Safe and effective delivery of supplemental iron to healthy older adults: The double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study

Erin D Lewis,Dayong Wu,Simin N Meydani,Gerald F Combs,Joel B Mason,Athar H Chishti,John M Leong,Kathryn Barger

doi:10.12688/gatesopenres.13039.1

Abstract

The forms of iron currently available to correct iron deficiency have adverse effects, including infectious diarrhea, increased susceptibility to malaria, inflammation and detrimental changes to the gut microbiome. These adverse effects limit their use such that the growing burden of iron deficiency has not abated in recent decades. Here, we summarize the protocol of the “Safe Iron Study”, the first clinical study examining the safety and efficacy of novel forms of iron in healthy, iron-replete adults. The Safe Iron Study is a double-blind, randomized, placebo-controlled trial conducted in Boston, MA, USA. This study compares ferrous sulfate heptahydrate (FeSO4·H2O) with two novel forms of iron supplements (iron hydroxide adipate tartrate (IHAT) and organic fungal iron metabolite (Aspiron™ Natural Koji Iron)). In Phase I, we will compare each source of iron administrated at a low dose (60 mg Fe/day). We will also determine the effect of FeSO4 co-administrated with a multiple micronutrient powder and weekly administration of FeSO4. The forms of iron found to produce no adverse effects or adverse effects no greater than FeSO4 in Phase I, Phase II will evaluate a higher, i.e., a therapeutic dose (120 mg Fe/day). The primary outcomes of this study include ex vivo malaria (Plasmodium falciparum) infectivity of host erythrocytes, ex vivo bacterial proliferation (of selected species) in presence of host plasma and intestinal inflammation assessed by fecal calprotectin. This study will test the hypotheses that the novel forms of iron, administered at equivalent doses to FeSO4, will produce similar increases in iron status in iron-replete subjects, yet lower increases in ex vivo malaria infectivity, ex vivo bacterial proliferation, gut inflammation. Ultimately, this study seeks to contribute to development of safe and effective forms of supplemental iron to address the global burden of iron deficiency and anemia. Registration: ClinicalTrials.gov identifier: NCT03212677; registered: 11 July 2017.

Highlights

The forms of iron currently available have adverse effects that limit their use in addressing prevalent iron deficiency
Unabsorbed, soluble iron can be used by the gut microbiome and favor the proliferation of pathogenic enteric bacteria[8], which can contribute to the inflammatory response[4,5,9,10] that leads to down-regulation of iron absorption[11]
Outcomes The Safe Iron Study has three primary outcomes to test the formal hypotheses in Phases I and II. These outcomes include malaria (Plasmodium falciparum) infectivity of host erythrocytes, bacterial proliferation in presence of host plasma and intestinal inflammation assessed by fecal calprotectin concentrations

Summary

Introduction

The forms of iron currently available have adverse effects that limit their use in addressing prevalent iron deficiency. Efforts to address iron deficiency through iron supplementation programs have been frustrated by the serious side effects of inorganic forms of iron, which due to low enteric absorptive efficiency, must be given in relatively high levels (i.e., 5–20 fold effective levels of heme-iron in foods). Those adverse effects include infectious diarrhea[1,2,3,4], detrimental changes in the gut microbiome[4,5] and increased serious morbidity among iron-replete children in malaria-endemic areas[6,7], as well as less serious consequences such as dyspepsia and constipation. Unabsorbed, soluble iron can be used by the gut microbiome and favor the proliferation of pathogenic enteric bacteria[8], which can contribute to the inflammatory response[4,5,9,10] that leads to down-regulation of iron absorption[11]

Objectives

Methods

Findings

Discussion

Conclusion