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Trial registered on ANZCTR


Registration number
ACTRN12617000660381
Ethics application status
Approved
Date submitted
29/04/2017
Date registered
8/05/2017
Date last updated
4/02/2019
Date data sharing statement initially provided
4/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Benefits and Risks of Iron interventionS in Children (BRISC): a randomized controlled trial in Bangladesh
Scientific title
Benefits and Risks of Iron Supplementation and Multiple Micronutrient Powders in Children: a three arm, individually randomized controlled trial in Bangladesh
Secondary ID [1] 291807 0
None
Universal Trial Number (UTN)
U1111-1196-1125
Trial acronym
BRISC
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Anaemia 303044 0
Iron Deficiency 303045 0
Undernutrition 303046 0
Diarrhoea 303047 0
Condition category
Condition code
Blood 302501 302501 0 0
Anaemia
Diet and Nutrition 302502 302502 0 0
Other diet and nutrition disorders
Neurological 302503 302503 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1: Iron supplements (12.5mg elemental iron/ day as syrup) and placebo micronutrient powders, once daily for 3 months.
Group 2: Multiple micronutrient powders (12.5mg elemental iron, 0.3 mg Vitamin A, 30 mg Vitamin C, 0.16 mg Folic Acid, 5 mg Zinc) and placebo syrup, once daily for 3 months
Group 3: Control - placebo micronutrient powders and placebo syrup once daily for 3 months.
Adherence will be confirmed by monitoring consumption of sachets/ residual volumes in bottles.
Intervention code [1] 297919 0
Treatment: Other
Comparator / control treatment
Double dummy placebo: placebo syrup, placebo powders.
Control group
Placebo

Outcomes
Primary outcome [1] 301915 0
Cognitive development assessed by the Bayley III Cognitive Composite Score
Timepoint [1] 301915 0
End of intervention (3 months)
Secondary outcome [1] 334267 0
Cognitive development measured by Bayley Cognitive Composite Score, after 9 months post-intervention
Timepoint [1] 334267 0
9 months post intervention (12 months follow up)
Secondary outcome [2] 334268 0
Infant motor and language development, Bayley-III Motor (MotCS) and Language (LangCS) Composite Scores
Timepoint [2] 334268 0
End intervention (+3 months) and Post follow up (+12 months)
Secondary outcome [3] 334269 0
Infant behaviour, Wolke’s Behaviour Ratings
Timepoint [3] 334269 0
End intervention (+3 months), and End follow up (+12 months)
Secondary outcome [4] 334270 0
Child temperament by Bates Child Charateristics Questionnaire
Timepoint [4] 334270 0
End intervention (+3 months) and post follow up (+12 months)
Secondary outcome [5] 334271 0
Growth (mean) z-scores: weight-for-age, length-for-age, weight-for-length, head circumference, (WHO Growth charts)
Timepoint [5] 334271 0
End intervention (+3 months) and Post follow up (+12 months)
Secondary outcome [6] 334272 0
Infectious morbidity (rate and number of days affected diarrhoea, bloody diarrhoea, respiratory infection and fever) - composite outcome, reported by direct questioning during weekly home visits
Timepoint [6] 334272 0
During intervention (0-3 months) and post intervention (3-12 months)
Secondary outcome [7] 334273 0
Unplanned hospital attendances and unplanned health-care facility attendance - composite outcome, recorded by direct questioning of participants during weekly home visits.
Timepoint [7] 334273 0
During intervention (0-3 months) and post intervention (3-12 months)
Secondary outcome [8] 334274 0
Anaemia (Hb<11g/dL) (%), as measured by HemoCue Hb assessment
Timepoint [8] 334274 0
Baseline, +3 months, +12 months
Secondary outcome [9] 334314 0
Iron deficiency, measured by low serum ferritin levels (ferritin <12ng/uL adjusted for inflammation).
Timepoint [9] 334314 0
+3, +12 months.
Secondary outcome [10] 334315 0
Iron deficiency anaemia (anaemia measured by HemoCue Hb measurement + ferritin<12ng/uL adjusted for inflammation on biochemistry analyser)
Timepoint [10] 334315 0
+3, +12 months
Secondary outcome [11] 334316 0
Diarrhoea: (Incidence) (measured by direct questioning during weekly visits)
Timepoint [11] 334316 0
0-3 months, 3-12 months
Secondary outcome [12] 334317 0
Respiratory infection (incidence) (measured by direct questioning during weekly visits)
Timepoint [12] 334317 0
0-3 months, 3-12 months
Secondary outcome [13] 334318 0
Bloody diarrhoea (incidence) (measured by direct questioning during weekly visits)
Timepoint [13] 334318 0
0-3 months, 3-12 months
Secondary outcome [14] 334319 0
Fever (incidence) (measured by direct questioning during weekly visits)
Timepoint [14] 334319 0
0-3 months, 3-12 months
Secondary outcome [15] 334320 0
Unplanned hospital admission (direct questioning during weekly home visits)
Timepoint [15] 334320 0
0-3 months, 3-12 months
Secondary outcome [16] 334321 0
Unplanned outpatient clinic visit (measured by direct questioning during weekly home visits)
Timepoint [16] 334321 0
0-3 months, 3-12 months
Secondary outcome [17] 334322 0
Cause specific unplanned clinic attendance (by inspection of medical records)
Timepoint [17] 334322 0
0-3 months, 3-12 months
Secondary outcome [18] 334323 0
Cause specific hospital admission (by inspection of medical records)
Timepoint [18] 334323 0
0-3 months, 3-12 months
Secondary outcome [19] 334515 0
Fever (number of days affected) (measured by direct questioning during routine visits)
Timepoint [19] 334515 0
0-3 months, 3-12 months
Secondary outcome [20] 334516 0
Bloody diarrhoea (number of days affected) (measured by direct questioning during weekly visits)
Timepoint [20] 334516 0
0-3 months, 3-12 months
Secondary outcome [21] 334517 0
Respiratory Infection (number of days affected) (measured by direct questioning during weekly visits)
Timepoint [21] 334517 0
0-3 months, 3-12 months
Secondary outcome [22] 334518 0
Diarrhoea (number of days affected) (measured by direct questioning during weeky visits)
Timepoint [22] 334518 0
0-3 months, 3-12 months
Secondary outcome [23] 366402 0
Neurodevelopment measured by electroencephalography (EEG).
Timepoint [23] 366402 0
+ 3 months (end intervention), +12 months (end follow up)
Sample size: up to 550 at midline, up to 800 at endline. Testing constraints maximise the number of tests per day to 5/ day. We will test the maximum number of children available per the number of slots available per day.

Eligibility
Key inclusion criteria
Each participant must meet all of the following criteria to be enrolled in this study:
-Is aged 8 months (+/-14 days) at the time of randomisation
-Is not expected to leave the study site (leave local village or the Rupganj area) for more than 1 week over the next 3 months, or for more than one month over the next 12 months.
-Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant’s behalf.
Minimum age
8 Months
Maximum age
8 Months
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Children meeting any of the following criteria will be excluded from the study:
- Has a capillary Hb at screening of <8.0g/dL at the time of screening
- Drinking water iron level >1gm/L
- Has an established diagnosis of any homozygous or compound heterozygous haemoglobinopathies (i.e. beta thalassaemia major, HbE-beta thalassaemia).
- Current infective illness with fever (respiratory infection, diarrhoea); however, children will be screened again after recovery and recruited as long as the meet the age eligibility criteria at second screening.
- Legal guardian unwilling or unable to provide written informed consent.
- Has not received iron supplements or iron-containing multiple micronutrient powders in the previous month. Families who self-procure iron/MMP during or after the intervention period will not be dropped from the study, but we will record the dose and duration and continue monitoring
- Known congental anomaly, developmental disorder or severe developmental delay
- It is not possible to test the child due to physical or behavioural problems
- Children of multiple birth e.g. twin, triplets

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)
Blinding will be achieved through the use of identical packaging which will carry the code. Allocation concealment will be achieved through use of central randomisation and use of number pouches containing study medications.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A statistician not involved in the study will generate a random sequence using a computer program to undertake randomisation and will hold the codes until the study ends. The study will use individual block randomization, with stratification by sex and sub-centre to maintain balance between intervention arms.
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
Double dummy
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary analysis will be by intention-to-treat and in accordance with International Conference on Harmonization E9 statistical principles. A detailed statistical analysis plan with details of the proposed analyses will be finalised before the trial database is locked for final analysis. Analyses will be undertaken on an intention-to-treat basis. Descriptive statistics will be presented for all outcomes, by treatment groups across the follow-up time points. Outcomes will be assessed using regression models, with placebo as the reference, and incorporating key confounders and unbalanced baseline factors into the model.

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] 8854 0
Bangladesh
State/province [1] 8854 0
Rupganj, Narayanganj district

Funding & Sponsors
Funding source category [1] 296307 0
Government body
Name [1] 296307 0
National Health and Medical Research Council
Address [1] 296307 0
GPO Box 1421
Canberra ACT 2601
Country [1] 296307 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Grattan Street,
Parkville,
VIC 3052
Country
Australia
Secondary sponsor category [1] 295235 0
None
Name [1] 295235 0
None
Address [1] 295235 0
NA
Country [1] 295235 0
Other collaborator category [1] 279549 0
Other
Name [1] 279549 0
International Centre for Diarrhoeal Diseases Research, Bangladesh
Address [1] 279549 0
GPO Box 128
Dhaka 1000
Bangladesh
Country [1] 279549 0
Bangladesh

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297537 0
International Centre for Diarrhoeal Diseases Research, Bangladesh - Ethical Review Committee
Ethics committee address [1] 297537 0
GPO Box 128
Dhaka 1000
Bangladesh
Ethics committee country [1] 297537 0
Bangladesh
Date submitted for ethics approval [1] 297537 0
21/09/2016
Approval date [1] 297537 0
27/11/2016
Ethics approval number [1] 297537 0
PR-16063
Ethics committee name [2] 297538 0
Melbourne Health
Ethics committee address [2] 297538 0
Melbourne Health
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Australia
Ethics committee country [2] 297538 0
Australia
Date submitted for ethics approval [2] 297538 0
09/11/2016
Approval date [2] 297538 0
23/01/2017
Ethics approval number [2] 297538 0
2016.269

Summary
Brief summary
Background (brief):
a. Burden: About 43% of pre-school children worldwide and 60% children 6-24 months of age in rural Bangladesh are anaemic and half of the burden of anaemia is assumed to be attributable to iron deficiency (ID) which may impair brain development in this critical period of life

b. Knowledge gap: Though WHO recommends universal supplementation of either iron supplements or iron-containing multiple micronutrient powders (MMPs) to children under 2yrs to improve iron status, little is known about the effects of these supplementations on child’s developmental outcomes and infectious morbidity

c. Relevance: The study will bring an opportunity to evaluate an immediate and long term effect of iron and MMPs supplementation at early childhood, which may form the platform for global anaemia control policy in young children.

Hypothesis: Both universal iron supplementation and MMPs will improve cognitive development across the population, both immediately after intervention and after a further 9 months

Objectives: Primary objective is to evaluate the impact of iron supplementation and MMPs on cognitive development in young children, compared with placebo, at end of intervention
Secondary objectives are a) to determine the effects of universal iron supplementation and MMPs on other key functional outcomes i.e. language and motor development and behaviour and growth of children, both immediately following intervention and after 9 months follow up, b) to determine the adverse effects of universal iron supplementation and MMPs, especially morbidity from diarrhoea and respiratory infections, and c) to determine the effects of iron and MMPs on haematologic and iron indices and child growth.

Methods: A three-arm, double-blind, placebo controlled RCT comparing daily (i) iron supplementation; (ii) MMPs; and (iii) placebo (double dummy) will be given for 03 months to children aged 8 months..

Detailed cognitive and clinical assessments at baseline, end of intervention (+3 months) and after a further 9 months (+12 months).

Inclusion criteria:
Children aged 8 months, without known inherited haematologic or developmental disorder or severe malnutrition, or who are exposed to high groundwater iron.

Outcome measures/variables: Childs’s cognitive, motor and language development measured on Bayley-III, behaviour on Wolke’s rating scales, temperament, quality of home stimulation using family care indicators, growth measured by length, weight and head circumference, morbidity, socioeconomic status, direct and indirect cost and haemoglobin, ferritin and CRP.
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 74370 0
Prof Beverley-Ann Biggs
Address 74370 0
Melbourne Health
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Australia
Country 74370 0
Australia
Phone 74370 0
+613 83443257
Fax 74370 0
+61383443257
Email 74370 0
babiggs@unimelb.edu.au
Contact person for public queries
Name 74371 0
Dr Sant-Rayn Pasricha
Address 74371 0
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Country 74371 0
Australia
Phone 74371 0
+613 9345 2618
Fax 74371 0
Email 74371 0
Pasricha.s@wehi.edu.au
Contact person for scientific queries
Name 74372 0
Dr Sant-Rayn Pasricha
Address 74372 0
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Country 74372 0
Australia
Phone 74372 0
+6139345 2618
Fax 74372 0
Email 74372 0
Pasricha.s@wehi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be made available but final decisions on the specifics have not yet been finalised.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Summary results
Not applicable