Iron Isomaltoside/Ferric Derisomaltose vs Iron Sucrose for the Treatment of Iron Deficiency Anemia (IDA)

Overview

Evaluate safety and efficacy of iron isomaltoside/ferric derisomaltose (Monofer®/Monoferric®) compared with iron sucrose (Venofer®), in subjects diagnosed with IDA.

Full Title of Study: “A Phase III, Randomised, Open-label, Comparative Safety and Efficacy Trial of Intravenous Iron Isomaltoside/Ferric Derisomaltose (Monofer®/Monoferric®) and Iron Sucrose in Subjects With Iron Deficiency Anemia (FERWON-IDA)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 28, 2018

Detailed Description

IDA is highly prevalent condition in subjects with cancer and gastrointestinal diseases such as inflammatory bowel diseases, menstruating or pregnant women, and subjects who have undergone bariatric procedure or surgery. IDA can have a substantial medical and quality of life (QoL) burden. Treatment of subjects diagnosed with IDA includes controlling the bleeding and replenishing lost iron. This study was designed to evaluate the safety and efficacy of iron isomaltoside/ferric derisomaltose compared with iron sucrose in subjects diagnosed with IDA. In a subfraction of 35 subjects treated with iron isomaltoside/ferric derisomaltose, ECG and iron will be frequently measured. The study subjects received either a single intravenous (IV) dose of iron isomaltoside/ferric derisomaltose (1000 mg at baseline) or iron sucrose (200 mg IV injections at baseline and repeated according to standard practice or physician choice up to a maximum of five times within the first two weeks starting at baseline; a cumulative dose of 1000 mg was recommended). The study subjects were monitored for up to 8 weeks from baseline.

Interventions

  • 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 set to 1000 mg. The dose was diluted in 100 mL 0.9 % sodium chloride (100 mL bags) and administered as a single IV infusion over approximately 20 minutes.
  • Drug: Iron sucrose
    • Iron sucrose (Venofer®; 20 mg elemental iron/mL) was the comparator in this trial. Iron sucrose was administered as 200 mg undiluted IV injections over approximately 2-5 minutes and repeated according to standard practice or physician choice up to a maximum of five times within the first two weeks starting at baseline. A cumulative dose of 1000 mg was recommended.

Arms, Groups and Cohorts

  • Experimental: Iron isomaltoside/ferric derisomaltose
    • Administered IV
  • Active Comparator: Iron sucrose
    • Administered IV

Clinical Trial Outcome Measures

Primary Measures

  • Change in Hemoglobin (Hb) From Baseline to Week 8
    • Time Frame: Baseline to week 8
    • Efficacy Evaluate the effect on the hemoglobin (Hb) level following treatment with iron isomaltoside/ferric derisomaltose vs iron sucrose in subjects with iron deficiency anaemia (IDA) . Response was defined as change from baseline in hemoglobin (Hb) to week 8, i.e. ability to increase Hb in subjects with IDA, when oral iron preparations were ineffective or could not be used or in whom the screening Hb measurement in Investigators’ opinion were sufficiently low to require rapid repletion of iron stores.
  • Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions
    • Time Frame: Baseline to week 8
    • Safety For this endpoint, the number of participants with serious or severe hypersensitivity reactions were evaluated. The hypersensitivity reactions that were included in the analysis were those that started on or after the first dose of randomised treatment (i.e. treatment emergent). The terms used to define hypersensitivity were those specified by the Standardised MedDRA Queries (SMQ) for hypersensitivity, plus four additional terms: loss of consciousness, seizure, syncope, unresponsiveness. The potential hypersensitivity AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). Results show only those participants that had adjudicated and confirmed serious or severe hypersensitivity reactions.

Secondary Measures

  • Composite Cardiovascular Adverse Events (AEs)
    • Time Frame: Baseline, week 1, 2, and 8
    • Safety Results show the composite cardiovascular adverse events (AEs), that started on or after the first dose of randomised treatment (i.e. treatment emergent) up to week 8. The reported potential cardiovascular AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). The potential cardiovascular AEs included the following: Death due to any cause Non-fatal myocardial infarction Non-fatal stroke Unstable angina requiring hospitalisation Congestive heart failure requiring hospitalisation or medical intervention Arrhythmias Hypertension Hypotension Results show only those participants that had adjudicated and confirmed treatment-emergent composite cardiovascular AEs.
  • Time to First Composite Cardiovascular Safety AE
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Safety Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit. Only the adjudicated and confirmed composite cardiovascular safety AEs, as judged by the CEAC, were considered for this endpoint. Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit.
  • S-phosphate <2 mg/dL at Any Time From Baseline to Week 1, 2, 4, and 8
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Safety Results show the number of subjects who had s-phosphate <2 mg/dL at any time from baseline to week 1, 2, 4, or 8.
  • Hb Concentration Increase of ≥2 g/dL From Baseline to Week 1, 2, 4, and 8
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Efficacy Results show responders to the treatment. A subject was considered a Hb responder to a certain week if an increase in Hb of at least 2 g/dL from baseline to the week in question was observed (week 1, 2, 4, and 8).
  • Time to Change in Hb Concentration ≥2 g/dL
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Efficacy Time to change in Hb concentration ≥2 g/dL. Subjects who achieved Hb concentration increase of ≥2 g/dL (from baseline to week 1, 2, 4, or 8). For responders, time to Hb response was defined as the scheduled time from baseline until the visit where the first Hb response was measured.
  • Hb Concentration of >12 g/dL at Any Time From Week 1 to Week 8
    • Time Frame: Week 1 to week 8
    • Efficacy Hb concentration of >12 g/dL at any time from week 1 to week 8. Results show the number of participants who achieved Hb concentration of >12 g/dL at any time from week 1 to week 8.
  • Hb Concentration Increase of ≥2 g/dL at Any Time From Week 1 to Week 8
    • Time Frame: Week 1 to week 8
    • Efficacy Results show the number of participants who achieved Hb concentration increase of ≥2 g/dL at any time from week 1 to week 8.
  • S-Ferritin Concentration of ≥100 ng/mL and Transferrin Saturation (TSAT) of 20-50% at Any Time From Week 1 to Week 8
    • Time Frame: Week 1 to week 8
    • Efficacy Proportion of subjects reaching the composite endpoint of s-ferritin concentration ≥100 ng/mL and TSAT of 20-50% at any time from week 1 to 8.
  • Change in Hb Concentration From Baseline to Week 1, 2, and 4
    • Time Frame: Baseline, week 1, 2, and 4
    • Efficacy Change in Hb concentration from baseline to week 1, 2, and 4.
  • Change in S-ferritin Concentration From Baseline to Weeks 1, 2, 4, and 8
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Efficacy Change in s-ferritin concentration from baseline to weeks 1, 2, 4, and 8.
  • Change in Transferrin Saturation (TSAT) From Baseline to Week 1, 2, 4, and 8
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Efficacy Changes in transferrin saturation (TSAT) from baseline to week 1, 2, 4, and 8. 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.
  • Change in Concentrations of Serum Iron (S-iron) From Baseline to Week 1, 2, 4, and 8
    • Time Frame: Baseline, week 1, 2, 4, and 8
    • Efficacy Changes in the concentrations of serum iron (s-iron) from baseline to week 1, 2, 4, and 8.
  • Change in Fatigue Symptoms From Baseline to Week 1, 2, and 8
    • Time Frame: Baseline, week 1, 2, and 8
    • Efficacy Change in fatigue symptoms from baseline to week 1, 2, and 8 was measured by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale. The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale consisted of 13 items ranging from 0 (not at all) to 4 (very much), except items #7 and #8 which are reversed scored. The total score range is 0-52. A score of less than 30 indicated severe fatigue, and the higher the score, the better outcome/quality of life (QoL). If more than 50% of the items for a subject at a given visit were missing, the total score was not calculated. Total score was calculated as shown below: Total score= Sum of individual scores x 13 / Number of items answered
  • Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Cost of Public Transport/Taxi And Parking
    • Time Frame: Baseline
    • Pharmacoeconomics The Intervals in Screening for Diabetic Retinopathy (ISDR) questionnaire at the baseline visit assessed the resources used by subjects to receive treatment. Resources used on other trial activities were not included. ISDR responses were summarised using descriptive statistics. The data for this endpoint show the responses at baseline for both treatment groups. The frequency of drug administration between the 2 treatment groups is different, however, (i.e. up to a factor 5 in the iron sucrose treatment group).
  • Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Return Journey by Car
    • Time Frame: Baseline
    • Pharmacoeconomics The Intervals in Screening for Diabetic Retinopathy (ISDR) questionnaire at the baseline visit assessed the resources used by subjects to receive treatment. Resources used on other trial activities were not included. ISDR responses were summarised using descriptive statistics. The data for this endpoint show the responses at baseline for both treatment groups. The frequency of drug administration between the 2 treatment groups is different, however, (i.e. up to a factor 5 in the iron sucrose treatment group).
  • Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Time Spent on Visit/Helping on Visit
    • Time Frame: Baseline
    • Pharmacoeconomics The Intervals in Screening for Diabetic Retinopathy (ISDR) questionnaire at the baseline visit assessed the resources used by subjects to receive treatment. Resources used on other trial activities were not included. ISDR responses were summarised using descriptive statistics. The data for this endpoint show the responses at baseline for both treatment groups. The frequency of drug administration between the 2 treatment groups is different, however, (i.e. up to a factor 5 in the iron sucrose treatment group).
  • Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Participants/Others Who Took Time Off Work to Attend Visits
    • Time Frame: Baseline
    • Pharmacoeconomics The Intervals in Screening for Diabetic Retinopathy (ISDR) questionnaire at the baseline visit assessed the resources used by subjects to receive treatment. Resources used on other trial activities were not included. ISDR responses were summarised using descriptive statistics. The data for this endpoint show the responses at baseline for both treatment groups. The frequency of drug administration between the 2 treatment groups is different, however, (i.e. up to a factor 5 in the iron sucrose treatment group).
  • Health Care Resource Use Questionnaire
    • Time Frame: Baseline
    • Pharmacoeconomics Resources used by the health care staff (per administration), measured by the health care resource use questionnaire. The questionnaire assessed the time used by the health care staff during administration of the investigational product and the administration time (including the observational time). The health care participants included in the evaluation were: investigator, pharmacist, physician, study coordinator, study nurse. The data for this endpoint show the responses at baseline for both treatment groups. The frequency of drug administration between the treatment groups is different (i.e. up to a factor 5 more frequent in the iron sucrose treatment group).

Participating in This Clinical Trial

Inclusion criteria includes: 1. Men or women ≥ 18 years 2. Subjects having IDA caused by different etiologies 3. Subjects with intolerance to oral iron therapy or a need for rapid repletion of iron stores: 4. Haemoglobin (Hb) ≤ 11 g/dL 5. Transferrin Saturation (TSAT) < 20 % 6. S-ferritin < 100 ng/mL 7. Willingness to participate and signing the informed consent form Exclusion Criteria includes : 1. Anemia predominantly caused by factors other than IDA 2. Hemochromatosis or other iron storage disorders 3. Previous serious hypersensitivity reactions to any IV iron compound 4. Erythropoiesis stimulating agent (ESA) treatment 5. Prior to screening or during the trial period; has or will be treated with a red blood cell transfusion, radiotherapy, and/or chemotherapy 6. Will require a surgical procedure that necessitated general anesthesia prior to screening or during the trial period 7. Alanine aminotransferase and/or aspartate aminotransferase > 3 times upper limit of normal 8. Required dialysis for treatment of chronic kidney disease (CKD) 9. Alcohol or drug abuse within the past 6 months 10. Pregnant or nursing women

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Pharmacosmos A/S
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Pharmacosmos A/S Clinical and Non-clinical Research, Study Director, Pharmacosmos A/S

Citations Reporting on Results

Auerbach M, Henry D, Derman RJ, Achebe MM, Thomsen LL, Glaspy J. A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial. Am J Hematol. 2019 Sep;94(9):1007-1014. doi: 10.1002/ajh.25564. Epub 2019 Jul 13.

Auerbach M and Lykke LL. A single infusion of iron isomaltoside 1000 allows a more rapid hemoglobin increment than multiple doses of iron sucrose with a similar safety profile in patients with iron deficiency anemia. Blood 2018 132:2334; doi: https://doi.org/10.1182/blood-2018-99-110199

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