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

OBJECTIVES: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 co...

Letter: the importance of dosing and baseline haemoglobin when establishing the relative efficacy of intravenous iron therapies—authors' reply

“…The meta-analysis at hand is for determination of direct and indirect differences based on studies as they are. Of note, however, the authors of the PROCEED study 3 found that the response rate did not significantly differ according to dosage (for < 1000 mg, 1000 mg and > 1000 mg, 1.25 (0.96;1.62), P = .097).…”

“…It could be shown in the PRO-CEED study 3 using logistic regression that there is an association of baseline haemoglobin values and response rate. However, contrary to the statement of the authors, the inter-study differences at baseline were not substantial, not even clinically relevant in terms of the overall mean values (Table 1).…”

How we diagnose and treat iron deficiency anemia

“…As with the other new formulations permitting a large (500-1,000 mg) dose in 15 min, iron isomaltoside has been shown to be safe and effective in chronic kidney disease, inflammatory bowel disease, chemotherapy induced anemia, and perioperatively [62][63][64][65].…”

Portuguese Consensus on the Diagnosis, Prevention and Treatment of Anaemia in Inflammatory Bowel Disease

“…Similarly there was no significant difference in the incidence of side effects in both groups. 90 A randomised study 91 compared IV iron isomaltoside 1 000 with oral iron sulphate 200 mg/day in the treatment of anaemia in patients with IBD. However, non-inferiority of IV iron isomaltoside in change of haemoglobin to week 8 could not be demonstrated.…”