Gates Open Research Open Peer Review Any reports and responses or comments on the article can be found at the end of the article. STUDY PROTOCOL Safe and effective delivery of supplemental iron to healthy older adults: The double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study [version 1; peer review: awaiting peer review] Erin D. Lewis , Dayong Wu , Joel B. Mason , Athar H. Chishti , John M. Leong , Kathryn Barger , Simin N. Meydani , Gerald F. Combs 1 Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, 02111, USA Department of Developmental, Molecular and Chemical Biology, Tufts University, Boston, Massachusetts, 02111, USA Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts, 02111, USA 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 (FeSO ·H O) 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 FeSO co-administrated with a multiple micronutrient powder and weekly administration of FeSO . The forms of iron found to produce no adverse effects or adverse effects no greater than FeSO 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 malaria ( ex vivo Plasmodium ) infectivity of host erythrocytes, bacterial proliferation (of falciparum ex vivo 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 FeSO , will produce similar increases in iron status in iron-replete subjects, yet lower increases in malaria infectivity, bacterial proliferation, gut ex vivo ex vivo 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. 1 1 1 2 3 1 1 1 1 2 3 Reviewer Status AWAITING PEER REVIEW 19 Jul 2019, :1510 ( First published: 3 ) https://doi.org/10.12688/gatesopenres.13039.1 19 Jul 2019, :1510 ( Latest published: 3 ) https://doi.org/10.12688/gatesopenres.13039.1 v1 4 2 4 4 4 4 Page 1 of 16 Gates Open Research 2019, 3:1510 Last updated: 19 JUL 2019