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

Authors: LEWIS, ERIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CHISHTI, ATHAR - Tufts University; LEONG, JOHN - Tufts University; BARGER, KATHRYN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MEYDANI, SIMIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; COMBS, GERALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Gates Open Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2019
Publication Date: 7/19/2019
Citation: Lewis, E.D., Wu, D., Mason, J.B., Chishti, A.H., Leong, J.M., Barger, K., Meydani, S.N., Combs, G.F. 2019. Safe and effective delivery of supplemental iron to healthy older adults: the double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study. Gates Open Research. 3:1510. https://doi.org/10.12688/gatesopenres.13039.1.
DOI: https://doi.org/10.12688/gatesopenres.13039.1

Interpretive Summary: Iron deficiency is a world-wide concern in human health. The inorganic forms of iron currently available to correct iron deficiency, such as ferrous sulfate, 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 problem of iron deficiency has not decreased in recent decades. In this study, a protocol is presented for a clinical trial aimed at evaluating three forms of iron supplements: the form most commonly used in dietary supplements, ferrous sulfate, and two novel forms, iron hydroxide adipate tartrate (IHAT) and a form made from food grade fungus, Aspiron. Iron supplementation will be given for four weeks to healthy, non-iron-deficient subjects to determine whether the forms of iron have comparable effects on iron status, gut irritation, malaria susceptibility, and bacterial proliferation potential in blood. The research paper describes the research objectives, hypothesis, and study design with the goal of examining how the two novel forms of iron supplements might be comparable or more effective than ferrous sulfate in the outcomes to be measured in the clinical trial. The outcome of this study will contribute to development of safe and effective forms of supplemental iron to address the global burden of iron deficiency and anemia.

Technical 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.