A Randomized Pilot Study of Ferric Carboxymaltose as Compared to Iron Sucrose for the Treatment of Functional Iron Deficiency Associated With Surgical Critical Illness
The inflammatory response associated with surgical critical illness rapidly induces a functional iron deficiency, characterized by hypoferremia, decreased transferrin saturation (TSAT), hyperferritinemia, and iron-deficient erythropoiesis (IDE). This functional iron deficiency both contributes to intensive care unit (ICU) anemia and increases the packed red blood cell (pRBCs) transfusion requirement.
The goals of iron supplementation of critically ill surgical patients are to reverse the serum iron debt, eliminate IDE, improve anemia, and decrease pRBCs transfusions. Issues surrounding iron supplementation of this patient population include formulation, dose, route of administration, and mitigation of the complications of iron overload, including infection.
The investigators first randomized clinical trial (RCT) of iron supplementation of critically ill surgical patients compared enteral ferrous sulfate 325 mg thrice daily to placebo (NCT00450177). Although a significant reduction in pRBCs transfusion requirement for the iron group was observed, low injury severity, intolerance of enteral medications, and a predominance of traumatic brain injury limited generalizability. In a second multicenter RCT, the investigators compared intravenous iron sucrose 100 mg thrice weekly to placebo among critically ill trauma patients (NCT01180894). Iron supplementation at this dose increased the TSAT only marginally (and not above the normal range) and increased the serum ferritin concentration significantly; however, there was no effect on IDE, anemia, or pRBCs transfusion requirement. In no instance did iron supplementation increase the risk of infection, despite a relatively high incidence of marked hyperferritinemia (serum ferritin concentration > 1,000 ng/mL) in the iron group.
The severity of both the serum and bone marrow iron debts observed in these trials led us to investigate alternative dosing schemes that deliver larger quantities of bioavailable iron safely. Ferric carboxymaltose (FCM) is a novel iron-containing complex that allows for the administration of a large replenishment dose of iron (up to 750 mg) over a short infusion period. Several pharmacodynamic properties of FCM render it appealing for use in the treatment of functional iron deficiency associated with surgical critical illness, including a short infusion time, a controlled, sustained delivery of iron to target tissues over a relatively long period of time (up to one week), and minimal hypersensitivity reactions. Increased efficacy and comparable safety have been reported for FCM as compared to iron sucrose for treatment of outpatients with iron-deficiency anemia. There are currently no data regarding the efficacy of FCM for the indication of functional iron deficiency associated with surgical critical illness.
The aim of the current pilot trial is to compare two novel dosing schemes for treatment of function iron deficiency in surgical ICU patients, both of which involve delivery of a larger total dose of iron as compared to both NCT00450177 and NCT01180894. The investigators hypothesize that iron supplementation with FCM, as compared to both iron sucrose and placebo, is more effective and equally safe for replacing the serum iron debt.
Functional Iron Deficiency
Drug: Ferric carboxymaltose
Drug: Iron sucrose
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Randomized Pilot Study of Ferric Carboxymaltose as Compared to Iron Sucrose for the Treatment of Functional Iron Deficiency Associated With Surgical Critical Illness|
- Reversal of the serum iron debt as measured by the transferrin saturation [ Time Frame: One week ] [ Designated as safety issue: No ]Because only a small fraction of total body iron is dissolved in blood, the TSAT is currently regarded as the most accurate indicator of iron substrate available for deposition in the bone marrow and eventual incorporation into erythrocytes. Data from outpatients indicate that TSAT is a more reliable predictor of hemoglobin response as compared to either serum iron concentration or serum ferritin concentration, with a target TSAT of 25-50% considered ideal for bone marrow iron delivery. In NCT01180894, TSAT began and remained <16% despite iron supplementation with iron sucrose 100 mg IV thrice weekly. The target TSAT for this trial will be 25%-50%.
- Bone marrow iron debt [ Time Frame: One week ] [ Designated as safety issue: No ]Bone marrow iron debt as measured by daily erythrocyte zinc protoporphyrin (eZPP) concentration. During normal erythropoiesis, iron is chelated to protoporphyrin IX to form heme. When inadequate iron is delivered to the bone marrow, zinc is substituted for iron, forming zinc protoporphyrin. An elevated eZPP is diagnostic of IDE and reflects the bone marrow iron supply regardless of total body iron.
- Serum ferritin concentration [ Time Frame: One week ] [ Designated as safety issue: Yes ]
- Hemoglobin [ Time Frame: 28 days ] [ Designated as safety issue: No ]
- Red blood cell transfusion requirement [ Time Frame: 28 days ] [ Designated as safety issue: No ]Total number of units transfused.
- Nosocomial infections [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]Infections will be defined according to the US CDC guidelines, with the exception of ventilator-associated pneumonia (VAP), which is defined as clinical suspicion for pneumonia along with a lower respiratory tract culture with ≥ 105 colony forming units per mL.
|Study Start Date:||February 2016|
|Estimated Study Completion Date:||September 2016|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
Experimental: Ferric carboxymaltose (FDA IND pending)
15 mg/kg, up to 750 mg IV x 1 on the day of study enrollment.
|Drug: Ferric carboxymaltose|
Active Comparator: Iron sucrose (FDA IND 109,877)
Iron sucrose 100 mg IV will be dosed daily using goal-direction up to a total of 700 mg over a 7-day period. Specifically, iron sucrose will be dosed daily if:
|Drug: Iron sucrose|
|No Intervention: Control|
Please refer to this study by its ClinicalTrials.gov identifier: NCT02009943
|Contact: Fredric M Pieracci, MD, MPH||303 436 firstname.lastname@example.org|
|Contact: Maria Rodil, BAemail@example.com|
|United States, Colorado|
|Denver Health Medical Center||Not yet recruiting|
|Denver, Colorado, United States, 80204|
|Contact: Fredric M Pieracci, MD, MPH 303-436-4029 firstname.lastname@example.org|
|Contact: Maria Rodil, BA 303-602-3793 email@example.com|
|Principal Investigator: Fredric M Pieracci, MD, MPH|
|Sub-Investigator: Donna Bigley, PharmD|
|Sub-Investigator: Candice Preslaski, PharmD|
|Sub-Investigator: Maria Rodil, BA|
|Sub-Investigator: Robert T Stovall, MD|
|Sub-Investigator: James Haenel, RRT|
|Sub-Investigator: Jeffrey L Johnson, MD|
|Sub-Investigator: Clay C Burlew, MD|
|Sub-Investigator: Christopher Silliman, MD|
|Sub-Investigator: Ernest E Moore, MD|