Clinical trial NCT02941081: A Novel Nano-iron Supplement to Safely Combat Iron Deficiency and Anaemia in Young Children: a Doubleblind Randomised Controlled Trial
Official title: A Novel Nano-iron Supplement (IHAT) to Safely Combat Iron Deficiency and Anaemia (IDA) in Young Children: a Doubleblind Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Iron Deficiency, Anaemia in Children
Keywords: iron supplement
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
Collaborators: name: National Nutrition Agency (NaNa), The Gambia
name: Wellcome Trust
name: King's College London
name: University of Cambridge
name: MRC UK Biostatistics Unit
First posted: 2016-10-21
Enrollment: 645
Sex: ALL
Minimum age (years): 6
Maximum age (years): 35
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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)

Primary outcomes:
measure: proportion of children with iron deficiency
timeFrame: at 12 weeks
measure: Proportion of children with anaemia
timeFrame: at 12 weeks
measure: incidence density' of moderate-severe diarrhea episodes
timeFrame: over 12 weeks
measure: period prevalence of moderate-severe diarrhoea
timeFrame: over 12 weeks
Secondary outcomes:
measure: Alpha diversity and beta diversity of the faecal microbiome
timeFrame: at baseline, 4 weeks and 12 weeks
measure: hospitalisation events
timeFrame: over 12 weeks period
measure: Ratio of enterobacteria/(bifidobacteria+lactobacilli) abundances
timeFrame: at baseline, 4 weeks and 12 weeks
measure: Proportion of children with episodes of respiratory tract infections and malaria
timeFrame: over 12 weeks
measure: Proportion of children with enteric pathogens
timeFrame: at baseline, 4 weeks and 12 weeks
measure: Gut inflammation
timeFrame: baseline day 1, day 15 and day 85
measure: Longitudinal prevalence of moderate-severe diarrhoea
timeFrame: over 12 weeks
measure: Incidence density of 'bloody' diarrhea per month
timeFrame: per month
measure: Serum C-reactive protein and Alpha-1-acid glycoprotein
timeFrame: baseline day 1, day 15 and day 85
measure: Serum hepcidin
timeFrame: baseline 1day 1, day 15 and day 85
measure: Serum non-transferrin bound iron
timeFrame: baseline day 1, day 15 and day 85
measure: Transferrin saturation
timeFrame: baseline5day 1, day 14 and day 85
Other outcomes:
Locations:
city: Basse
country: Gambia
facility: MRC Unit The Gambia
state: Upper River Region
Study officials:
affiliation: Cambridge University, UK
name: Dora Pereira, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Goffau MC, Jallow AT, Sanyang C, Prentice AM, Meagher N, Price DJ, Revill PA, Parkhill J, Pereira DIA, Wagner J. Gut microbiomes from Gambian infants reveal the development of a non-industrialized Prevotella-based trophic network. Nat Microbiol. 2022 Jan;7(1):132-144. doi: 10.1038/s41564-021-01023-6. Epub 2021 Dec 31.
citation: Pereira DIA, Mohammed NI, Ofordile O, Camara F, Baldeh B, Mendy T, Sanyang C, Jallow AT, Hossain I, Wason J, Prentice AM. A novel nano-iron supplement to safely combat iron deficiency and anaemia in young children: The IHAT-GUT double-blind, randomised, placebo-controlled trial protocol. Gates Open Res. 2018 Oct 11;2:48. doi: 10.12688/gatesopenres.12866.2. eCollection 2018.