Background
Iron deficiency anemia in patients with renal disease: clinical challenges
Study rationale and objectives
Studya, b | Patients | N | HD patients, n | Treatments | Duration | Primary endpoint |
---|---|---|---|---|---|---|
Active comparator | ||||||
Anirban et al. 2008 [24] | CKD-HD, CKD-CAPD, and CKD-NDD | 339 | 210 | IV iron dextran IV sodium ferric gluconate complex IV iron sucrose | 48 h | Incidence of serious/nonserious adverse drug events |
Besarab et al. 2000 [25] | CKD-HD | 42 | 42 | IV iron dextran (patients assigned to 1 of 2 dosing regimens) | 6 months | Determine if maintenance iron protocol that increased TSAT levels from 20–30% to 30–50% increased erythropoiesis and reduced rHuEPO doses needed to maintain Hb of 9.5–12.0 g/dL (95.0–120.0 g/L) vs. protocol targeting TSAT levels of 20–30% |
Charytan et al. 2013 [26] | CKD-HD and CKD-NDD | 254 | 50 | IV ferric carboxymaltose Oral, IV, or no iron (standard medical care) | 30 days | Safety of the maximum administered dose of ferric carboxymaltose vs. standard medical care |
Goldstein et al. 2013 [27] | CKD-HD, CKD-NDD, or CKD-PD | 145 | 91 | IV iron sucrose (patients assigned to 1 of 3 doses by weight) | 3 months | Composite of Hb ≥10.5–14.0 g/dL (≥105.0–140.0 g/L), inclusive; TSAT ≥20–50%, inclusive; and stable ESA dosing (± 25% of baseline dose) |
Kosch et al. 2001 [28] | CKD-HD | 59 | 59 | IV ferric gluconate (Ferrlecit) IV iron sucrose | 6 months | Differences in Hb, TSAT, ferritin, % hypochromic red blood cells, and rHuEpo dose requirements |
Macdougall et al. 2014 [17] | CKD-HD and CKD-NDD | 162 | 70 | IV ferumoxytol IV iron sucrose | 7 weeks | Descriptive review of adverse effects; change in Hb from Baseline to Day 35 |
Sav et al. 2007 [29] | CKD-HD, CKD-CAPD, and CKD-NDD | 60 | 60 | IV iron dextran IV iron sucrose | 48 hourss | Adverse reactions immediately (i.e., within 30 min) or up to 48 h after infusion |
Sheashaa et al. 2005 [30] | CKD-HD | 48 | 48 | IV iron saccharate complex IV sodium ferric gluconate complex | 6 months | Change in serum iron, serum ferritin, TSAT, Hb, and hematocrit |
Warady et al. 2005 [31] | CKD-HD Pediatric | 66 | 66 | IV sodium ferric gluconate complex 1.5 mg/kg IV sodium ferric gluconate complex 3.0 mg/kg | 8-dose treatment with each dialysis + 4 weeks | Mean changes in Hb, hematocrit, TSAT, serum ferritin, and reticulocyte Hb content values from Baseline to 2 weeks after dosing cessation |
Methods/Design
Main study
Inclusion criteria | Exclusion criteria |
---|---|
Main study | |
•Males and females aged ≥18 years | •History of allergy to either oral or intravenous iron |
•Patients with iron deficiency anemia defined as hemoglobin <11.5 g/dL (<115.0 g/L) and transferrin saturation <30% | •Female patients who are pregnant or intend to become pregnant, breastfeeding, within 3 months postpartum, or have a positive serum or urine pregnancy test |
•Serum ferritin <800 ng/mL (<1798 pmol/L) | •Parenteral iron therapy within 30 days prior to screening or red blood cell/whole blood transfusion within 14 days prior to screening or planned during the study |
•Patients must have been on hemodialysis for ≥3 months prior to screening | •Untreated vitamin B12 or folate deficiency |
•Female patients of childbearing potential who are sexually active must be on an effective method of birth control for ≥1 month prior to screening and agree to remain on birth control until study completion | •ESA therapy initiated, stopped, or dose changed by >20% within 30 days prior to screening, or an anticipated ESA dose change of >20% during the initial treatment period |
•Patient is capable of understanding and complying with the protocol requirements and available for the study duration | •Received an investigational agent within 30 days prior to screening or planned receipt of an investigational agent not specified by this protocol during the study period |
•Provide written informed consent | •Any other clinically significant medical disease or psychiatric disease or condition that, in the investigator’s opinion, may interfere with the patient’s ability to give informed consent or adhere to the protocol, interfere with assessment of the study agent, or serve as a contraindication to the patient’s participation in the study |
MRI substudy | |
•Same as main study | •Same as main study •Has any contraindication to MRI or otherwise unable to undergo MRI (e.g., pacemaker, recent wound clips, severe claustrophobia, or unable to lay flat for sufficient time to undergo imaging) |
•Baseline cardiac T2*-weighted MRI value <20 msec |
Oxidative stress substudy
MRI substudy
Study objectives
Randomization and interventions
Assessments
Laboratory tests
Biomarkers
MRI
Other assessments
Safety assessments
Study endpoints
Endpoints | |
---|---|
Main study | |
Primary efficacy endpoint | •Mean change in hemoglobin from Baseline to Week 5 for each treatment period |
Secondary efficacy endpoints | •Mean change in transferrin saturation from Baseline to Week 5 for each treatment period •Proportion of patients with an increase in hemoglobin of ≥1.0 g/dL at any time from Baseline to Week 5 for each treatment period |
Safety evaluations | •An evaluation of the AE profile over the course of the study and following each course of ferumoxytol or iron sucrose, including serious AEs, AEs leading to study drug discontinuation, all AEs, vital signs (blood pressure, heart rate, respiration rate, and body temperature); physical examination findings; and routine laboratory parameters (hematology, chemistry, and iron panel) |
Exploratory endpoints | •Time to subsequent treatment courses of ferumoxytol or iron sucrose •Cumulative intravenous iron exposure per patient over the course of the study •Proportion of patients requiring blood transfusion •Proportion of patients who had a change in ESA dose (≥20% increase or decrease or initiation/cessation of ESA therapy) over the course of the study |
Oxidative stress substudy | |
Exploratory endpoints | Mean change in the following blood biomarkers from Baseline to Week 5 of the initial treatment period in the main study: •Protein carbonyl content •13-hydroxyoctadecadienoic acid •4-hydroxynonenal •Monocyte chemoattractant protein-1 •Neutrophil gelatinase-associated lipocalin •High-sensitivity interleukin-6 |
Endpoints | |
---|---|
MRI substudy | |
Primary efficacy endpoint | Absolute change in cardiac T2* from Baseline to each follow-up evaluation |
Secondary endpoints | •Proportion of patients who develop cardiac T2* value <20 msec at any time point •Proportion of patients who develop cardiac T2* value <10 msec at any time point •Change in liver iron concentration as determined by T2* from Baseline to each follow-up evaluation •Change in pancreatic T2* from Baseline to each follow-up period •Change in mean ferritin, transferrin saturation, liver function test, and thyroid function test values from Baseline to each follow-up evaluation •Change in blood glucose and glycosylated hemoglobin from Baseline to each follow-up evaluation |