Safe and effective delivery of supplemental iron to healthy adults: A two-phase, randomized, double-blind trial - the Safe Iron Study

Authors: LEWIS, ERIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ORTEGA, EDWIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DAO, MARIA CARLOTA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BARGER, KATHRYN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LEONG, JOHN - Tufts University; OSBURNE, MARCIA - Tufts University; MAGOUN, LORANNE - Tufts University; NEPVEUX, FELIX - Tufts University; CHISHTI, ATHAR - Tufts University; SCHWAKE, CHRISTOPHER - Tufts University; QUYHN, ANH - Tufts University; GILHOOLY, CHERYL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PETTY, GAYLE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GUO, WEIMIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MATUSZEK, GREGORY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PEREIRA, DORA - Tufts University; REDDY, MANJU - Iowa State University; WANG, JIFAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - 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: Frontiers in Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/28/2023
Publication Date: 10/11/2023
Citation: Lewis, E., Ortega, E.F., Dao, M., Barger, K., Mason, J.B., Leong, J.M., Osburne, M.S., Magoun, L., Nepveux, F.J., Chishti, A.H., Schwake, C., Quyhn, A., Gilhooly, C.H., Petty, G., Guo, W., Matuszek, G.H., Pereira, D., Reddy, M., Wang, J., Wu, D., Meydani, S.N., Combs, G.F. 2023. Safe and effective delivery of supplemental iron to healthy adults: A two-phase, randomized, double-blind trial - the Safe Iron Study. Frontiers in Nutrition. https://doi.org/10.3389/fnut.2023.1230061.
DOI: https://doi.org/10.3389/fnut.2023.1230061

Interpretive Summary: The safety of novel forms of iron in healthy, iron-replete adults has been questioned since some observations suggest they may increase the susceptibility to malaria infection. We therefore tested the hypotheses that supplementation with two novel forms of iron are safe as indicated by susceptibility to malarial infection, bacterial infectivity, and gut irritation compared to a conventional form of iron supplementation. Two phases of randomized, double-blinded trials were conducted by HNRCA investigators. Supplementation with any form of iron did not affect any primary endpoint. In regard to symptoms of gut irritation, there were inconsistent findings between the two phases of the study and no form of iron consistently fared worse. In sum, few differences were found between groups in the primary endpoints, indicating that 28 days of any form of iron may be safe for healthy, iron-replete adults.

Technical Abstract: Background: We examined the safety of supplementation with novel forms of iron in healthy, iron-replete adults. It is relevant to the safety of population-based iron supplementation programs addressing iron deficiency and anemia which inevitably expose individuals who are iron-replete. Objectives: We tested the hypotheses that supplementation of a nanoparticulate iron hydroxide adipate tartrate (IHAT), an organic fungal iron supplement (Aspiron, ASP), and ferrous sulphate heptahydrate (FS) are each safe as indicated by three parameters: ex-vivo susceptibility to malaria infection, ex-vivo bacterial proliferation, and gut inflammation. We also compared responses to FS administered daily or weekly, and daily with or without other micronutrients. Design: The study was conducted in two phases, each a randomized, double-blinded trial in Boston, MA. In Phase I, 160 subjects were randomized to six treatments comprised of a placebo, IHAT, ASP, and FS each administrated daily at the rate of 60 mg Fe/day. FS was also administered with a micronutrient powder (MNP) or as a single weekly dose of 420 mg Fe. In Phase II, 86 subjects were randomized to IHAT, ASP or FS administered at 120 mg Fe/day. In each phase, ex-vivo studies were conducted to determine the susceptibility of subject erythrocytes to infection by Plasmodium falciparum and the proliferation potential of selected pathogenic bacteria in subject sera. Indicators of iron status and gut inflammation were also measured. Results: In both phases, supplementation with any form of iron did not affect the susceptibility to malaria infectivity, the proliferation potential of selected pathogenic bacteria, or indicators of gut inflammation and iron status. Further, the safety of FS administered at 60 mg Fe/day was not affected by either combined dosing with MNP or by the weekly administration of 420 mg Fe. Conclusions: All forms of iron produced comparable responses. These results indicate that 28 days of 60 mg/day or 120 mg/day of two novel forms of iron are safe for healthy, iron-replete older adults compared to FS.