title: A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED).
abstract: OBJECTIVE
  In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA).
  
  
  METHODS
  This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of -0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response.
  
  
  RESULTS
  Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was -0.37 (95% confidence interval (CI): -0.80, 0.06) with P=0.09 in the full analysis set (N=327) and -0.45 (95% CI: -0.88, -0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of -4.4 (95% CI: -7.4, -1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67%; oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP).
  
  
  CONCLUSIONS
  We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose-response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Hospital, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Michael
authors.initials: M
authors.lastname: Staun
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Tandon
authors.forename: Istvan
authors.initials: I
authors.lastname: Altorjay
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Thillainayagam
authors.forename: Cornelia
authors.initials: C
authors.lastname: Gratzer
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nijhawan
authors.forename: Lars L
authors.initials: LL
authors.lastname: Thomsen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018798:Anemia, Iron-Deficiency / Q000188:drug therapy* / Q000209:etiology*; D004187:Disaccharides / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications*; D007275:Injections, Intravenous; D007501:Iron / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011446:Prospective Studies; D011788:Quality of Life; D016896:Treatment Outcome
chemical_list: D004187:Disaccharides; D005290:Ferric Compounds; C557707:iron isomaltoside 1000; D007501:Iron