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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

17/03/2020

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]

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

Iron Deficiency

Undernutrition

Diarrhoea

Condition category

Condition code

Blood

Anaemia

Diet and Nutrition

Other diet and nutrition disorders

Neurological

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]

Treatment: Other

Comparator / control treatment

Double dummy placebo: placebo syrup, placebo powders.

Control group

Placebo

Outcomes

Primary outcome [1]

Cognitive development assessed by the Bayley III Cognitive Composite Score

Timepoint [1]

End of intervention (3 months)

Secondary outcome [1]

Cognitive development measured by Bayley Cognitive Composite Score, after 9 months post-intervention

Timepoint [1]

9 months post intervention (12 months follow up)

Secondary outcome [2]

Infant motor and language development, Bayley-III Motor (MotCS) and Language (LangCS) Composite Scores

Timepoint [2]

End intervention (+3 months) and Post follow up (+12 months)

Secondary outcome [3]

Infant behaviour, Wolke’s Behaviour Ratings

Timepoint [3]

End intervention (+3 months), and End follow up (+12 months)

Secondary outcome [4]

Child temperament by Bates Child Charateristics Questionnaire

Timepoint [4]

End intervention (+3 months) and post follow up (+12 months)

Secondary outcome [5]

Growth (mean) z-scores: weight-for-age, length-for-age, weight-for-length, head circumference, (WHO Growth charts)

Timepoint [5]

End intervention (+3 months) and Post follow up (+12 months)

Secondary outcome [6]

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]

During intervention (0-3 months) and post intervention (3-12 months)

Secondary outcome [7]

Unplanned hospital attendances and unplanned health-care facility attendance - composite outcome, recorded by direct questioning of participants during weekly home visits.

Timepoint [7]

During intervention (0-3 months) and post intervention (3-12 months)

Secondary outcome [8]

Anaemia (Hb<11g/dL) (%), as measured by HemoCue Hb assessment

Timepoint [8]

Baseline, +3 months, +12 months

Secondary outcome [9]

Iron deficiency, measured by low serum ferritin levels (ferritin <12ng/uL adjusted for inflammation).

Timepoint [9]

+3, +12 months.

Secondary outcome [10]

Iron deficiency anaemia (anaemia measured by HemoCue Hb measurement + ferritin<12ng/uL adjusted for inflammation on biochemistry analyser)

Timepoint [10]

+3, +12 months

Secondary outcome [11]

Diarrhoea: (Incidence) (measured by direct questioning during weekly visits)

Timepoint [11]

0-3 months, 3-12 months

Secondary outcome [12]

Respiratory infection (incidence) (measured by direct questioning during weekly visits)

Timepoint [12]

0-3 months, 3-12 months

Secondary outcome [13]

Bloody diarrhoea (incidence) (measured by direct questioning during weekly visits)

Timepoint [13]

0-3 months, 3-12 months

Secondary outcome [14]

Fever (incidence) (measured by direct questioning during weekly visits)

Timepoint [14]

0-3 months, 3-12 months

Secondary outcome [15]

Unplanned hospital admission (direct questioning during weekly home visits)

Timepoint [15]

0-3 months, 3-12 months

Secondary outcome [16]

Unplanned outpatient clinic visit (measured by direct questioning during weekly home visits)

Timepoint [16]

0-3 months, 3-12 months

Secondary outcome [17]

Cause specific unplanned clinic attendance (by inspection of medical records)

Timepoint [17]

0-3 months, 3-12 months

Secondary outcome [18]

Cause specific hospital admission (by inspection of medical records)

Timepoint [18]

0-3 months, 3-12 months

Secondary outcome [19]

Fever (number of days affected) (measured by direct questioning during routine visits)

Timepoint [19]

0-3 months, 3-12 months

Secondary outcome [20]

Bloody diarrhoea (number of days affected) (measured by direct questioning during weekly visits)

Timepoint [20]

0-3 months, 3-12 months

Secondary outcome [21]

Respiratory Infection (number of days affected) (measured by direct questioning during weekly visits)

Timepoint [21]

0-3 months, 3-12 months

Secondary outcome [22]

Diarrhoea (number of days affected) (measured by direct questioning during weeky visits)

Timepoint [22]

0-3 months, 3-12 months

Secondary outcome [23]

Neurodevelopment measured by electroencephalography (EEG).

Timepoint [23]

+ 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

Sex

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

Completed

Date of first participant enrolment

Anticipated

1/06/2017

Actual

6/07/2017

Date of last participant enrolment

Anticipated

31/03/2019

Actual

16/02/2019

Date of last data collection

Anticipated

31/03/2020

Actual

10/02/2020

Sample size

Target

3300

Accrual to date

Final

3300

Recruitment outside Australia

Country [1]

Bangladesh

State/province [1]

Rupganj, Narayanganj district

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

University of Melbourne

Address

Grattan Street,
Parkville,
VIC 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

Country [1]

Other collaborator category [1]

Other

Name [1]

International Centre for Diarrhoeal Diseases Research, Bangladesh

Address [1]

GPO Box 128
Dhaka 1000
Bangladesh

Country [1]

Bangladesh

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

International Centre for Diarrhoeal Diseases Research, Bangladesh - Ethical Review Committee

Ethics committee address [1]

GPO Box 128 
Dhaka 1000 
Bangladesh

Ethics committee country [1]

Bangladesh

Date submitted for ethics approval [1]

21/09/2016

Approval date [1]

27/11/2016

Ethics approval number [1]

PR-16063

Ethics committee name [2]

Melbourne Health

Ethics committee address [2]

Melbourne Health
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Australia

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

09/11/2016

Approval date [2]

23/01/2017

Ethics approval number [2]

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

Prof Beverley-Ann Biggs

Address

Melbourne Health
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Australia

Country

Australia

Phone

+613 83443257

Fax

+61383443257

babiggs@unimelb.edu.au

Contact person for public queries

Name

Sant-Rayn Pasricha

Address

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

Australia

Phone

+613 9345 2618

Fax

Pasricha.s@wehi.edu.au

Contact person for scientific queries

Name

Sant-Rayn Pasricha

Address

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

Australia

Phone

+6139345 2618

Fax

Pasricha.s@wehi.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Data, Data Dictionaries, Summary Results

When will data be available (start and end dates)?

Start date: 31st December 2022. No end date determined.

Available to whom?

Researchers who provide a methodologically sound proposal, decided on a case-by-case basis at the discretion of Principal Investigators

Available for what types of analyses?

Only to achieve the aims in the approved proposal, for IPD meta-analyses

How or where can data be obtained?

Access subject to approvals by Principal Investigator (contact pasricha.s@wehi.edu.au)

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
7372	Study protocol			pasricha.s@wehi.edu.au

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Benefits and risks of Iron interventions in children (BRISC): Protocol for a three-arm parallel-group randomised controlled field trial in Bangladesh.	2017	https://dx.doi.org/10.1136/bmjopen-2017-018325
Embase	Immediate impact of stay-at-home orders to control COVID-19 transmission on socioeconomic conditions, food insecurity, mental health, and intimate partner violence in Bangladeshi women and their families: an interrupted time series.	2020	https://dx.doi.org/10.1016/S2214-109X%2820%2930366-1
Embase	Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.	2021	https://dx.doi.org/10.1056/NEJMoa2034187
Embase	Preanalytic and analytic factors affecting the measurement of haemoglobin concentration: Impact on global estimates of anaemia prevalence.	2021	https://dx.doi.org/10.1136/bmjgh-2021-005756
Embase	Effects of iron supplementation on neural indices of habituation in Bangladeshi children.	2023	https://dx.doi.org/10.1016/j.ajcnut.2022.11.023
Embase	Supplementation With Iron Syrup or Iron-Containing Multiple Micronutrient Powders Alters Resting Brain Activity in Bangladeshi Children.	2023	https://dx.doi.org/10.1016/j.tjnut.2022.12.026
Dimensions AI	Haemoglobin thresholds to define anaemia from age 6 months to 65 years: estimates from international data sources	2024	https://doi.org/10.1016/s2352-3026(24)00030-9

N.B. These documents automatically identified may not have been verified by the study sponsor.

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