Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000386932
Ethics application status
Approved
Date submitted
5/02/2020
Date registered
20/03/2020
Date last updated
19/04/2022
Date data sharing statement initially provided
20/03/2020
Date results information initially provided
19/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Benefits and safety of IRon supplementation with MAlaria chemoprevention to children in Malawi (IRMA) - A randomised controlled trial
Scientific title
Benefits and safety of IRon supplementation with MAlaria chemoprevention to children in Malawi (IRMA) - A randomised controlled trial
Secondary ID [1] 300455 0
Nil Known
Universal Trial Number (UTN)
U1111-1247-7739
Trial acronym
IRMA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 316117 0
Malaria 316118 0
Impaired child cognitive development 316119 0
Stunting 316120 0
Diarrhoea 316121 0
Iron Deficiency 316122 0
Condition category
Condition code
Blood 314408 314408 0 0
Anaemia
Infection 314409 314409 0 0
Other infectious diseases
Diet and Nutrition 314410 314410 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Combinations of three drugs will be administered to participants:
1. DP 20mg dihydroartemisinin/ 160mg piperaquine tablets) orally, three consecutive days every 4 weeks for 6 months

DP will be dosed by weight according to WHO recommendations: <8kg 1 tablet/d for 3d; 8-<11kg 1.5 tablets/d for 3d; 11-<17kg 2 tablets/d for 3d

2. Multiple Micronutrient Powders: sprinkled over food or dissolved in breastmilk Composition per one gram sachet:
• Iron 10 mg (as coated Ferrous fumerate, NaFe EDTA*or Ferrous bisglycinate)
• Zinc 4.1. mg (as Zinc sulphate, or gluconate)
• Vitamin A 400 µg (as dry CWS vitamin A acetate or palmitate beadlets) Vitamin C 30 mg (as sodium or calcium ascorbate)
• Vitamin D 5 µg (200IU) (as dry CWS Cholecalciferol)
• Vitamin E 5 mg TE (as CWS d or dl-alpha tocopheryl acetate)
• Vitamin B1 0.5 mg (as Thiamine mononitrate)
• Vitamin B2 0.5. mg (Riboflavin or riboflavin -5-phosphate)
• Vitamin B3 6 mg (as Nicotinamide)
• Vitamin B6 0.5. mg (as Pyridoxine hydrochloride)
• Vitamin B12 0.9 µg (1% or 0.1% Cyanocobalamin on a carrier )
• Folic acid 90 µg (anhydrous)
• Copper 0.56 mg (as Copper gluconate or sulphate)
• Selenium 17 µg (as Sodium selenate or selenite or selenomethionine)
• Iodine 90 µg (as Potassium iodide, or potassium iodate)
• Maltodextrin as vehicle for micronutrients

3. Iron syrup: Elemental Iron 10mg as ferrous sulfate, provided as 1.3mL of of 8mg/mL solution.

There will be four groups in this trial:
1) Placebo DP plus placebo MNPs plus placebo iron syrup (No intervention): Placebo MNPs (maltodextrin vehicle only) daily for 6 months plus placebo DP (tablets) three consecutive days every 4 weeks for 6 months plus placebo iron syrup daily.
2) Active DP plus placebo MNPs plus placebo iron syrup (DP alone): Active DP (20mg dihydroartemisinin/ 180mg piperaquine tablets) dosed by body weight, three consecutive days every 4 weeks plus daily placebo MNPs (maltodextrin) daily, plus daily placebo iron syrup, for 6 months
3) Active DP plus active MNPs plus placebo iron syrup (DP+MNP): Active DP as above, plus daily active MNPs containing 10.0mg iron and other micronutrients (see below), plus placebo iron syrup daily for 6 months
4) Active DP plus placebo MNPs plus active iron syrup (DP+iron syrup): Active DP as above, plus placebo MNPs as above, plus active iron syrup containing 10.0mg ferrous sulfate daily.

Adherence will be monitored by direct questioning of parents/ guardians at fortnightly home visits.

Based on the National Health Sciences Research Committee's guidance, a pandemic rationalisation plan was developed in 2020 to preemptively minimise any impacts of the pandemic on the health of the participants and staff involved in the trial. Once the pandemic rationalisation plan was active, the fortnightly monitoring home visits of parents/guardians were reduced to a monthly visit instead. The pandemic rationalisation plan received ethics approval in Malawi and Australia.
Intervention code [1] 316751 0
Treatment: Drugs
Comparator / control treatment
1. Placebo DP Vehicle used for active drug without active ingredient
2. Placebo MNPs Maltodextrin with colouring and flavouring
3. Placebo Iron syrup Sugar liquid with colouring to darken to similar colour as iron
Control group
Placebo

Outcomes
Primary outcome [1] 322759 0
Cognitive development: assessed by the Bayley® 3rd Edition (Bayley-III) Cognitive Composite Score (CogCS)
Timepoint [1] 322759 0
End Intervention period (6 months post recruitment)
Secondary outcome [1] 379598 0
Cognitive development (Bayley® 3rd Edition (Bayley-III) Cognitive Composite Score (CogCS))
Timepoint [1] 379598 0
Following 6 month post-intervention follow up period (18 months of age, 12 months post randomisation)
Secondary outcome [2] 379599 0
Motor and language development , using Bayley-III Motor (MotCS) and Language (LangCS) Composite Scores
Timepoint [2] 379599 0
6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [3] 379600 0
Behaviour, assessed by Wolke’s Behaviour Ratings (WBR)
Timepoint [3] 379600 0
6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [4] 379601 0
Growth (mean) z-scores: weight-for-age (measured using digital scales and calculated using WHO child growth standards)
Timepoint [4] 379601 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [5] 379602 0
Growth (mean) z-scores: length-for-age (measured using infantometer and calculated using WHO child growth standards)
Timepoint [5] 379602 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [6] 379604 0
Growth (mean) z-scores: weight-for-length, (measured using digital scale/ infantometer, and calculated using WHO child growth standards)
Timepoint [6] 379604 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [7] 379605 0
Head circumference (measured using standardised tape measure, using WHO growth standards)
Timepoint [7] 379605 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [8] 379606 0
Stunting (length for age z score as measured using infantometer <-2) according to WHO Growth Standards
Timepoint [8] 379606 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [9] 379607 0
Underweight (weight for age z score as measured using digital scales <-2, WHO child growth standards)
Timepoint [9] 379607 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [10] 379608 0
Wasting (length measured by infantometer and weight measured by digital scales, weight for length <-2), WHO child growth standards
Timepoint [10] 379608 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [11] 379609 0
Haemoglobin (g/dL) in whole blood measured by HemoCue
Timepoint [11] 379609 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [12] 379610 0
Anaemia (Haemoglobin <11g/dL) calculated using haemoglobin measurement above
Timepoint [12] 379610 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [13] 379611 0
Ferritin measured on serum by automated biochemistry analyser
Timepoint [13] 379611 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [14] 379612 0
Iron Deficiency (ferritin as measured on serum above, <12ug/L adjusted for inflammation)
Timepoint [14] 379612 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [15] 379614 0
Iron deficiency anaemia (iron deficiency AND anaemia simultaneously as measured using hemoCue to detect anaemia (Haemoglobin<11g/dL) on whole blood, and ferritin (<15ug/L on serum)
Timepoint [15] 379614 0
Baseline, 6 months post recruitment (end intervention); 12 months post recruitment (end follow up)
Secondary outcome [16] 379615 0
Clinical malaria: defined as fever >37.5oC measured by thermometer + >5000 parasites/mL3 measured using thin film slide examination by microscopist. Clinical malaria will be detected via active and passive clinical visits.
Timepoint [16] 379615 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [17] 379616 0
Severe malaria (hospitalization, severe anaemia, cerebral malaria, death) via hospitalisation medical records
Timepoint [17] 379616 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [18] 379617 0
Unplanned hospital / other unplanned health-care facility attendance. Field worker direct questioning:
0 to 6m: unplanned visits in previous fortnight.
6m to 12m: unplanned visits in previous month.
Timepoint [18] 379617 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [19] 379618 0
Infectious morbidity - diarrhoea (Field worker direct questioning:
0 to 6m: episodes in the previous fortnight.
6m to 12m: episodes in the previous month.)
Timepoint [19] 379618 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [20] 379619 0
Infectious morbidity - respiratory infection (Field worker direct questioning:
0 to 6m: episodes in the previous fortnight.
6m to 12m: episodes in the previous month.)
Timepoint [20] 379619 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [21] 379620 0
Infectious morbidity - fever (Field worker direct questioning:
0 to 6m: episodes in the previous fortnight.
6m to 12m: episodes in the previous month.)
Timepoint [21] 379620 0
0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [22] 379621 0
Adverse effects - constipation. Field worker passive questioning:
0 to 6m: events in previous fortnight.
Timepoint [22] 379621 0
0 to 6 months (intervention period)
Secondary outcome [23] 379622 0
Adverse effects - vomiting. Field worker passive questioning:
0 to 6m: events in previous fortnight.
Timepoint [23] 379622 0
0 to 6 months (intervention period)
Secondary outcome [24] 379623 0
Adherence - audit of medication packs
Timepoint [24] 379623 0
During intervention period
Secondary outcome [25] 379624 0
Home stimulation using Family Care Indicators tool
Timepoint [25] 379624 0
Baseline, +6 months, +12 months
Secondary outcome [26] 379625 0
Sub microscopic parasitaemia by PCR (Capillary blood for filter paper for PCR)
Timepoint [26] 379625 0
Baseline, +6 months, +12 months; 0 to 6 months (intervention period); 6-12 months (post-intervention period)
Secondary outcome [27] 379626 0
Microscopic parasitaemia (whole blood analysed by microscopy of slides, rapid diagnostic tests)
Timepoint [27] 379626 0
+ 6 months, +12 months
Secondary outcome [28] 379627 0
Healthcare utilisation measured by questionnaire, Hospital/ clinic records on diagnostic tests, drugs and supplies used, length of stay adapted for use in this study.
Timepoint [28] 379627 0
Baseline, +6 months, +12 months, during intervention and post-intervention period
Secondary outcome [29] 379628 0
Program and Healthcare unit costs measured by questionnaire and calculation of unit cost of field worker time, clinic visits, hospital bed day, medications, diagnostics from national price lists, clinic and hospital invoices, drug prices adapted for use in this study.
Timepoint [29] 379628 0
Baseline, +6 months, +12 months

Eligibility
Key inclusion criteria
1. Infants aged 6 months (+/- 14 days) at the time of randomisation
2. Has a legally acceptable guardian/representative capable of understanding the informed consent document and providing consent on the participant’s behalf
Minimum age
6 Months
Maximum age
6 Months
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Severe anaemia (Hb<7g/dL) or
2. Current infective illness with fever (respiratory infection, diarrhoea, malaria); however, children will be screened again after recovery and recruited as long as they meet the age eligibility criteria at second screening
3. Severe malnutrition (weight-for-length z-score<-3);
4. Established diagnosis of haemoglobinopathy (e.g. sickle cell disease, beta thalassaemia major, HbE-beta thalassaemia).
5. Legal guardian unwilling or unable to provide written informed consent
6. Known congenital anomaly, developmental disorder or severe developmental delay
7. Children with physical or behavioural problems that will make it impossible to test the child
8. Children of multiple birth e.g. twin, triplets etc.
9. Currently consuming MNPs e.g. from the National MNP programme

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
Active, not recruiting
Date of first participant enrolment
Anticipated
6/04/2020
Actual
13/04/2020
Date of last participant enrolment
Anticipated
28/05/2021
Actual
10/10/2021
Date of last data collection
Anticipated
27/05/2022
Actual
Sample size
Target
2168
Accrual to date
Final
2168
Recruitment outside Australia
Country [1] 22314 0
Malawi
State/province [1] 22314 0
Chikwawa DIstrict

Funding & Sponsors
Funding source category [1] 304870 0
Government body
Name [1] 304870 0
National Health and Medical Research Council
Country [1] 304870 0
Australia
Primary sponsor type
University
Name
College of Medicine, University of Malawi
Address
Private Bag 360, Chichiri, Blantyre 3,
Country
Malawi
Secondary sponsor category [1] 305218 0
None
Name [1] 305218 0
Address [1] 305218 0
Country [1] 305218 0
Other collaborator category [1] 281172 0
Other Collaborative groups
Name [1] 281172 0
Walter and Eliza Hall Institute of Medical Research
Address [1] 281172 0
1G Royal Pde
Parkville VIC 3052
Country [1] 281172 0
Australia
Other collaborator category [2] 281173 0
University
Name [2] 281173 0
University of Melbourne
Address [2] 281173 0
Grattan Street,
Parkville,
VIC 3052
Country [2] 281173 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305278 0
National Health Sciences Research Committee (NHSRC)
Ethics committee address [1] 305278 0
MINISTRY OF HEALTH AND POPULATION
P.O. BOX 30377 LILONGWE 3
MALAWI
Ethics committee country [1] 305278 0
Malawi
Date submitted for ethics approval [1] 305278 0
18/02/2019
Approval date [1] 305278 0
25/03/2019
Ethics approval number [1] 305278 0
19/01/2213
Ethics committee name [2] 305291 0
Walter and Eliza Hall Research Institute
Ethics committee address [2] 305291 0
1G Royal Pde
Parkville VIC 3052
Ethics committee country [2] 305291 0
Australia
Date submitted for ethics approval [2] 305291 0
19/06/2019
Approval date [2] 305291 0
11/09/2019
Ethics approval number [2] 305291 0
19/01

Summary
Brief summary
Hypothesis: Cognitive development at the end of intervention in children receiving iron syrup plus DP, or iron-containing MNPs plus DP, is superior to that of children receiving DP alone, or DP alone is superior to placebo.

The primary objective for this study is to deterimine if iron supplements or iron-containing MNPs given under DP cover is superior to DP alone or DP alone is superior to placebo on child cognitive development at the end of intervention.

Methods: This will be a four-arm parallel-group, double blinded, placebo controlled, triple dummy, individually randomised trial. The study will compare the effects of: a) no intervention, b) DP alone, c) MNP+DP, and d) iron supplements +DP after both 6-months intervention and 6 months follow-up post-intervention to evaluate both immediate and medium-term effects. 2168 six months (+/- 14 days) old children (542 in each arm) will be recruited. Eligible children will include those with Hb>=7.0g/dL while those with gross developmental delay, congenital anomalies and severe infective illness will be excluded.

Expected findings: In this study, we will measure childs’s cognitive, motor and language development after iron supplementation and DP cover as measured on Bayley-III, child’s behaviour measured on Wolke’s rating scales, temperament, quality of home stimulation using family care indicators. The safety of iron supplements and MNPs will be measured though morbidity assessment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99862 0
A/Prof Sant-Rayn Pasricha
Address 99862 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Pde
Parkville VIC 3052
Country 99862 0
Australia
Phone 99862 0
+61 3 9345 2618
Fax 99862 0
Email 99862 0
[email protected]
Contact person for public queries
Name 99863 0
A/Prof Sant-Rayn Pasricha
Address 99863 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Pde
Parkville VIC 3052
Country 99863 0
Australia
Phone 99863 0
+61 3 9345 2618
Fax 99863 0
Email 99863 0
[email protected]
Contact person for scientific queries
Name 99864 0
A/Prof Sant-Rayn Pasricha
Address 99864 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Pde
Parkville VIC 3052
Country 99864 0
Australia
Phone 99864 0
+61 3 9345 2618
Fax 99864 0
Email 99864 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?
individual participant data underlying published results only
When will data be available (start and end dates)?
IPD available from 31st December 2025 onwards (no end date)
Available to whom?
case-by-case basis at the discretion of Principal Investigator
Available for what types of analyses?
To achieve the aims in an approved proposal, for IPD meta-analyses.
How or where can data be obtained?
access subject to approvals by Principal Investigator (email [email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15821Study protocolNA [email protected]



Results publications and other study-related documents

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