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

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.

Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial – the safe iron study

“…The Safe Iron Study design has been described previously (26). Briefly, it was a randomized, double-blind, placebo-controlled, two-phase study with iron supplementation in adults who were ironreplete.…”

“…It consisted of taking a blood sample (7 ml), reviewing participant medical history and general health (including gastrointestinal health history), administering a gut irritation questionnaire, and inquiring about the use of medications and nutritional supplements including iron. Volunteers were eligible on the basis of the criteria previously described (26). Briefly, those included: Inclusion -apparently healthy males and post-menopausal females (no menses for ≥1 year); 50-80 years of age; BMI 18-35 kg/m 2 ; typical bowel pattern of at least one stool every other day; willing to comply with study procedures; Exclusion -taking an iron supplement; any major illness or condition that may interfere with study outcomes at the discretion of the study physician (JBM).…”

“…The sample sizes used in both phases were based on power calculations for each primary outcome as previously described (26). For malarial infectivity, a standard deviation (SD) of 0.202 was estimated from published studies with P. falciparum infectivity (62).…”

“…Effects on iron status were also assessed. The study was conducted in two phases, each comprised of a clinical intervention trials described previously (26,27).…”

“…1Sample sizes due to missing data are indicated for individual variables.2 Interquartile range.pair-wise comparisons. The formal hypotheses of the study(26) were tested by evaluating the following outcomes: metabolic responses as assessed by biomarkers of iron status; the susceptibility of participant RBCs to infection by P. falciparum as assessed ex vivo; the ability of participant plasma to facilitate proliferation of selected species of pathogenic bacteria as assessed ex vivo; and inflammatory responses as assessed by fecal biomarkers of inflammation. Treatment effects were evaluated by the following sets of pairwise comparisons:• Phase I (six treatments each providing 60 mg Fe/day):1.…”