An active new formulation of iron carried by aspartyl casein for iron-deficiency anemia: results of the ACCESS trial

Annals of Hematology https://doi.org/10.1007/s00277-023-05197-3 ORIGINAL ARTICLE An active new formulation of iron carried by aspartyl casein for iron‑deficiency anemia: results of the ACCESS trial Maria Tsilika1 · John Mitrou1 · Nikolaos Antonakos1 · Ioulia K. Tseti2 · Georgia Damoraki1 · Konstantinos Leventogiannis1 · Evangelos J. Giamarellos‑Bourboulis1,3 Received: 17 June 2022 / Accepted: 23 March 2023 © The Author(s) 2023 Abstract Oral iron supplementation is the cornerstone for the management of iron-deficiency anemia. A new oral formulation of iron conjugated with N-aspartyl-casein (Fe-ASP) (Omalin®, Uni-Pharma) is studied in the ACCESS double-blind, doubledummy randomized clinical trial; 60 patients were randomized to 12-week oral treatment twice every day either with oral ferrous sulfate (FeSO4) delivering 47 mg elementary iron or oral Fe-ASP delivering 40 mg elementary iron. Participants had hemoglobin less than 10 g/dl, decreased red blood cell (RBC) count, and ferritin lower than 30 ng/ml; patients with a medical history of malignancy were excluded. The primary endpoint was the increase of Hb in the first 4 weeks of treatment, and the study was powered for non-inferiority. A new score of global improvement was introduced where all participants were given one point for any at least 10% increase of Hb, RBC, and reticulocytes. At week 4, the mean (SE) change of Hb was 0.76 g/dl in the FeSO4 group and 0.83 g/dl in the Fe-ASP group (p: 0.876). The odds for worse allocation of the global score were 0.35 in the Fe-ASP group compared to the F eSO4 group. Patients in the Fe-ASP group experienced a significant decrease in the number of IDA-related physical signs by week 4. No differences were found between the two groups in any of the patient-reported outcomes of fatigue and of gastrointestinal adverse events either at week 4 or at week 12. ACCESS is the most recent clinical trial showing the non-inferiority of Fe-ASP to FeSO4 for the primary endpoint of the Hb change. Keywords Iron deficiency anemia · Iron sulfate · Casein · Hemoglobin · Physical signs Introduction Despite the undeniable progress in Western societies, iron deficiency anemia (IDA) remains the most common cause of anemia with 8.18, 8.93, 12.42, and 14.14 incident cases per 1000 person-years in Belgium, Italy, Germany, and Spain repectively [1]. IDA develops as a result of increased iron requirements (usually happening during infancy, childhood, adolescence, and pregnancy), low iron intake (such as malnutrition or a vegan diet), decreased intestinal absorption of iron (usually after gastrectomy, duodenal bypass * Evangelos J. Giamarellos‑Bourboulis 1 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece 2 UNI-PHARMA SA, Kifissia, Greece 3 4th Department of Internal Medicine, ATTIKON University General Hospital, 1 Rimini Street, 124 62 Athens, Greece and bariatric surgery, infection by Helicobacter pylori, and intake of proton pump inhibitors and H2 blockers), chronic blood loss (such as gastrointestinal and uterine neoplasms and intake of anticoagulants), chronic kidney disease, chronic systolic heart failure, and inflammatory bowel disease (IBD), postoperatively [2]. Iron deficiency and IDA have deleterious effects. IDA is an independent comorbidity associated with a 1.88 hazard ratio for death in patients with chronic heart failure [3]. Among elderly patients, those with hemoglobin less than 12 g/dl have a 3-fold greater risk for death [4]. Anemia is also increasing by an average of 65% the risk of death among cancer patients [5]. IDA in pregnancy increases the odds of premature birth [6]; it is associated with prolongation of the QRS and the QTc interval in the electrocardiogram [7]; and it affects children’s immune function of the neutrophils [8]. The deleterious effect of IDA makes early recognition and management mandatory. The cornerstones of management are recognition of the cause of iron deficiency or malabsorption, management of the cause of iron loss and efficient iron 13 Vol.:(0123456789) Annals of Hematology supplementation. Indeed, appropriate replacement of iron storage through parenteral or enteral iron supplementation improves the quality of life in cancer patients [5] and decreases the odds of death in patients with chronic heart failure [9]. In patients with cancer and chronic heart failure, most of the clinical benefit is coming after the administration of intravenous iron formulations [5, 9] probably because oral formulations are hampered by limited intestinal absorption [10]. The main available oral iron preparations for iron supplementation are ferrous sulfate ( FeSO4), ferrous gluconate, and ferrous fumarate. The main limitations of treatment are gastrointestinal (GI) side effects observed in almost 40% of cases. These are gastric discomfort, nausea, vomiting, and constipation, and they are caused due to the oxidation of ferrous irons in the stomach by acidic gastric fluid into insoluble salts. A recent meta-analysis of 43 trials showed that the cumulative odds ratio (OR) for the GI side effects with the use of preparations of F eSO4 ranged between 2.43 and 3.05 [11]. The limited intestinal absorption of oral iron preparations leads to modulation of the composition of the gut microbiome. Two randomized controlled trials (RCT) in infants from Africa showed that the consumption of iron-enriched micronutrient powders was associated with the acquisition of pathogenic enterobacteria in the gut flora [12]. A formulation of iron conjugated to one N-acetyl-aspartylated derivative of casein (Fe-ASP) has recently been developed. Due to the casein coating, it is anticipated that iron is converted to a smaller extent in the stomach into insoluble salts. In this way, more iron reaches the duodenum to become absorbed whereas GI side effects are less often [13]. ACCESS (ferrous ACetyl-aspartylated Casein formulation Evaluation over ferrouS Sulfate in iron deficiency anemia) is a randomized clinical trial aiming to show that the new oral formulation of Fe-ASP is non-inferior to oral FeSO4 for the restoration of hemoglobin (Hb) in IDA. The effect on the symptoms of anemia and on biomarkers of iron deficiency and the incidence of GI tract side effects are also investigated. Patients and methods 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; ClinicalTrials.gov NCT03524651) 13 Enrolled patients were adults of eith (...truncated)