Patients and methods
®, fatigue, pallor, cheilitis, koilonychia, skin pallor, hepatomegaly, constipation, splenomegaly, glossitis, nausea,
ADVERSE EVENT, CONJUNCTIVA, GLOSSITIS, SECONDARY
ACCESS is a double-dummy, double-blind, randomized, and phase IV clinical trial which took place in the 4th Department of Internal Medicine of the ATTIKON University General Hospital. The study was approved by the Ethics Committees of ATTIKON hospital (approval 2596/31-10-2017), by the National Ethics Committee of Greece (approval 93/17) and by the National Organization for Medicines of Greece (approval IS091/17). Written informed consent was obtained from all study participants before screening. The study was registered (EudraCT number: 2017-002972-5; Enrolled patients were adults of either gender who provided written informed consent and who were meeting all following criteria, also considered by others to frame the characteristics of IDA [Screening was done against all exclusion criteria. If none was met, then the absolute RBC count, Hb, MCV, MCH, and ferritin were analyzed. If the obtained values for all these parameters were within the inclusion criteria, then the patient could be enrolled in the study. The total screening period could not last for more than 1 week.Patients were randomly 1:1 assigned to double-blind and double-dummy treatment with FeSOFeSOFe-ASP: Patients were taking every day for 12 weeks two oral placebo capsules. The capsules were containing the following inactive excipients: polyvidone K30, titanium dioxide CI 77891 E171, glyceryl monostearate, beeswax white, sucrose, iron oxide red CI 77491 E172, green lake 180790, starch maize, talc purified, kaolin heavy, erythrosine CI 45430 E127, patent blue V CI 42051 E131, gelatin. Patients were instructed to receive the capsules either 2 h before meal or 2 h after meal. The same patients were taking every day at the same time for 12 weeks two vials of 15 ml volume of the Fe-Asp preparation Omalin® (Uni-Pharma SA) delivering 40 mg of elementary iron.Every participant was subject to four study visits: at baseline (time 0), at 7 ± 1 days from the start of the study drug, at 4 weeks from the start of the study drug, and at 12 weeks from the start of the study drug. On visit days of baseline, 4 weeks, and 12 weeks, patients were (i) subject to complete physical examination with emphasis on the number of IDA-related findings, namely skin pallor, pallor at the conjunctiva, glossitis, cheilitis, koilonychia, splenomegaly, hepatomegaly, and enlarged lymph nodes. These eight signs were always evaluated by the same two evaluators: (ii) asked to grade the intensity of fatigue at a scale of 0 to 100mm. Patients were informed that 0 refers to the absence of fatigue, 1 to 30 to mild fatigue, 30 to 60 to moderate fatigue, and more than 60 to severe fatigue and that at each range of fatigue, he/she had to remember that the upper limit was the worst of the precise fatigue subcategory he/she had ever experienced; (iii) recording of any treatment-emergent adverse event (TEAE) with special emphasis given on the intensity of gastric discomfort, nausea, vomiting, and constipation. Patients were asked to grade each of these symptoms on a scale of 0 to 100mm. Patients were informed that 0 refers to the absence of the symptom and 100 to the worst intensity of this symptom they ever felt. On study visits of 7 days, 3ml of blood was collected after venipuncture of one forearm vein under aseptic conditions and collected into one EDTA-coated tube for absolute RCB counting, determination of the absolute reticulocyte count, and determination of MCV and MCH. On study visits of week 4 and week 12, 6 ml of blood was collected after venipuncture of one forearm vein under aseptic conditions; three milliliters is collected into one EDTA-coated tube for absolute blood cell counting, determination of the absolute reticulocyte count, and determination of MCV and MCH. Another 3 ml was collected into one pyrogen-free tube for measurements of ferritin and hepcidin. These two tubes are transported into the central lab. In blood collected at weeks 4 and 12, measurements of ferritin and hepcidin were done by enzyme immunosorbent assays (ferritin: ORGENTEC Diagnostika GmbH, Mainz, Germany; lower detection limit 75ng/ml; hepcidin Cloud-Clone Corp, Katy, TX, USA; lower detection limit 63 pg/ml).The primary study endpoint was the non-inferiority of the increase of baseline Hb in the FeSOThe secondary study endpoints were the differences between the two groups of treatment in absolute reticulocyte count, absolute RBC count, Hb, MCV, and MCH; change of the fatigue symptoms; change of physical findings of IDA; circulating hepcidin and ferritin; and in the incidence of GI side effects. Since the daily amount of elementary iron delivered with the ferrous sulfate regimen was 94 mg and with the Fe-ASP regimen 80 mg, the increase of baseline Hb was adjusted per mg of delivered elementary iron.The study was powered for the primary endpoint considering that the mean baseline increase of Hb after 4 weeks of treatment with the formulation of FeSOComparisons of quantitative characteristics between groups were done by the Student’s “t-test” and of qualitative characteristics by the Fisher’s exact test. The analysis was done for the intent-to-treat (ITT) population and for the per-protocol (PP) population for week 4 and for actual patients for week 12. The ITT population comprised all randomized patients. The PP population consisted of patients who did not prematurely stop the study drug and who were not in need of intravenous iron supplementation before the completion of week 4 of follow-up. The absolute and relative changes of each hematology index from baseline were calculated and expressed as means ±SE; comparisons were done by the Student’s 