A Novel Nano-Iron Supplement Versus Standard Treatment for Iron Deficiency Anaemia in Children 6-35 Months (IHAT-GUT Trial): A Double-Blind, Randomised, Placebo-Controlled Non-Inferiority Trial in the Gambia

Background: Iron deficiency anaemia (IDA) is the leading cause of years lost to disability in most sub-Saharan African countries and is especially common in young children. The IHAT-GUT trial assessed the efficacy and safety of a novel nano iron supplement, which is a dietary ferritin analogue termed iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in children under 3 years of age. Methods: In this single-centre, randomised, double-blind, parallel, placebo-controlled, non-inferiority study in The Gambia, children 6-35 months with IDA (7£Hb<11g/dL and ferritin<30mg/L) were randomly assigned (1:1:1) to receive either IHAT, ferrous sulphate (FeSO4) or placebo daily for 3 months (85 days). The daily iron dose was 12.5mg Fe equivalent for FeSO4 and the estimated bioequivalent dose for IHAT (20mg Fe). The primary efficacy endpoint was the composite of haemoglobin response at day 85 and correction of iron deficiency. The non-inferiority margin was 10%. The primary safety endpoint was moderate-severe diarrhoea analysed as incidence density and prevalence over the 3 months intervention. Secondary endpoints reported herein include hospitalisation, acute respiratory infection, malaria, treatment failures, iron handling markers, inflammatory markers, longitudinal prevalence of diarrhoea and incidence density of bloody diarrhoea. Main analyses were per-protocol (PP) and intention-to-treat (ITT) analyses. Findings: Between Nov 2017 and Nov 2018, 642 children were randomised into the study (214 per study group). A total of 50 children (26.5%) in the IHAT group achieved the primary efficacy endpoint, as compared with 42 (21.2%) in the FeSO4 group (OR 1.39, 80% CI 1.01-1.91, P=0.0002 for non-inferiority) and with 2 (1%) in the placebo group. Diarrhoea prevalence was similar between groups, with 40 children (21.2%) in the IHAT group developing at least one episode of moderate-severe diarrhoea over the 85 days intervention, compared with 47 (23.7%) in the FeSO4 group (OR 1.18, 80% CI 0.86-1.62,P=0.25 for superiority) and 40 (20.5%) in the placebo group (OR 0.96, 80% CI 0.7-1.33, P=0.001 for noninferiority). Incidence density of moderate-severe diarrhoea was 2.74 in the IHAT group, 3.51 in the FeSO4 group and 2.96 in the placebo group (RR 0.77, 80% CI 0.59-1.01, P=0.11 for superiority). There were 143 children with adverse events (AEs) in the IHAT group, 146 in the FeSO4 group and 143 in the placebo group. There were overall 35 cases of diarrhoea reported as AEs in the IHAT group compared with 51 cases in the FeSO4 group and 37 cases in the placebo group. Interpretation: In young children with IDA, IHAT was non-inferior to standard-of-care FeSO4 in terms of ID correction and haemoglobin response and was not associated with increased adverse events or cases of diarrhoea in comparison with placebo. Clinical Trial Registration Details: This trial is registered with clinicaltrials.gov (NCT02941081). Funding Information: Bill & Melinda Gates Foundation (OPP1140952). Declaration of Interests: D.I.A.P., N.F. and J.J.P. are inventors of the IHAT iron supplementation technology, for which they could receive future awards to inventors through the MRC Awards to Inventor scheme. They are also scientific advisors to Nemysis Ltd, who now hold the license for IHAT. They have received honoraria or consultancy fees from some or all of: Vifor Pharma UK, Shield Therapeutics, Entia Ltd, Danone Nutricia, UN Food and Agriculture Organisation (FAO) and Nemysis Ltd, for work concerning iron in health. D.I.A.P. has since moved to full employment in the iron and health industry with Vifor Pharma UK but all work pertaining to this publication was conducted whilst at the University of Cambridge and MRC Unit The Gambia at LSHTM. Notwithstanding, the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics Approval Statement: The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki, and that are consistent with the International Conference on Harmonisation (ICH) requirements for Good Clinical Practice (GCP), and the applicable regulatory requirements. The study sponsor was the London School of Hygiene and Tropical Medicine (LSHTM) and the study was conducted at the Medical Research Council (MRC) Unit The Gambia at LSHTM (MRCG). Scientific advice on the study protocol was given by the UK Medicines and Healthcare products Regulatory Agency (MHRA 1400, 21/12/2016). The study protocol and any subsequent amendments were reviewed and approved by The Gambia Government/MRC Joint Ethics Committee(reference SCC1489). Clinical Trials Authorisation was granted by the Medicines Control Agency, The Gambia (HP373/347/16/MJK(80)). Informed consent given by parent or guardian.