Incidence of Hypophosphatemia After Treatment With Iron Isomaltoside/Ferric Derisomaltose vs Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia

This trial was designed to evaluate the effect of IV iron isomaltoside/ferric derisomaltose compared with IV ferric carboxymaltose on s-phosphate in subjects with IDA caused by different etiologies.

The subjects received either a single intravenous (IV) dose of iron isomaltoside/ferric derisomaltose (1000 mg at baseline) or two IV doses of ferric carboxymaltose (one dose 750 mg at baseline and a second dose 750 mg on day 7; cumulative dose: 1500 mg). The study subjects were monitored for up to 35 days from baseline.

• Iron isomaltoside/ferric derisomaltose (Drug), also known as Monofer®, Monoferric®, Monover®, Monofar®, Monoferro®: Iron isomaltoside/ferric derisomaltose (Monofer®/Monoferric®; 100 mg/mL) was the test product in this trial. The dose of iron isomaltoside/ferric derisomaltose for the individual subject was a single IV infusion of 1000 mg (10 mL containing 1000 mg iron isomaltoside/ferric derisomaltose diluted in 100 mL 0.9 % sodium chloride), given over approximately 20 minutes (50 mg iron/min) at baseline (cumulative dose: 1000 mg).
• Ferric carboxymaltose (Drug), also known as Injectafer®, Ferinject®: Ferric carboxymaltose (Injectafer®; 50 mg/mL) was the comparator in this trial. Ferric carboxymaltose was administered as 750 mg, infused over at least 15 minutes at baseline and on day 7 (cumulative dose: 1500 mg).

Primary outcomes

• Incidence of Hypophosphatemia (S-phosphate Level <2 mg/dL) [Baseline to day 35]: Safety The incidence of hypophosphatemia (defined as s-phosphate <2 mg/dL) at any time from baseline up to day 35.

Secondary outcomes

• Time With Hypophosphatemia ( S-phosphate Level <2.0 mg/dL) [Baseline to day 35]: Safety Time with hypophosphatemia (i.e. time with s-phosphate level < 2.0 mg/dL) from baseline up to day 35. The time with hypophosphatemia was calculated as the actual number of days from the first day where s-phosphate was <2 mg/dL until the first day when s-phosphate was ≥2 mg/dL. If the subject did not reach s-phosphate ≥2 mg/dL, the subject was regarded as censored on day 35.
• Proportion of Subjects With Hypophosphatemia on Day 35 ( S-phosphate Level <2.0 mg/dL) [Baseline to day 35]: Safety Evaluate the proportion of subjects with hypophosphatemia (s-phosphate level <2.0 mg/dL) on day 35.
• Absolute [∆] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Absolute \[∆\] changes in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35.
• Relative [%] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Relative \[%\] changes in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35.
• Change From Baseline in Fractional Phosphate Urinary Excretion [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in absolute fractional phosphate urinary excretion from baseline to days 1, 7, 8, 14, 21, and 35. Fractional excretion of phosphate (FEPi) is calculated as (\[phosphate in urine X creatinine in serum\]/\[phosphate in serum X creatinine in urine\]) X 100, and the unit is %.
• Change in Concentration of (Intact) Fibroblast Growth Factor 23 (iFGF23) From Baseline to Day 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in concentration of (Intact) Fibroblast Growth Factor 23 (iFGF23) from baseline to day 1, 7, 8, 14, 21, and 35.
• Change in C-terminal Fibroblast Growth Factor 23 (cFGF23) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in C-terminal Fibroblast Growth Factor 23 (cFGF23) from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in Vitamin 25-Hydroxyvitamin D (Vitamin D 25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in vitamin 25-Hydroxyvitamin D (vitamin D 25) from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in 1,25-Dihydroxyvitamin D (Vitamin D 1.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in 1,25-Dihydroxyvitamin D (vitamin D 1.25) from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in 24,25-Dihydroxyvitamin D (Vitamin D 24.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in 24,25-Dihydroxyvitamin D (vitamin D 24.25) from baseline to days 1, 7, 8, 14, 21, and 35
• Change in Intact Parathyroid Hormone (PTH) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in intact Parathyroid hormone (PTH) from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in Ionized Calcium From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Safety Change in ionized calcium from baseline to days 1, 7, 8, 14, 21, and 35.
• Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions [Baseline to day 35]: Safety For this endpoint, the number of participants with serious or severe hypersensitivity reactions were evaluated.
• Change in Hemoglobin (Hb) Per Gram Iron From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Efficacy Change in hemoglobin (Hb) per gram iron from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in S-ferritin From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Efficacy Change in s-ferritin from baseline to days 1, 7, 8, 14, 21, and 35.
• Change in Transferrin Saturation (TSAT) From Baseline to Days 1, 7, 8, 14, 21, and 35 [Baseline, days 1, 7, 8, 14, 21, and 35]: Efficacy Change in Transferrin Saturation (TSAT) from baseline to days 1, 7, 8, 14, 21, and 35. TSAT is the value of serum iron divided by the total iron-binding capacity and the unit is %, which referrers to % of iron-binding sites of transferrin being occupied by iron.

Sex: All, ages: 18 Years to any

Inclusion Criteria include:

* Subjects diagnosed with IDA, caused by different aetiologies
* Haemoglobin (Hb) ≤ 11 g/dL
* Body weight > 50 kg
* Serum ferritin (S-ferritin) < 100 ng/mL
* Estimated glomerular filtration rate (eGFR) ≥ 65 mL/min/1.73 m2
* Serum phosphate (S-phosphate) > 2.5 mg/dL
* Intolerance or unresponsiveness to oral iron
* Willingness to participate and signing the Informed Consent Form (ICF)

Exclusion Criteria include:

* Acute bleeding > 500 mL within 72 hours
* Anaemia predominantly caused by factors other than IDA
* Hemochromatosis or other iron storage disorders
* Previous serious hypersensitivity reactions to any IV iron compounds
* Treatment with IV iron within the last 30 days prior to screening
* Treatment with erythropoietin or erythropoietin-stimulation agents
* Red blood cell transfusion, radiotherapy, and/or chemotherapy
* Received an investigational drug within the last 30 days prior to screening
* Planned surgical procedure within the trial period
* Hepatic enzymes > 3 times upper limit of normal
* Surgery under anaesthetic within the last 30 days prior to screening
* Any non-viral infection within the last 30 days prior to screening
* Alcohol or drug abuse within the past 6 months
* Vitamin D deficiency
* Untreated hyperparathyroidism
* Kidney transplantation
* Active malignant disease, disease-free for less than 5 years
* History of a psychological illness or seizures
* Pregnant or nursing women.

Participant flow

Outcome results

• Incidence of Hypophosphatemia (S-phosphate Level <2 mg/dL) (Primary), Count of participants, Participants: Iron Isomaltoside/Ferric Derisomaltose 5; Ferric Carboxymaltose 45 (p <0.0001)
• Time With Hypophosphatemia ( S-phosphate Level <2.0 mg/dL) (Secondary), Median, days: Iron Isomaltoside/Ferric Derisomaltose 15 (7 to 56); Ferric Carboxymaltose 29 (21 to 42) (p 0.8979)
• Proportion of Subjects With Hypophosphatemia on Day 35 ( S-phosphate Level <2.0 mg/dL) (Secondary), Count of participants, Participants: Iron Isomaltoside/Ferric Derisomaltose 1; Ferric Carboxymaltose 24 (p <0.0001)
• Absolute [∆] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 (Secondary), Mean, mg/dL: Iron Isomaltoside/Ferric Derisomaltose 0.25 +/- 0.55; Ferric Carboxymaltose -0.24 +/- 0.61 (p <0.0001)
• Relative [%] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 (Secondary), Mean, Percentage change from baseline: Iron Isomaltoside/Ferric Derisomaltose 9.31 +/- 18.98; Ferric Carboxymaltose -5.94 +/- 16.59 (p <0.0001)
• Change From Baseline in Fractional Phosphate Urinary Excretion (Secondary), Mean, percentage excreted: Iron Isomaltoside/Ferric Derisomaltose -1.73 +/- 4.85; Ferric Carboxymaltose 2.44 +/- 5.09
• Change in Concentration of (Intact) Fibroblast Growth Factor 23 (iFGF23) From Baseline to Day 1, 7, 8, 14, 21, and 35 (Secondary), Mean, pg/mL: Iron Isomaltoside/Ferric Derisomaltose -2.7 +/- 28.6; Ferric Carboxymaltose 103.6 +/- 89.5 (p <0.0001)
• Change in C-terminal Fibroblast Growth Factor 23 (cFGF23) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, RU/mL: Iron Isomaltoside/Ferric Derisomaltose -742.3 +/- 800.7; Ferric Carboxymaltose -390.2 +/- 665.7 (p <0.0001)
• Change in Vitamin 25-Hydroxyvitamin D (Vitamin D 25) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, ng/mL: Iron Isomaltoside/Ferric Derisomaltose 0.04 +/- 2.26; Ferric Carboxymaltose 0.32 +/- 2.26 (p 0.5620)
• Change in 1,25-Dihydroxyvitamin D (Vitamin D 1.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, pg/mL: Iron Isomaltoside/Ferric Derisomaltose 5.13 +/- 13.05; Ferric Carboxymaltose -20.57 +/- 17.56 (p <0.0001)
• Change in 24,25-Dihydroxyvitamin D (Vitamin D 24.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, ng/mL: Iron Isomaltoside/Ferric Derisomaltose -0.02 +/- 0.41; Ferric Carboxymaltose 0.13 +/- 0.51 (p 0.0552)
• Change in Intact Parathyroid Hormone (PTH) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, pg/mL: Iron Isomaltoside/Ferric Derisomaltose -1.3 +/- 20.2; Ferric Carboxymaltose 0.7 +/- 21.3 (p 0.7447)
• Change in Ionized Calcium From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, mg/dL: Iron Isomaltoside/Ferric Derisomaltose 0.04 +/- 0.18; Ferric Carboxymaltose 0.00 +/- 0.20 (p 0.2670)
• Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions (Secondary), Count of participants, Participants: Iron Isomaltoside/Ferric Derisomaltose 1; Ferric Carboxymaltose 0
• Change in Hemoglobin (Hb) Per Gram Iron From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, g/dL per g of iron: Iron Isomaltoside/Ferric Derisomaltose -0.16 +/- 1.29; Ferric Carboxymaltose 0.28 +/- 1.82 (p 0.4618)
• Change in S-ferritin From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, ng/mL: Iron Isomaltoside/Ferric Derisomaltose 82.0 +/- 58.3; Ferric Carboxymaltose 94.7 +/- 62.4 (p 0.1922)
• Change in Transferrin Saturation (TSAT) From Baseline to Days 1, 7, 8, 14, 21, and 35 (Secondary), Mean, percentage of saturation: Iron Isomaltoside/Ferric Derisomaltose 118.9 +/- 52.0; Ferric Carboxymaltose 85.7 +/- 40.4 (p <0.0001)
• Incidence of S-phosphate Level ≤1.0 mg/dL at Any Time From Baseline to Day 35 (Post hoc), Count of participants, Participants: Iron Isomaltoside/Ferric Derisomaltose 0; Ferric Carboxymaltose 7 (p 0.0050)

Adverse events

Time frame: From the time subjects signed the informed consent form (CRF) and until they completed the study, all adverse events (AEs) or serious adverse events (SAEs) were reported in the CRF. The actual study duration was 35 days (or shorted if the trial was discontinued). Overall, eligible subjects participated in the trial for approximately 9 weeks (including a 28-day screening period).

Serious adverse events by term

Other adverse events by term

• Results publication: Wolf M, Rubin J, Achebe M, Econs M, Peacock M, Imel E, Thomsen L, Carpenter T, Weber T, Zoller H. Effects of iron isomaltoside versus ferric carboxymaltose on hormonal control of phosphate homeostasis: The PHOSPHARE-IDA04/05 randomized controlled trials. Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, OR13-3, https://doi.org/10.1210/js.2019-OR13-3
• Results publication: Wolf M, Rubin J, Achebe M, Econs MJ, Peacock M, Imel EA, Thomsen LL, Carpenter TO, Weber T, Brandenburg V, Zoller H. Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials. JAMA. 2020 Feb 4;323(5):432-443. doi: 10.1001/jama.2019.22450. PMID 32016310

• Study Protocol (PDF, 2017-11-29)
• Statistical Analysis Plan (PDF, 2018-03-12)

• Pharmacosmos A/S Clinical and Non-clinical Research, Study director, Pharmacosmos A/S