Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001271493
Ethics application status
Approved
Date submitted
6/09/2016
Date registered
9/09/2016
Date last updated
21/01/2019
Date data sharing statement initially provided
21/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of nutrition-improved wheat-based food on the health of primary school children aged 6-12 years in Morobe province
Scientific title
Efficacy of multi-micronutrient fortified wheat-based food on the nutrition status of primary school children aged 6-12 years in Lae, Papua New Guinea
Secondary ID [1] 289327 0
Nil known
Universal Trial Number (UTN)
U1111-1183-3705
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Micronutrient malnutrition 298927 0
Condition category
Condition code
Diet and Nutrition 299004 299004 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be assessing the efficacy of micronutrient fortified biscuits on improving the nutrition status of children aged between 6 and 12 years in schools within the city of Lae. Two schools will be selected from urban Lae for the study, which is planned to commence at the end of January 2018 and conclude in June 2018 for 2 terms of the school year. This equates to approximately 100 school days.

Following screening, enrolment, baseline assessment, deworming and allocation (randomised, stratified by age, and blocked by sex), each child will receive wheat flour-based biscuits. In the case of the 'Intervention Group', these biscuits will be fortified with food-grade vitamins and minerals. Specifically, thiamin mononitrate (Vit. B1), riboflavin (B2), nicotinamide (B3), folic acid (B9), cyanocobalamin (B12), retinyl palmitate (Vit. A), iron (ferrous fumarate), and zinc (zinc oxide).

The recommended fortification level in wheat flour is provided below based on a per capita daily consumption of between 75-149g of wheat flour:

Micronutrient (compound form) - concentration (microgram/g in wheat flour)
Iron (Ferrous fumarate) - 60 microgram/g
Vitamin A (Retinyl palmitate) - 3 microgram/g
Zinc (Zinc oxide) - 80 microgram/g
Folic Acid - 2.6 microgram/g
Thiamine (Thiamine mononitrate) - 10 microgram/g
Riboflavin - 2 microgram/g
Niacin (Nicotinamide) - 130 microgram/g
Vitamin B12 (Cyanocobalamin) - 0.02 microgram/g

When formulating the biscuits for children, the targets for addition have been based on the lower end of the consumption range. Therefore, the dose of vitamins in each biscuit has been calculated to provide the equivalent intake as would be found in the daily consumption of 75g of fortified wheat flour, These figures will be:

Micronutrient (compound form) - concentration (microgram/g in biscuit formulation)
Iron (Ferrous fumarate) - 225.00 microgram/g
Vitamin A (Retinyl palmitate) - 11.25 microgram/g
Zinc (Zinc oxide) - 300 microgram/g
Folic Acid - 9.75 microgram/g
Thiamine (Thiamine mononitrate) - 37.5 microgram/g
Riboflavin - 7.5 microgram/g
Niacin (Nicotinamide) - 487.50 microgram/g
Vitamin B12 (Cyanocobalamin) - 0.08 microgram/g

Each child will receive one biscuit per day of attendance throughout the study period except school and public holidays.

Biscuits will be provided to students by their school teachers, who will have been trained by the research team on allocation methods and compliance. Teachers will have access to a sheet linking students' identities to biscuit code allocations, but will be blind to which biscuits are intervention or control. Students will be called from a roll sheet by name to collect their biscuits from the teacher.

Intervention fidelity will be assessed by means of spot checks by local researchers and assistants from the PNG University of Technology in Lae. Teachers will also be asked to record absentees, and reasons for absenteeism. This will assist in post-trial association between intervention and morbidity throughout the course of the intervention.

Researchers and assistants will also be blinded to intervention product code identities throughout the trial from allocation to after statistical analysis (by means of an academic statistician otherwise unaffiliated with our project, from the School of Public Health & Community Medicine at UNSW Sydney), so privacy and research fidelity will likewise be secure from the researcher side during spot-checking activities.

Deworming treatment will be provided to all participants at the time of baseline assessment when biological sample collection and assessments are being taken. This treatment will be in the form of a single 400mg tablet dose of Albendazole administered by trained nurses. Albendazole is effective on Hookworm, Roundworm and Whipworm soil transmitted helminth (STH) infections common in PNG, and is recommended by the World Health Organization for use in Mass Drug Administration (MDA) programs.
Intervention code [1] 294881 0
Treatment: Other
Comparator / control treatment
The Control Group's treatment will consist of wheat flour-based biscuits with the same macronutrient profile and sensory/organoleptic characteristics as the intervention product, but with the exclusion of added vitamins or minerals.
Control group
Placebo

Outcomes
Primary outcome [1] 298663 0
A change in blood haemoglobin concentration.
Assessment conducted on capillary blood collected via finger puncture using semi-automated lancets. Between 250-500 microlitres of blood to be collected in a microtainer, from which the blood is transferred to a HemoCue Haemoglobin analyser using the appropriate cuvette.
Timepoint [1] 298663 0
Assessed at baseline and at project closeout,
Secondary outcome [1] 327552 0
Plasma Ferritin
Reflects total body iron stores and is decreased in deficient subjects. Cutoff for mild deficiency <15 micrograms/litre (children aged 5 years or older)

Chemiluminescent immunoassay
Timepoint [1] 327552 0
Assessed at baseline and at project closeout,
Secondary outcome [2] 327553 0
Plasma Zinc
Evaluated in conjunction with a secondary indicator, namely red rlood rell zinc, due to homeostatic regulation. Cutoff for deficiency is <70 micrograms/decilitre.

Inductively Coupled Mass Spectrometer (ICP-MS)
Timepoint [2] 327553 0
Assessed at baseline and at project closeout
Secondary outcome [3] 327554 0
Plasma Retinol
Good indicator of vitamin A status at population level.
Mild deficiency 0.35-0.7 micromole/Litre; Severe <0.35 micromole/Litre

HPLC Analysis
Timepoint [3] 327554 0
Assessed at baseline and at project closeout,
Secondary outcome [4] 327555 0
Serum Holo-TC in addition to the already indicated total Vitamin B12 and MMA, will also be tested as this is a more sensitive indicator compared to serum total Vitamin B12 alone. This is a composite outcome for assessing Vitamin B1 status.
Timepoint [4] 327555 0
Assessed at baseline and at project closeout,
Secondary outcome [5] 327561 0
Serum: Transferrin Receptors (TfR)
Useful indicator of iron status; not affected by infection and thus can be used in combination with measurement of serum ferritin to confirm deficiency in cases of infection.

Turbidimetric immunoassay
Timepoint [5] 327561 0
Assessed at baseline and at project closeout,
Secondary outcome [6] 327562 0
Serum C-Reactive Protein (CRP)
Acute phase protein which is used to indicate presence of infection.

Turbidimetric immunoassay
Timepoint [6] 327562 0
Assessed at baseline and at project closeout,
Secondary outcome [7] 327563 0
Serum Folate
Serum folate is the most widely used indicator of folate status. It is considered to be a sensitive indicator of recent intake. Cutoff for deficiency: <10nmol/L

Chemiluminescent immunoassay
Timepoint [7] 327563 0
Assessed at baseline and at project closeout,
Secondary outcome [8] 327564 0
Serum B12
Reflects both recent intake and body stores, however values above the cut-off do
not necessarily indicate adequate status. Hence, this is used in conjunction with Plasma MMA. Cutoff to define deficiency: <203 mg/L

Chemiluminescent immunoassay
Timepoint [8] 327564 0
Assessed at baseline and at project closeout,
Secondary outcome [9] 327565 0
Red Cell Zinc
Used as a secondary indicator with plasma zinc.

Inductively Coupled Mass Spectrometer (ICP-MS)
Timepoint [9] 327565 0
Assessed at baseline and at project closeout,
Secondary outcome [10] 327566 0
Red Cell Thiamine Transketolase Activity Coefficient (ETKA)
Cutoff to define deficiency: >=1.2% (mild); >=1.25% Severe

HPLC Analysis
Timepoint [10] 327566 0
Assessed at baseline and at project closeout,
Secondary outcome [11] 327567 0
Red Cell Flavin nucleotides
Method involves hydrolysis of FAD to flavin nucleotide.
Cutoff to define deficiency: <400 nmol/L (mild);<270 nmol/L (Severe)

HPLC analysis.
Timepoint [11] 327567 0
Assessed at baseline and at project closeout,
Secondary outcome [12] 327568 0
Red Cell Pyridine nucleotides,
A potentially sensitive indicator of niacin inadequacy, however there are no universally agreed cutoffs at this time. Will be used to chart changes from the commencement of fortification.

HPLC Analysis
Timepoint [12] 327568 0
Assessed at baseline and at project closeout,
Secondary outcome [13] 327569 0
Red Cell Folate
Erythrocyte folate concentrations reflect long-term folate status and tissue folate stores.
Cutoff to define deficiency: <305 nmol/L (140 micrograms/L)

Chemiluminescent immunoassay
Timepoint [13] 327569 0
Assessed at baseline and at project closeout,

Eligibility
Key inclusion criteria
Generally healthy male and female children aged 6-12 years, from Lae in the Morobe Province of Papua New Guinea.
Minimum age
6 Years
Maximum age
12 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria will include severe anaemia (hemoglobin concentration < 70 g/L), signs of xeropthalmia and evidence of serious chronic disease as observed by clinical nurses who will perform examinations and samples collection.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Recruitment will be conducted by the research team (UNSW and PNG University of Technology) with the direct assistance of the Morobe Divisions of Health and Education, and through the assistance of an academic statistician otherwise unaffiliated with our project from the School of Public Health & Community Medicine at UNSW Sydney.

Personally identifiable details of the participating children will be blinded from the recruitment and research teams through the allocation of Participant ID numbers at the time participant survey completion.

Study foods, control and intervention will be identified according to unique code numbers. Randomisation, blocking and allocation concealment will be managed by a biostatistician from the School of Public Health and Community Medicine at UNSW Sydney. The randomisation will be performed double-blind so that neither the researchers and their associates, nor students are aware of the linkage between participant and food allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible study participants will be stratified into seven groups on the basis of age (ages 6-12 years) at the time of enrolment. Every child in each stratum will then be allocated food products with randomly permuted blocking, taking gender into account as a potential prognostic factor.
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
Phase
Type of endpoint/s
Efficacy
Statistical methods / analysis
Owing to high endemic morbidity from malaria and soil-transmitted helminth (STH) infections (Hookworm) in Papua New Guinea, the primary outcome factor for this study will be haemoglobin concentration as an indicator of anaemia, with remaining nutrients playing a supportive and complementary role in addressing micronutrient deficiencies in the local diet.

According to the 2005 National Nutrition Survey conducted in PNG, the baseline mean haemoglobin levels of the target population in the Mamose region of Papua New Guinea was found to be 102 g/L (+/- SD 18). Other studies conducted in the same region have revealed Hb levels in the range of 91 - 105 g/L (SD: 11-18), all of which fall within deficient levels. On the basis of these findings and the results of a wider literature search into similar fortification studies globally, calculations to compare two independent means (2-sided) have determined a sample size requirement of 308 children per treatment group (616 students total), with a power of 0.91, an alpha of 0.05, a standard deviation of 18g/L, and a minimum difference of 5 g/L haemoglobin. This calculation takes into consideration a possible ‘loss to followup’ of approximately 25%, with the power of the study remaining over 80% with 224 students per treatment group (448 students total).

Blood samples will each be pooled into two groups per strata, per intervention arm, for analysis, which will reduce the burden of analytical assessment & associated requirements whilst maintaining the statistical validity of the study outcome. Individual student’s samples will continue to be stored separately in long term storage (-80C) should further testing be required.

308 subjects per study arm (total of 616 children) will be aimed for with an attempt to include equal number of children in each age group- 6-12 years (pre-pubertal) from urban elementary and primary schools. Random allocation of students within each group will be done. Two urban schools will be targeted for the intervention, with unfortified wheat flour based products as control and fortified wheat flour products (having the recommended level of the nutrients in one portion) being randomly distributed according to the sampling plan. The baseline levels of serum albumin, retinol, ferritin (and C-Reactive Protein), folate and zinc will be measured in the 616 school children. Anthropometric measures such as height, weight, body mass index, mid upper arm circumference (MUAC) will be measured using standard anthropometric measurement tools.

Data analysis will be conducted using statistical package in SPSS, and comparisons will be made between control and intervention subjects assessing for nutritional changes as a consequence of the food products consumed. This will assist the local authorities in shaping a public health response as necessary.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/01/2018
Actual
5/02/2018
Date of last participant enrolment
Anticipated
9/02/2018
Actual
12/02/2018
Date of last data collection
Anticipated
8/12/2017
Actual
15/11/2018
Sample size
Target
616
Accrual to date
Final
403
Recruitment outside Australia
Country [1] 8208 0
Papua New Guinea
State/province [1] 8208 0
Morobe

Funding & Sponsors
Funding source category [1] 294484 0
Commercial sector/Industry
Name [1] 294484 0
Goodman Fielder
Country [1] 294484 0
Australia
Primary sponsor type
University
Name
University of New South Wales (UNSW Australia)
Address
UNSW Australia
School of Chemical Engineering
F10 Chemical Sciences Building
Faculty of Engineering
SYDNEY NSW 2052
Country
Australia
Secondary sponsor category [1] 293353 0
Commercial sector/Industry
Name [1] 293353 0
Goodman Fielder
Address [1] 293353 0
T2, 39 Delhi Road,
North Ryde, NSW 2113,
Country [1] 293353 0
Australia
Other collaborator category [1] 279210 0
University
Name [1] 279210 0
PNG University of Technology
Address [1] 279210 0
University of Technology (Unitech),
Independence Drive,
East Taraka, Lae
Morobe Province, 411
Country [1] 279210 0
Papua New Guinea
Other collaborator category [2] 279211 0
Government body
Name [2] 279211 0
PNG National Department of Health
Address [2] 279211 0
PO Box 807
WAIGANI 131,NCD
Country [2] 279211 0
Papua New Guinea
Other collaborator category [3] 279212 0
Government body
Name [3] 279212 0
Morobe Provincial Administration - Division of Health
Address [3] 279212 0
PO Box 458
Lae, 411 Morobe Province
Country [3] 279212 0
Papua New Guinea
Other collaborator category [4] 279213 0
Government body
Name [4] 279213 0
Morobe Provincial Administration - Division of Education
Address [4] 279213 0
PO Box 315
Lae, 411 Morobe Province
Country [4] 279213 0
Papua New Guinea

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295923 0
UNSW Human Research Ethics Committee (HREC)
Ethics committee address [1] 295923 0
Ethics committee country [1] 295923 0
Australia
Date submitted for ethics approval [1] 295923 0
30/03/2016
Approval date [1] 295923 0
04/07/2016
Ethics approval number [1] 295923 0
HC16256
Ethics committee name [2] 295924 0
PNG Medical Research Advisory Committee (MRAC)
Ethics committee address [2] 295924 0
Ethics committee country [2] 295924 0
Papua New Guinea
Date submitted for ethics approval [2] 295924 0
06/09/2016
Approval date [2] 295924 0
30/01/2017
Ethics approval number [2] 295924 0
MRAC No. 16.37

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1550 1550 0 0
/AnzctrAttachments/369948-MRAC Proposal Approval_ARCOT_J 20170130.pdf (Ethics approval)

Contacts
Principal investigator
Name 62850 0
A/Prof Jayashree Arcot
Address 62850 0
UNSW Australia
School of Chemical Engineering
Room 711, F10 Chemical Sciences Building
Faculty of Engineering
Sydney NSW 2052
Country 62850 0
Australia
Phone 62850 0
+61 2 9385 5360
Fax 62850 0
+61 2 9385 5966
Email 62850 0
[email protected]
Contact person for public queries
Name 62851 0
Jayashree Arcot
Address 62851 0
UNSW Australia
School of Chemical Engineering
Room 711, F10 Chemical Sciences Building
Faculty of Engineering
Sydney NSW 2052
Country 62851 0
Australia
Phone 62851 0
+61 2 9385 5360
Fax 62851 0
+61 2 9385 5966
Email 62851 0
[email protected]
Contact person for scientific queries
Name 62852 0
Jayashree Arcot
Address 62852 0
UNSW Australia
School of Chemical Engineering
Room 711, F10 Chemical Sciences Building
Faculty of Engineering
Sydney NSW 2052
Country 62852 0
Australia
Phone 62852 0
+61 2 9385 5360
Fax 62852 0
+61 2 9385 5966
Email 62852 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
At this point we have not decided on what data can be shared.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.