by the trial steering committee and completion of a signed data access agreement.
Available for what types of analyses?
For the approved purpose following approval of a proposal and signed data access agreement.
How or where can data be obtained?
Requests can be made to [email protected]


What supporting documents are/will be available?

Current supporting documents:


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23740Study protocol https://bmjopen.bmj.com/content/10/11/e040416.abstract 

Results publications and other study-related documents

Documents added manually
Current Study Results
No documents have been uploaded by study researchers.

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
New Record*Study results articleYeshttps://doi.org/10.1136/ bmjopen-2020-040416 Sulistyoningrum D, Green T, Palmer D, Sullivan T, ... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStudy protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation.2020https://dx.doi.org/10.1136/bmjopen-2020-040416
Dimensions AINew Methodologies for Conducting Maternal, Infant, and Child Nutrition Research in the Era of COVID-192021https://doi.org/10.3390/nu13030941
N.B. These documents automatically identified may not have been verified by the study sponsor.