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Trial registered on ANZCTR


Registration number
ACTRN12619000818134
Ethics application status
Approved
Date submitted
14/03/2019
Date registered
6/06/2019
Date last updated
16/09/2019
Date data sharing statement initially provided
6/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Once weekly folic acid supplementation in Malaysian women
Scientific title
The effect of once weekly folic acid supplementation on red cell folate concentrations in women to determine potential to prevent neural tube defects: A randomised controlled dose-finding trial in Malaysia
Secondary ID [1] 297527 0
None.
Universal Trial Number (UTN)
Trial acronym
None.
Linked study record
Not applicable.

Health condition
Health condition(s) or problem(s) studied:
Red blood cell folate 311707 0
Condition category
Condition code
Diet and Nutrition 310328 310328 0 0
Other diet and nutrition disorders
Public Health 310329 310329 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a three-arm, parallel-group, randomised controlled trial with a 16-week (with an additional scheduling allowance of +2 weeks) intervention period followed by a 4-week (with an additional scheduling allowance of +2 weeks) washout period. Interventions include:

Arm 1: 60 mg of elemental iron as ferrous fumarate and 2.8 mg of folic acid once weekly. This dose will be administered orally in tablet form once weekly for 16 weeks (with an additional scheduling allowance of +2 weeks). Adherence will be assessed by counting remaining tablets at the end of the intervention period by study staff.

Arm 2: 60 mg of elemental iron as ferrous fumarate and 0.4 mg of folic acid. This dose will be administered orally in tablet form once weekly for 16 weeks (with an additional scheduling allowance of +2 weeks). Adherence will be assessed by counting remaining tablets at the end of the intervention period by study staff.
Intervention code [1] 313749 0
Prevention
Comparator / control treatment
The comparator will consist of 60 mg of elemental iron as ferrous fumarate and 0 mg of folic acid. This dose will be administered orally in tablet form once weekly for 16 (with an allowance of 2 weeks) weeks. Adherence will be assessed by counting remaining tablets at the end of the intervention period by study staff.
Control group
Active

Outcomes
Primary outcome [1] 319212 0
Red blood cell folate (nmol/L)
Measurement: Microtiter technique with chloramphenicol-resistant Lactobacillus casei as the test microorganism. This will be calculated from whole blood folate by subtracting plasma folate and correcting for haematocrit.
Timepoint [1] 319212 0
16 weeks (post-treatment)
Secondary outcome [1] 367313 0
Plasma folate (nmol/L) Measurement: Microtiter technique with chloramphenicol-resistant Lactobacillus casei as the test microorganism.
Timepoint [1] 367313 0
16 weeks (post-treatment)
Secondary outcome [2] 367315 0
Plasma vitamin B12 (pmol/L)
Measurement: Elecsys® 2010 (Roche Diagnostics, Switzerland) automated electrochemiluminescence immunoassay
Timepoint [2] 367315 0
Baseline (0 weeks), 16 weeks, and 20 weeks with a scheduling allowance of +2 for the 16 and 20 week visits.
Secondary outcome [3] 367317 0
Anaemia prevalence (haemoglobin < 120 g/L)
Measurement: complete blood count
Timepoint [3] 367317 0
Baseline (0 weeks), 16 weeks, and 20 weeks with a scheduling allowance of +2 for the 16 and 20 week visits.
Secondary outcome [4] 367318 0
Haemoglobin (g/L)
Measurement: complete blood count
Timepoint [4] 367318 0
Baseline (0 weeks), 16 weeks, and 20 weeks with a scheduling allowance of +2 for the 16 and 20 week visits.
Secondary outcome [5] 367319 0
Plasma ferritin (µg/L)
Measurement: Single sandwich-enzyme linked immunosorbent assay
Timepoint [5] 367319 0
Baseline (0 weeks) and 16 weeks with a scheduling allowance of +2 weeks for the 16 week visit.
Secondary outcome [6] 368343 0
Soluble transferrin receptor (sTfR, mg/L)
Measurement: Single sandwich-enzyme linked immunosorbent assay
Timepoint [6] 368343 0
Baseline (0 weeks) and 16 weeks with a scheduling allowance of +2 weeks for the 16 week visit.
Secondary outcome [7] 368344 0
a-1 acid glycoprotein (AGP, g/L)
Measurement: Single sandwich-enzyme linked immunosorbent assay
Timepoint [7] 368344 0
Baseline (0 weeks) and 16 weeks with a scheduling allowance of +2 weeks for the 16 week visit.
Secondary outcome [8] 368345 0
C-reactive protein (CRP, mg/L)
Measurement: Single sandwich-enzyme linked immunosorbent assay
Timepoint [8] 368345 0
Baseline (0 weeks) and 16 weeks with a scheduling allowance of +2 weeks for the 16 week visit.
Secondary outcome [9] 368346 0
Retinol binding protein (RBP, µmol/L)]
Measurement: Single sandwich-enzyme linked immunosorbent assay
Timepoint [9] 368346 0
Baseline (0 weeks) and 16 weeks with a scheduling allowance of +2 weeks for the 16 week visit.
Secondary outcome [10] 374866 0
Red blood cell folate (nmol/L) Measurement: Microtiter technique with chloramphenicol-resistant Lactobacillus casei as the test microorganism. This will be calculated from whole blood folate by subtracting plasma folate and correcting for haematocrit.
Timepoint [10] 374866 0
20 weeks (post-washout)
Secondary outcome [11] 374867 0
Plasma folate (nmol/L) Measurement: Microtiter technique with chloramphenicol-resistant Lactobacillus casei as the test microorganism.
Timepoint [11] 374867 0
20 weeks (post-washout)

Eligibility
Key inclusion criteria
Non-pregnant (self-reported), not planning on becoming pregnant, not currently taking micronutrient supplements containing folic acid or participating in another nutritional intervention, not taking any medication known to inhibit folate status (methotrexate, anti-convulsants, or sulphasalazine), and not planning to leave the community for the timeline of the study.
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Pregnant, planning on becoming pregnant, currently taking micronutrient supplements containing folic acid or participating in another nutritional intervention, taking any medication known to inhibit folate status (methotrexate, anti-convulsants, or sulphasalazine), or planning to leave the community in durations that would interfere with the study timeline.

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)
Participants will be randomly assigned to receive 60 mg of iron as ferrous fumarate and either 0, 0.4, or 2.8 mg of folic acid in the ratio of 2:2:2 which was randomly allocated by an off-site central computer to which the enrolment staff do not have access. Tablet bottles will be labeled with a serial number and coloured sticker. One serial number and two coloured stickers will be used for each treatment group to assist with blinding.

All participants, study staff, and data analysts will be blinded to randomization group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomization schedule will be prepared by the study statisticians. The randomization procedure will use randomly permuted blocks of size six to assign participants to one of six serial numbers. One serial number and two coloured stickers will be used for each treatment group to assist with blinding. An experienced statistician, who is independent of the trial will determine which serial numbers belong to which treatment group. The randomization will be performed using computer software (REDCap).
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
None.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary analysis will be performed on an ‘intention-to-treat’ basis, according to treatment allocation at randomisation. A secondary ‘per-protocol’ analysis will also be performed including only women who complete the study and are >80% adherent to the treatment regime. Continuous outcomes, including the primary outcome RBC folate concentration at 16 weeks, will be analysed using linear regression models and binary outcomes will be analysed using log binomial regression models. Predictors will include randomised treatment group, time point (16 or 20 weeks) and a treatment group by time point interaction. Treatment effects (0.4 mg vs 0 mg, 2.8 mg vs 0 mg and 2.8 mg vs 0.4 mg) will be estimated for each time point separately (16 and 20 weeks) along with 95% confidence intervals and two-sided p-values. Clustering due to repeated measurements on the same individuals at different time points will be considered using generalised estimating equations. Adjustment will be made for the baseline measure of the analyzed outcome. Missing data will be addressed using multiple imputation to create 100 complete datasets for analysis, with a sensitivity analysis performed on the available data. All analyses will follow a pre-specified statistical analysis plan. Statistical analyses will be conducted using Stata/IC 15.0 (Stata Corp, TX, USA).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21304 0
Malaysia
State/province [1] 21304 0
Kuala Lumpur

Funding & Sponsors
Funding source category [1] 302056 0
Charities/Societies/Foundations
Name [1] 302056 0
Nutrition International
Address [1] 302056 0
180 Elgin Street, Suite 1000
Ottawa, Ontario, Canada, K2P 2K3
Country [1] 302056 0
Canada
Primary sponsor type
University
Name
South Australian Health and Medical Research Institute (SAHMRI)
Address
North Terrace,
Adelaide SA
5000, Australia
Country
Australia
Secondary sponsor category [1] 301867 0
University
Name [1] 301867 0
University of British Columbia
Address [1] 301867 0
2205 East Mall
Vancouver, BC
V6T1Z4
Country [1] 301867 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302738 0
Ethics Committee for Research Involving Human Subjects of Universiti Putra Malaysia
Ethics committee address [1] 302738 0
Universiti Putra Malaysia
43400 UPM Serdang
Selangor Darul Ehsan
Ethics committee country [1] 302738 0
Malaysia
Date submitted for ethics approval [1] 302738 0
Approval date [1] 302738 0
19/12/2018
Ethics approval number [1] 302738 0
JKEUPM-2018-255
Ethics committee name [2] 302750 0
The University of British Columbia Clinical Research Ethics Board
Ethics committee address [2] 302750 0
Room 210, Research Pavilion
828 West 10th Avenue
Vancouver, BC Canada V5Z 1L8
Ethics committee country [2] 302750 0
Canada
Date submitted for ethics approval [2] 302750 0
04/04/2018
Approval date [2] 302750 0
18/01/2019
Ethics approval number [2] 302750 0
H18-00768

Summary
Brief summary
Neural tube defects (NTDs) are serious birth defects affecting the brain and spine. Folic acid supplementation in early pregnancy has been shown to reduce the incidence of NTDs. Currently, the World Health Organization recommends weekly iron (60 mg) and folic acid (2.8 mg) (IFA) supplementation among women and adolescents in areas where anaemia prevalence is >=20%. A weekly dose of 2.8 mg folic acid was chosen because it was seven times the daily dose known to reduce NTDs; however, evidence is lacking to confirm this is an optimal dose. We aim to conduct a three-arm randomised controlled trial to examine the effects of three different weekly doses of folic acid on red blood cell folate concentrations.

We will recruit women (n=300; 18-45 y) from Kuala Lumpur, Malaysia. We will randomise women individually, to receive one of three weekly doses of folic acid (2.8, 0.4 or 0 mg) with 60 mg iron for 16 weeks (with a scheduling allowance of +2 weeks), followed by a 4-week washout period (with a scheduling allowance of +2 weeks). Fasting venous blood will be drawn at baseline, 16, and 20 weeks. We will measure plasma folate, red blood cell folate, and other markers of nutrition and inflammation, and genetic polymorphisms in folate metabolism. The primary outcome is baseline adjusted red blood cell folate at 16 weeks, analyzed with use of a generalized estimating equation (intention-to-treat). This research is expected to inform the WHO guidelines for weekly iron and folic acid supplementation, particularly on the optimal folic acid dose.
Trial website
None.
Trial related presentations / publications
None.
Public notes
None.

Contacts
Principal investigator
Name 91222 0
Dr Tim Green
Address 91222 0
South Australian Health and Medical Research Institute
North Terrace,
Adelaide SA 5000,
Australia
Country 91222 0
Australia
Phone 91222 0
+61 (0) 8 8128 4406
Fax 91222 0
Email 91222 0
Tim.green@sahmri.com
Contact person for public queries
Name 91223 0
Dr Tim Green
Address 91223 0
South Australian Health and Medical Research Institute
North Terrace,
Adelaide SA 5000,
Australia
Country 91223 0
Australia
Phone 91223 0
+61 (0) 8 8128 4406
Fax 91223 0
Email 91223 0
Tim.green@sahmri.com
Contact person for scientific queries
Name 91224 0
Dr Tim Green
Address 91224 0
South Australian Health and Medical Research Institute
North Terrace,
Adelaide SA 5000,
Australia
Country 91224 0
Australia
Phone 91224 0
+61 (0) 8 8128 4406
Fax 91224 0
Email 91224 0
Tim.green@sahmri.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will remain anonymous. Only summary results will be shared.
What supporting documents are/will be available?
No other documents available
Summary results
No Results