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Randomized Controlled Trial
. 2023 Apr;72(4):644-653.
doi: 10.1136/gutjnl-2022-327897. Epub 2022 Sep 9.

Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial

Heinz Zoller  1 , Myles Wolf  2 , Irina Blumenstein  3 , Christian Primas  4 , Stefan Lindgren  5 , Lars L Thomsen  6 , Walter Reinisch  7 , Tariq Iqbal  8
Affiliations
Randomized Controlled Trial

Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial

Heinz Zoller et al. Gut. 2023 Apr.

Abstract

Objective: Intravenous iron-a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)-can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI).

Design: This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured.

Results: A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration.

Conclusion: Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.

Keywords: IBD; anemia; iron deficiency.

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Conflict of interest statement

Competing interests: HZ has received honoraria for lecturing, for consulting and grant support for research from Vifor, the manufacturer of ferric carboxymaltose, and from Pharmacosmos, the manufacturer of ferric derisomaltose, as well as from Medice and Pierre Fabre, the distributors of ferric derisomaltose in Austria and Switzerland. HZ has also received payments for lecturing and consulting from Abbvie, Bayer, Falk, Gilead, Merz, and Sanofi during the 36 months prior to submission of this manuscript. MW reports personal fees from Pharmacosmos, during the conduct of the study; personal fees from Amgen, personal fees from Bayer, personal fees and other from Akebia, personal fees from Jnana, personal fees from Walden, personal fees from Reata, personal fees from Enyo, personal fees from Unicycive, outside the submitted work. IB has no competing interests to declare. CP has served as a speaker for Abbvie, MSD, Falk, Janssen, Takeda, Merck, Ferring, and Astro Pharma, and at an advisory board meeting/as a consultant for Abbvie, MSD, Takeda, and Janssen. SL has no competing interests to declare. LLT is a full-time employee of Pharmacosmos A/S, which funded and was the GCP sponsor of the trial. LLT is co-inventor of patents related to parenteral iron products. WR has served as a speaker for Abbvie, Boehringer Ingelheim, Celltrion, Falk Pharma GmbH, Ferring, Galapagos, Janssen, Medice, Mitsubishi Tanabe Pharma Corporation, Pfizer, Pharmacosmos, PLS Education, Roche, Takeda, Therakos, at an advisory board meeting/as a consultant for Abbvie, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Roland Berger GmbH, Bioclinica, Boehringer-Ingelheim, Bristol-Myers Squibb, Calyx, Celgene, Celltrion, Covance, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Fresenius, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Landos Biopharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Prometheus, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, Tigenix, Zealand, and has received research funding from Abbvie, Amgen, Janssen, MSD, Sandoz, and Takeda. TI has attended paid advisory boards for Pharmacosmos and has received fees for presenting at academic meetings.

Figures

Figure 1
Figure 1
Trial profile. aFive patients were not eligible due to low serum phosphate at screening, that is, did not meet the inclusion criteria of serum phosphate >2.5 mg/dL. Two of the five also met additional exclusion criteria. bOne patient was randomised to FDI, but received FCM. AE, adverse event; FCM, ferric carboxymaltose; FDI, ferric derisomaltose; ITT, intention-to-treat; SAE, serious adverse event.
Figure 2
Figure 2
(A) Incidence of hypophosphataemia from baseline at each study visit, and changes from baseline in key phosphaturic hormone biochemical parameters—(B) Phosphate; (C) Intact FGF23; (D) Fractional excretion of phosphate—according to intravenous iron treatment. (A) Data are presented for the safety analysis set. For baseline to Day 35 (primary safety endpoint), two patients in the FDI group and one patient in the FCM group did not have a postbaseline observation and were, therefore, set as having hypophosphataemia. Black arrows indicate infusion of intravenous iron (FDI or FCM). aP-values are for risk difference with 95% Newcombe CI adjusted for stratum using Cochran–Mantel–Haenszel method. bP-values for unadjusted risk difference and 95% Wald CI. (B–D) Data are presented for the safety analysis set. Black arrows indicate infusion of intravenous iron (FDI or FCM). Due to lack of space, the x-axis Day one labels and tick marks are not shown. (A–D) P-values are for between-group differences. FCM, ferric carboxymaltose; FDI, ferric derisomaltose; FGF23, fibroblast growth factor 23; LS, least squares.
Figure 3
Figure 3
Changes from baseline in mineral and bone parameters, according to intravenous iron treatment—(A) 25-Hydroxyvitamin D; (B) Ionised calcium; (C) 1,25-Dihydroxyvitamin D; (D) 24,25-Dihydroxyvitamin D; (E) Intact PTH; (F) Bone-specific ALP. Data are presented for the safety analysis set. P-values are for between-group differences. Black arrows indicate infusion of intravenous iron (FDI or FCM). Due to lack of space, the x-axis Day one labels and tick marks are not shown. ALP, alkaline phosphatase; FCM, ferric carboxymaltose; FDI, ferric derisomaltose; LS, least squares; PTH, parathyroid hormone.
Figure 4
Figure 4
Changes from baseline in haemoglobin and FACIT Fatigue Scale score, according to intravenous iron treatment (A, B), and by serum phosphate quartiles (C, D). Data are presented for the ITT analysis set (A, B), and for the safety analysis set with FDI and FCM pooled (C, D). P-values are for between-group differences. Black arrows indicate infusion of intravenous iron (FDI or FCM). Due to lack of space, the x-axis Day 1 labels and tick marks are not shown. FACIT, Functional Assessment of Chronic Illness Therapy; FCM, ferric carboxymaltose; FDI, ferric derisomaltose; ITT, intention-to-treat; LS, least squares; Q, quartile.
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