A Phase 2 interventional study of IHAT and Ferrous Sulphate in Iron Deficiency, Anaemia in Children, sponsored by London School of Hygiene and Tropical Medicine. Completed at 1 site in Gambia. Open to participants aged 6 Months to 35 Months, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-08-14.
Sponsored by London School of Hygiene and Tropical Medicine · Phase 2, Interventional, and Treatment
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.
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
Exclusion Criteria:
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
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
Placebo arm: 'no iron' arm - 1 dose/day containing saccharose powder
Other: Placebo
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)
1 dose/day single IMP containing FeSO4 powder equivalent to 12.5 mg Fe
1 dose/day containing a placebo powder (no-iron, 'sugar' compound)
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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: over 12 weeks
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)
Time frame: at baseline, 4 weeks and 12 weeks
hospitalisation events
Number of new hospitalization events per child over the 12 weeks (questionnaire
Time frame: 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)
Time frame: 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)
Time frame: over 12 weeks
Proportion of children with enteric pathogens
Proportion of children with enteric pathogens at baseline, 4 weeks and 12 weeks (targeted qPCR)
Time frame: at baseline, 4 weeks and 12 weeks
Gut inflammation
Gut inflammation measured with faecal calprotectin (ELISA)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: baseline day 1, day 15 and day 85
Serum hepcidin
Serum hepcidin (ELISA). Marker of systemic iron handling
Time frame: 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.
Time frame: baseline day 1, day 15 and day 85
Transferrin saturation
Transferrin saturation (Cobas analyser). Marker of systemic iron handling
Time frame: baseline5day 1, day 14 and day 85
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London School of Hygiene and Tropical Medicine