Iron Isomaltoside/Ferric Derisomaltose vs Iron Sucrose for Treatment of Iron Deficiency Anemia in Non-Dialysis-Dependent Chronic Kidney Disease

Chronic Kidney Disease Clinical Trial

Official title:

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 Anaemia and Non-dialysis-dependent Chronic Kidney Disease (FERWON-NEPHRO)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02940860
• Other study ID #: P-Monofer-CKD-04
• Status: Completed
• Phase: Phase 3
• Start date: November 29, 2016
• Est. completion date: May 29, 2018

Study information

• Verified date: February 2020
• Source: Pharmacosmos A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Evaluation of safety and efficacy of iron isomaltoside/ferric derisomaltose compared with iron sucrose, in subjects with both non-dialysis-dependent chronic kidney disease (NDD-CKD) and iron deficiency anaemia (IDA).

Description:

Iron deficiency anaemia (IDA) is a common problem associated with many chronic diseases such as chronic kidney disease (CKD). IDA can have a substantial medical and quality of life (QoL) burden on the subjects. Therapy of these subjects includes treating the underlying cause of IDA and restoring haemoglobin (Hb) concentration and iron stores.

This study evaluated the safety and efficacy of iron isomaltoside/ferric derisomaltose compared with iron sucrose in subjects with both non-dialysis-dependent chronic kidney disease (NDD-CKD) and iron deficiency anaemia (IDA).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1538
• Est. completion date: May 29, 2018
• Est. primary completion date: May 29, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria includes:

1. Men and women, = 18 years

2. Hb = 11 g/dL

3. Chronic renal impairment, as defined by either (i) eGFR < 60 mL/min/1.73m2 at screening (as calculated by modification of diet in renal disease (MDRD)), or (ii) Estimated Glomerular Filtration Rate (eGFR) < 90 mL/min/1.73m2 at screening and kidney damage as indicated by abnormalities in urine composition per medical history and/or intermediate/high risk of cardio-vascular disease based on the Framingham model

4. Screening s-ferritin = 100 ng/mL, or = 300 ng/mL if Transferrin Saturation (TSAT) = 30 %

5. Either no Erythropoiesis Stimulating Agent (ESAs) or ESAs as a stable dose 4 weeks before randomisation

6. Willingness to participate and signing the informed consent form

Exclusion Criteria includes:

1. Anaemia predominantly caused by factors other than IDA

2. Hemochromatosis or other iron storage disorders

3. Previous serious hypersensitivity reactions to any IV iron compounds

4. Prior to screening or during the trial period; has or will be treated with a red blood cell transfusion, radiotherapy, and/or chemotherapy

5. Undergoing dialysis for treatment of CKD

6. Planned surgical procedure within the trial period

7. Decompensated liver cirrhosis or active hepatitis

8. Alcohol or drug abuse within the past 6 month.

9. Pregnant or nursing women.

Related Conditions & MeSH terms

• Anemia
• Anemia, Iron-Deficiency
• Chronic Kidney Disease
• Deficiency Diseases
• Iron Deficiency Anaemia
• Iron Deficiency Anemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Pharmacosmos Investigational Site	Albuquerque	New Mexico
United States	Pharmacosmos Investigational Site	Annapolis	Maryland
United States	Pharmacosmos Investigational Site	Arlington	Virginia
United States	Pharmacosmos Investigational Site	Arvada	Colorado
United States	Pharmacosmos Investigational Site	Asheville	North Carolina
United States	Pharmacosmos Investigational Site	Atlanta	Georgia
United States	Pharmacosmos Investigational Site	Augusta	Georgia
United States	Pharmacosmos Investigational Site	Austin	Texas
United States	Pharmacosmos Investigational Site	Baton Rouge	Louisiana
United States	Pharmacosmos Investigational Site	Beaumont	Texas
United States	Pharmacosmos Investigational Site	Bethesda	Maryland
United States	Pharmacosmos Investigational Site	Bethlehem	Pennsylvania
United States	Pharmacosmos Investigational Site	Boynton Beach	Florida
United States	Pharmacosmos Investigational Site	Brandon	Florida
United States	Pharmacosmos Investigational Site	Chicago	Illinois
United States	Pharmacosmos Investigational Site	Chicago	Illinois
United States	Pharmacosmos Investigational Site	Chula Vista	California
United States	Pharmacosmos Investigational Site	Cincinnati	Ohio
United States	Pharmacosmos Investigational Site	Cincinnati	Ohio
United States	Pharmacosmos Investigational Site	Cleveland	Ohio
United States	Pharmacosmos Investigational Site	Columbia	South Carolina
United States	Pharmacosmos Investigational Site	Coral Gables	Florida
United States	Pharmacosmos Investigational Site	Coral Springs	Florida
United States	Pharmacosmos Investigational Site	Covington	Louisiana
United States	Pharmacosmos Investigational Site	Crystal Lake	Illinois
United States	Pharmacosmos Investigational Site	Denver	Colorado
United States	Pharmacosmos Investigational Site	DeSoto	Texas
United States	Pharmacosmos Investigational Site	Doral	Florida
United States	Pharmacosmos Investigational Site	El Paso	Texas
United States	Pharmacosmos Investigational Site	Fairfax	Virginia
United States	Pharmacosmos Investigational Site	Florissant	Missouri
United States	Pharmacosmos Investigational Site	Flushing	New York
United States	Pharmacosmos Investigational Site	Fort Lauderdale	Florida
United States	Pharmacosmos Investigational Site	Fort Wayne	Indiana
United States	Pharmacosmos Investigational Site	Fort Worth	Texas
United States	Pharmacosmos Investigational Site	Fresno	California
United States	Pharmacosmos Investigational Site	Gastonia	North Carolina
United States	Pharmacosmos Investigational Site	Glendale	California
United States	Pharmacosmos Investigational Site	Glendale	California
United States	Pharmacosmos Investigational Site	Granada Hills	California
United States	Pharmacosmos Investigational Site	Grand Rapids	Michigan
United States	Pharmacosmos Investigational Site	Greenville	North Carolina
United States	Pharmacosmos Investigational Site	Greenville	South Carolina
United States	Pharmacosmos Investigational Site	Greenville	Texas
United States	Pharmacosmos Investigational Site1	Hialeah	Florida
United States	Pharmacosmos Investigational Site2	Hialeah	Florida
United States	Pharmacosmos Investigational Site3	Hialeah	Florida
United States	Pharmacosmos Investigational Site	Hinsdale	Illinois
United States	Pharmacosmos Investigational Site	Hollywood	Florida
United States	Pharmacosmos Investigational Site	Homestead	Florida
United States	Pharmacosmos Investigational Site	Houston	Texas
United States	Pharmacosmos Investigational Site	Houston	Texas
United States	Pharmacosmos Investigational Site1	Houston	Texas
United States	Pharmacosmos Investigational Site1	Houston	Texas
United States	Pharmacosmos Investigational Site2	Houston	Texas
United States	Pharmacosmos Investigational Site2	Houston	Texas
United States	Pharmacosmos Investigational Site	Huntsville	Alabama
United States	Pharmacosmos Investigational Site	Jackson	Tennessee
United States	Pharmacosmos Investigational Site	Jacksonville	North Carolina
United States	Pharmacosmos Investigational Site	Kansas City	Kansas
United States	Pharmacosmos Investigational Site	La Mesa	California
United States	Pharmacosmos Investigational Site	Lake City	Florida
United States	Pharmacosmos Investigational Site1	Lauderdale Lakes	Florida
United States	Pharmacosmos Investigational Site2	Lauderdale Lakes	Florida
United States	Pharmacosmos Investigational Site	Little Rock	Arkansas
United States	Pharmacosmos Investigational Site	Little Rock	Arkansas
United States	Pharmacosmos Investigational Site	Los Angeles	California
United States	Pharmacosmos Investigational Site	Los Angeles	California
United States	Pharmacosmos Investigational Site	Los Angeles	California
United States	Pharmacosmos Investigational Site1	Los Angeles	California
United States	Pharmacosmos Investigational Site2	Los Angeles	California
United States	Pharmacosmos Investigational Site	Lufkin	Texas
United States	Pharmacosmos Investigational Site	Lynwood	California
United States	Pharmacosmos Investigational Site	Macon	Georgia
United States	Pharmacosmos Investigational Site	Marion	Indiana
United States	Pharmacosmos Investigational Site	McKinney	Texas
United States	Pharmacosmos Investigational Site	Merrillville	Indiana
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site1	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site2	Miami	Florida
United States	Pharmacosmos Investigational Site3	Miami	Florida
United States	Pharmacosmos Investigational Site3	Miami	Florida
United States	Pharmacosmos Investigational Site	Miami Beach	Florida
United States	Pharmacosmos Investigational Site	Miami Lakes	Florida
United States	Pharmacosmos Investigational Site	Michigan City	Indiana
United States	Pharmacosmos Investigational Site	Middlebury	Connecticut
United States	Pharmacosmos Investigational Site	Montebello	California
United States	Pharmacosmos Investigational Site	Naples	Florida
United States	Pharmacosmos Investigational Site	New York	New York
United States	Pharmacosmos Investigational Site	New York	New York
United States	Pharmacosmos Investigational Site	Norman	Oklahoma
United States	Pharmacosmos Investigational Site	Northridge	California
United States	Pharmacosmos Investigational Site	Northridge	California
United States	Pharmacosmos Investigational Site	Ocala	Florida
United States	Pharmacosmos Investigational Site	Orangeburg	South Carolina
United States	Pharmacosmos Investigational Site	Owensboro	Kentucky
United States	Pharmacosmos Investigational Site	Palmetto Bay	Florida
United States	Pharmacosmos Investigational Site	Pearland	Texas
United States	Pharmacosmos Investigational Site	Pembroke Pines	Florida
United States	Pharmacosmos Investigational Site	Philadelphia	Pennsylvania
United States	Pharmacosmos Investigational Site	Plainville	Connecticut
United States	Pharmacosmos Investigational Site	Plantation	Florida
United States	Pharmacosmos Investigational Site	Port Charlotte	Florida
United States	Pharmacosmos Investigational Site	Porterville	California
United States	Pharmacosmos Investigational Site	Rialto	California
United States	Pharmacosmos Investigational Site	Riverside	California
United States	Pharmacosmos Investigational Site	Rockville	Maryland
United States	Pharmacosmos Investigational Site	Sacramento	California
United States	Pharmacosmos Investigational Site	Saint George	Utah
United States	Pharmacosmos Investigational Site	Saint Petersburg	Florida
United States	Pharmacosmos Investigational Site1	San Antonio	Texas
United States	Pharmacosmos Investigational Site2	San Antonio	Texas
United States	Pharmacosmos Investigational Site	San Dimas	California
United States	Pharmacosmos Investigational Site	San Francisco	California
United States	Pharmacosmos Investigational Site	Shreveport	Louisiana
United States	Pharmacosmos Investigational Site	Tampa	Florida
United States	Pharmacosmos Investigational Site1	Tampa	Florida
United States	Pharmacosmos Investigational Site2	Tampa	Florida
United States	Pharmacosmos Investigational Site	Tarzana	California
United States	Pharmacosmos Investigational Site	Tulsa	Oklahoma
United States	Pharmacosmos Investigational Site	W. Miami	Florida
United States	Pharmacosmos Investigational Site	Westminster	Colorado
United States	Pharmacosmos Investigational Site	Wichita	Kansas
United States	Pharmacosmos Investigational Site	Wilmington	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Pharmacosmos A/S

Country where clinical trial is conducted

United States, 

References & Publications (1)

Sunil Bhandari, Lars Lykke Thomsen. Single 1000 mg infusion of iron isomaltoside1000 single 1000 mg infusion of iron isomaltoside 1000 demonstrates a more rapid hemoglobin response and reduced risk of cardiovascular adverse events compared to multiple dos

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Hemoglobin (Hb) From Baseline to Week 8	Efficacy; Evaluate the effect of iron isomaltoside/ferric derisomaltose vs iron sucrose in subjects with non-dialysis-dependent chronic kidney disease (NDD-CKD) and 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 NDD-CKD and IDA, when oral iron preparations were ineffective or could not be used, or in whom the Hb measurement at screening in Investigators' opinion were sufficiently low to require rapid repletion of iron stores.	Baseline to week 8
Primary	Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions	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.	Baseline to week 8
Secondary	Composite Cardiovascular Adverse Events (AEs)	Safety; Results show the composite cardiovascular 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.	Baseline, week 1, 2, and 8
Secondary	Time to First Composite Cardiovascular Safety AE	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.	Baseline, week 1, 2, 4, and 8
Secondary	S-phosphate <2 mg/dL at Any Time From Baseline to Week 1, 2, 4, and 8	Safety; Results show the number of participants who had s-phosphate <2 mg/dL at any time from baseline to week 1, 2, 4, or 8.	Baseline, week 1, 2, 4, and 8
Secondary	Hb Concentration Increase of =1 g/dL From Baseline to Week 1, 2, 4, and 8	Efficacy; Results show Hb responders to the treatment. A subject was considered a Hb responder to a certain week if an increase in Hb of at least 1 g/dL from baseline to the week in question was observed (from baseline to week 1, 2, 4, and 8).	Baseline, week 1, 2, 4, and 8
Secondary	Time to Change in Hb Concentration =1 g/dL	Efficacy; Time to change in Hb concentration =1 g/dL.; Subjects who showed Hb concentration increase of =1 g/dL (from baseline to week 1, 2, 4, and 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.	Baseline, week 1, 2, 4, and 8
Secondary	Hb Concentration of >12 g/dL at Any Time From 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.	Week 1 to week 8
Secondary	Hb Concentration Increase of =2 g/dL at Any Time From 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.	Week 1 to week 8
Secondary	S-Ferritin Concentration of =100 ng/mL and Transferrin Saturation (TSAT) of 20-50% at Any Time From 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.	Week 1 to week 8
Secondary	Change in Hb Concentration From Baseline to Week 1, 2, and 4	Efficacy; Change in Hb concentration from baseline to week 1, 2, and 4.	Baseline, week 1, 2, and 4
Secondary	Change in S-ferritin From Baseline to Weeks 1, 2, 4, and 8	Efficacy; Changes in s-ferritin from baseline to weeks 1, 2, 4, and 8.	Baseline, week 1, 2, 4, and 8
Secondary	Change in Transferrin Saturation (TSAT) From Baseline to Week 1, 2, 4, and 8	Efficacy; Changes in transferrin saturation (TSAT) from baseline to week 1, 2, 4, and 8.	Baseline, week 1, 2, 4, and 8
Secondary	Change in Concentration of S-iron From Baseline to 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.	Baseline, week 1, 2, 4, and 8
Secondary	Change in Fatigue Symptoms From Baseline to 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	Baseline, week 1, 2, and 8
Secondary	Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Cost of Public Transport/Taxi And Parking	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).	Baseline
Secondary	Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Return Journey by Car	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).	Baseline
Secondary	Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Time Spent on Visit/Helping on Visit	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).	Baseline
Secondary	Intervals in Screening for Diabetic Retinopathy (ISDR) Questionnaire, Participants/Others Who Took Time Off Work to Attend Visits	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).	Baseline
Secondary	Health Care Resource Use Questionnaire	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 2 treatment groups is different (i.e. up to a factor 5 more frequent in the iron sucrose treatment group).	Baseline

External Links

•   The FERWON-NEPHRO trial; comparison of iron isomaltoside/ferric derisomaltose versus iron sucrose in NDD-CKD patients with iron deficiency anemia