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

• ClinicalTrials.gov Identifier: NCT03237065
• Recruitment Status: Completed
• First Posted: August 2, 2017
• Results First Posted: February 25, 2020
• Last Update Posted: February 25, 2020
• Sponsor: Pharmacosmos A/S
• Information provided by (Responsible Party): Pharmacosmos A/S

Study Description

Brief Summary:

The trial was designed to evaluate the incidence of unintended hypophosphatemia (low level of phosphate in the blood) in subjects with iron deficiency anaemia (IDA).

Condition or disease	Intervention/treatment	Phase
Iron Deficiency Anaemia; Iron Deficiency Anemia	Drug: Iron isomaltoside/ferric derisomaltose; Drug: Ferric carboxymaltose	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Comparative Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside/Ferric Derisomaltose and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia (Phosphare-IDA-05)
• Actual Study Start Date: October 30, 2017
• Actual Primary Completion Date: May 29, 2018
• Actual Study Completion Date: May 29, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Iron isomaltoside/ferric derisomaltose; Administered IV	Drug: Iron isomaltoside/ferric derisomaltose; 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).; Other Name: Monofer®, Monoferric®, Monover®, Monofar®, Monoferro®
Active Comparator: Ferric carboxymaltose; Administered IV	Drug: Ferric carboxymaltose; Ferric carboxymaltose (Injectafer®; 50 mg/mL) was the comparator in this trial. The dose of ferric carboxymaltose for the individual subject was 750 mg, infused over at least 15 minutes at baseline and on day 7 (cumulative dose: 1500 mg).; Other Name: Injectafer®, Ferinject®

Outcome Measures

Primary Outcome Measures :

1. Incidence of Hypophosphatemia (S-phosphate Level <2 mg/dL) [ Time Frame: 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 Outcome Measures :

1. Time With Hypophosphatemia ( S-phosphate Level <2.0 mg/dL) [ Time Frame: 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.

2. Proportion of Subjects With Hypophosphatemia on Day 35 (S-phosphate Level <2.0 mg/dL) [ Time Frame: Baseline to day 35 ]

   Safety

   Evaluate the proportion of subjects with hypophosphatemia (s-phosphate level <2.0 mg/dL) on day 35.

3. Absolute [∆] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

4. Relative [%] Changes in S-phosphate From Baseline to Day 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

5. Change From Baseline in Fractional Phosphate Urinary Excretion [ Time Frame: 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 %.

6. Change in Concentration of (Intact) Fibroblast Growth Factor 23 (iFGF23) From Baseline to Day 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

7. Change in C-terminal Fibroblast Growth Factor 23 (cFGF23) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

8. Change in Vitamin 25-Hydroxyvitamin D (Vitamin D 25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

9. Change in 1,25-Dihydroxyvitamin D (Vitamin D 1.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

10. Change in 24,25-Dihydroxyvitamin D (Vitamin D 24.25) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

11. Change in Intact Parathyroid Hormone (PTH) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

12. Change in Ionized Calcium From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

13. Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions [ Time Frame: Baseline to day 35 ]

    Safety

    For this endpoint, the number of participants with serious or severe hypersensitivity reactions were evaluated.

14. Change in Hemoglobin (Hb) Per Gram Iron From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

15. Change in S-ferritin From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

16. Change in Transferrin Saturation (TSAT) From Baseline to Days 1, 7, 8, 14, 21, and 35 [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria include:

• Subjects having 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.

Contacts and Locations

Locations

United States, Alabama

Pharmacosmos Investigational Site

Muscle Shoals, Alabama, United States, 35661

United States, Florida

Pharmacosmos Investigational Site

Doral, Florida, United States, 33122

Pharmacosmos Investigational Site

Miami Lakes, Florida, United States, 33014

Pharmacosmos Investigational Site

Miami, Florida, United States, 33144

Pharmacosmos Investigational Site

Miami, Florida, United States, 33165

Pharmacosmos Investigational Site

Orlando, Florida, United States, 32819

United States, Idaho

Pharmacosmos Investigational Site

Idaho Falls, Idaho, United States, 83404

United States, Illinois

Pharmacosmos Investigational Site

Oak Brook, Illinois, United States, 60523

United States, Michigan

Pharmacosmos investigational Site

Flint, Michigan, United States, 48504

United States, Missouri

Pharmacosmos Investigational Site

Saint Louis, Missouri, United States, 63119

United States, Nevada

Pharmacosmos Investigational Site

Las Vegas, Nevada, United States, 89146

United States, New Mexico

Pharmacosmos Investigational Site

Albuquerque, New Mexico, United States, 87102

United States, North Carolina

Pharmacosmos Investigational Site

Morehead City, North Carolina, United States, 28557

Pharmacosmos Investigational Site

Raleigh, North Carolina, United States, 27607

Pharmacosmos Investigational Site

Winston-Salem, North Carolina, United States, 27103

Sponsors and Collaborators

Pharmacosmos A/S

Investigators

• Study Director: Pharmacosmos A/S Clinical and Non-clinical Research; Pharmacosmos A/S

  Study Documents (Full-Text)

Documents provided by Pharmacosmos A/S:

Study Protocol  [PDF] November 29, 2017

Statistical Analysis Plan  [PDF] March 12, 2018

More Information

Additional Information:

Effects of iron isomaltoside/ferric derisomaltose versus ferric carboxymaltose on hormonal control of phosphate homeostasis 

Publications of Results:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Pharmacosmos A/S
• ClinicalTrials.gov Identifier: NCT03237065
• Other Study ID Numbers: P-Monofer-IDA-05
• First Posted: August 2, 2017
• Results First Posted: February 25, 2020
• Last Update Posted: February 25, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pharmacosmos A/S:

Iron Deficiency Anaemia; Iron Deficiency Anemia; IDA; Iron deficiency; Intravenous iron replacement therapy; Iron isomaltoside; Ferric derisomaltose; Hypophosphatemia; Ferric carboxymaltose; Monofer; Monoferric; Monover; Monofar; Monoferro

Additional relevant MeSH terms:

Anemia; Anemia, Iron-Deficiency; Deficiency Diseases; Hypophosphatemia; Hematologic Diseases; Anemia, Hypochromic; Iron Metabolism Disorders; Metabolic Diseases; Malnutrition; Nutrition Disorders; Phosphorus Metabolism Disorders; Iron isomaltoside 1000; Hematinics