A Novel Nano-iron Supplement to Safely Combat Iron Deficiency and Anaemia in Young Children: a Doubleblind Randomised Controlled Trial

Study Overview
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Brief Summary
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This study aims to determine whether IHAT is non-inferior to ferrous sulphate at correcting iron deficiency and anaemia, and if IHAT does not increase diarrhoea risk in young children living in rural and resource-poor areas of the Gambia. The study hypothesis is that IHAT will eliminate iron deficiency and improve haemoglobin levels in young children without increasing infectious diarrhoea or promoting inflammation in the gut.

Detailed Description
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The primary objectives of this trial are: (i) show non-inferiority of IHAT compared to ferrous sulphate for efficacy (in terms of Hb and iron deficiency correction); (ii) show superiority of IHAT compared to ferrous sulphate in terms of moderate-severe diarrhoea (incidence and prevalence); (iii) show non-inferiority of IHAT compared to placebo in terms of prevalence of moderate-severe diarrhoea. Secondary objectives are: (i) show that IHAT supplementation does not increase enteric pathogen burden; (ii) show that IHAT supplementation is non-detrimental to the gut microbiome; (iii) show that IHAT supplementation does not cause intestinal inflammation; (iv) describe the impact of IHAT supplementation on hospitalisation and morbidity; (v) determine the effect of IHAT supplementation on systemic inflammation; (vi) determine the effect of IHAT supplementation on systemic markers of iron handling. To investigate the primary and secondary objectives the investigators will conduct a 3-arm, parallel, randomised, double-blind, placebo-controlled, phase 2, clinical trial. Participants will be iron deficient anaemic young children living in rural communities in the North Bank of the Upper River Division in The Gambia. The communities and health centres within the study catchment area (Wuli and Sandu districts) will be sensitised to the study. Young children will be identified using the immunisation records at the health centres. At screening, once mothers/guardians of the child have signed the informed consent form, the child will be physically examined by a study nurse and, if the child is considered as generally healthy, their height and weight will be measured and a finger prick blood sample will be collected for Hb and RDT testing. If z-scores are >-3, 7 ≤Hb< 11 g/dL and the RDT is negative, a small venous blood sample will be collected to confirm the Hb levels and determine serum ferritin. A total of 705 eligible children will be randomised into the 3 study arms (n=235 per arm). In each study arm, the children will be supplemented daily for 12 weeks (84 days) with either placebo, ferrous sulphate or IHAT. Blood and stool samples will be collected at baseline (Day 1) and at day 15 and day 85 during the intervention period. Following the 12 weeks of intervention there will be an additional active follow-up period of 4 weeks without intervention. Highly trained and experienced field workers will be visiting all children every day during the 12 weeks supplementation period in order to administer the iron supplements or placebo and on these occasions they will check on the children's general health and actively look for signs of malaria and co-infections. If a child shows signs of these infections, the field worker will refer to the study nurse who will perform adequate tests and the child will be offered the appropriate treatment/referral to the next health center. Three times per week, morbidity data (including questions regarding fever, diarrhoea, vomiting, cough, any other illness, appetite and any mediation taken and assessment of body temperature) will be captured. Every week children will be screened using a finger prick blood sample to determine their malaria and Hb status and children found with a positive RDT during the study will be further tested with a blood film and treated according to national guidelines. These visits will continue 4 weeks post intervention to follow-up on AE/SAEs. Any child where Hb falls below 7 g/dL during the follow-up study period will stop the study and will be referred to the next health centre for managemen

Official Title
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A Novel Nano-iron Supplement (IHAT) to Safely Combat Iron Deficiency and Anaemia (IDA) in Young Children: a Doubleblind Randomised Controlled Trial

Conditions
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Iron Deficiency, Anaemia in Children

Intervention / Treatment
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* Dietary Supplement: IHAT
* Dietary Supplement: Ferrous Sulphate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6-35 mo. Free of malaria (RDT negative) HAZ, WAZ, WHZ >-3 SD IDA defined as 7≤ Hb <11 g/dl AND ferritin<30 μg/L Resident in the study area (and planning to remain in the study area for the duration of the trial) Ability and willingness to comply with the study protocol (daily intake of supplement and daily study visits with weekly finger prick) Informed consent given by parent or guardian Exclusion Criteria: Congenital disorders Chronic disease Currently participating in another study Currently taking iron supplements/multiple micronutrient supplements Currently experiencing moderate-severe diarrhoea, defined as those diarrhoea episodes where (i) the child passes more than 5 loose or watery stools per day, (ii) there is blood in the stool (dysentery), or (iii) the child shows signs of clinical dehydration (assessed by the study nurse based on physical signs such as little or no urination, sunken eyes, and skin that lacks its normal elasticity), will usually require treatment (including ORS)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 35 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IHAT<br>IHAT arm: novel iron supplement - 1 dose/day single IMP containing IHAT (iron hydroxide adipate tartrate) powder bioequivalent to 12.5 mg elemental iron (i.e. 20 mg Fe taking into account IHAT's relative bioavailability to ferrous sulphate) | Dietary Supplement: IHAT<br>* 1 dose/day single IMP containing IHAT powder bioequivalent to 12.5 mg Fe (i.e. 20 mg Fe taking into account IHAT's relative bioavailability to FeSO4)<br>|
| Active Comparator: ferrous sulphate<br>Ferrous sulphate arm: clinical standard of oral iron supplementation - 1 dose/day single IMP containing ferrous sulphate (FeSO4 ) powder equivalent to 12.5 mg elemental iron | Dietary Supplement: Ferrous Sulphate<br>* 1 dose/day single IMP containing FeSO4 powder equivalent to 12.5 mg Fe<br>|
| Placebo Comparator: placebo<br>Placebo arm: 'no iron' arm - 1 dose/day containing saccharose powder | Other: Placebo<br>* 1 dose/day containing a placebo powder (no-iron, 'sugar' compound)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of children with iron deficiency | Proportion of children at 12 weeks with iron deficiency (Cobas analyser). The choice of the marker to use to define iron deficiency will be made at the time of locking the data analysis plan and we will use the most up to date WHO recommendation at the time. But most likely it will be: ferritin <12 mcg/liter, or <30 mcg/liter in the presence of inflammation (CRP>5), and (soluble transferrin receptor - sTfR)/log10 ferritin index >2. | at 12 weeks | 
| Proportion of children with anaemia | Proportion of children at 12 weeks with anaemia (Medonic analyser). Anaemia is defined as haemoglobin < 11 g/dl. | at 12 weeks | 
| incidence density' of moderate-severe diarrhea episodes | Incidence density of moderate-severe diarrhoea episodes over the 12 weeks (questionnaire/assessment by study nurse). Incidence density is defined as the number of new episodes of moderate-severe diarrhoea per child over the 12 weeks intervention | over 12 weeks | 
| period prevalence of moderate-severe diarrhoea | Period prevalence of moderate-severe diarrhea over the 12 weeks (questionnaire/assessment by study nurse). Period prevalence is defined as the proportion of children with at least one episode of moderate-severe diarrhea over the 12 weeks intervention | over 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alpha diversity and beta diversity of the faecal microbiome | Alpha diversity and beta diversity of the faecal microbiome at baseline, 4 weeks and 12 weeks data from MiSeq sequencing of faecal 16S rRNA) | at baseline, 4 weeks and 12 weeks | 
| hospitalisation events | Number of new hospitalization events per child over the 12 weeks (questionnaire | over 12 weeks period | 
| Ratio of enterobacteria/(bifidobacteria+lactobacilli) abundances | Ratio of enterobacteria/(bifidobacteria+lactobacilli) abundances in the faecal microbiome at baseline, 4 weeks and 12 weeks (data from MiSeq sequencing of faecal 16S rRNA) | at baseline, 4 weeks and 12 weeks | 
| Proportion of children with episodes of respiratory tract infections and malaria | Proportion of children with episodes of respiratory tract infections and malaria over the 12 weeks (questionnaire) | over 12 weeks | 
| Proportion of children with enteric pathogens | Proportion of children with enteric pathogens at baseline, 4 weeks and 12 weeks (targeted qPCR) | at baseline, 4 weeks and 12 weeks | 
| Gut inflammation | Gut inflammation measured with faecal calprotectin (ELISA) | baseline day 1, day 15 and day 85 | 
| Longitudinal prevalence of moderate-severe diarrhoea | Longitudinal prevalence of moderate-severe diarrhoea (questionnaire/assessment by study nurse). Longitudinal prevalence is defined as the number of days a child has moderate-severe diarrhea over the 12 weeks intervention | over 12 weeks | 
| Incidence density of 'bloody' diarrhea per month | Incidence density of 'bloody' diarrhea per month (questionnaire/assessment by study nurse). Defined as the number of diarrhea episodes with blood in the stool, as a sign of severe intestinal infection, per child-month of observation | per month | 
| Serum C-reactive protein and Alpha-1-acid glycoprotein | Serum C-reactive protein and Alpha-1-acid glycoprotein (Cobas analyser). Markers of systemic inflammation | baseline day 1, day 15 and day 85 | 
| Serum hepcidin | Serum hepcidin (ELISA). Marker of systemic iron handling | baseline 1day 1, day 15 and day 85 | 
| Serum non-transferrin bound iron | Serum non-transferrin bound iron (flurescence chemical assay). Marker of systemic iron handling. | baseline day 1, day 15 and day 85 | 
| Transferrin saturation | Transferrin saturation (Cobas analyser). Marker of systemic iron handling | baseline5day 1, day 14 and day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iron supplement