A Randomized Pilot Study of Ferric Carboxymaltose as Compared to Iron Sucrose for the Treatment of Functional Iron Deficiency Associated With Surgical Critical Illness

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified July 2014 by Denver Health and Hospital Authority
Sponsor:
Information provided by (Responsible Party):
Fredric Pieracci, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier:
NCT02009943
First received: December 5, 2013
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
ICU Anemia
Functional Iron Deficiency
Drug: Ferric carboxymaltose
Drug: Iron sucrose
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Denver Health and Hospital Authority:

Primary Outcome Measures:
  • 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%.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 30
Study Start Date: February 2015
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:

  1. TSAT < 25%
  2. Serum iron concentration < 150 ug/mL
  3. Serum ferritin concentration < 1,500 ng/mL
Drug: Iron sucrose
No Intervention: Control

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Anemia (hemoglobin < 12 g/dL).
  • Functional iron deficiency:

    1. Serum iron concentration < 40 ug/dL
    2. TSAT < 25%
    3. Serum ferritin concentration > 28 ng/mL
  • < 72 hours from ICU admission.
  • Expected ICU length of stay ≥ 7 days.

Exclusion Criteria:

  • Age < 18 years.
  • Active bleeding requiring pRBCs transfusion
  • Iron overload (serum ferritin concentration ≥ 1,500 ng/mL). The serum ferritin concentration is an acute phase reactant that is increased during critical illness regardless of total body iron [3]. Substantial levels of hyperferritinemia (serum ferrinin concentration > 1,000 ng/dL) were observed in both NCT00450177 and NCT01180894 without increased risk of infection and despite both low TSAT and IDE. For these reasons, we believe that relative hyperferritinemia (serum ferritin concentration 500 - 1,500 ng/dL) is neither harmful nor indicative of bone marrow iron availability.
  • Infection, defined using US Centers for Disease Control and Prevention (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.
  • Chronic inflammatory conditions (e.g., systemic lupus erythematosis, rheumatoid arthritis, ankylosing spondilitis).
  • Pre-existing hematologic disorders (e.g., thalassemia, sickle cell disease, hemophilia, von Willibrand's disease, or myeloproliferative disease).
  • Macrocytic anemia (admission mean corpuscular volume ≥ 100 fL).
  • Current or recent (within 30 days) use of immunosuppressive agents.
  • Use of any recombinant human erythropoietin formulation within the previous 30 days.
  • Pregnancy or lactation.
  • Legal arrest or incarceration.
  • Prohibition of pRBCs transfusion.
  • Stay of ≥ 48 hours duration in the ICU of a transferring hospital.
  • History of intolerance or hypersensitivity to iron.
  • Moribund state in which death was imminent.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02009943

Contacts
Contact: Fredric M Pieracci, MD, MPH 303 436 4029 fredric.pieracci@dhha.org
Contact: Maria Rodil, BA 303-602-3793 maria.rodil@dhha.org

Locations
United States, Colorado
Denver Health Medical Center Not yet recruiting
Denver, Colorado, United States, 80204
Contact: Fredric M Pieracci, MD, MPH    303-436-4029    fredric.pieracci@dhha.org   
Contact: Maria Rodil, BA    303-602-3793    maria.rodil@dhha.org   
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         
Sponsors and Collaborators
Denver Health and Hospital Authority
  More Information

No publications provided

Responsible Party: Fredric Pieracci, Assistant Professor of Surgery, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT02009943     History of Changes
Other Study ID Numbers: COMIRB 13-3151
Study First Received: December 5, 2013
Last Updated: July 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Denver Health and Hospital Authority:
critical illness
iron supplementation
functional iron deficiency
ICU anemia
red blood cell transfusion

Additional relevant MeSH terms:
Anemia, Iron-Deficiency
Critical Illness
Anemia, Hypochromic
Anemia
Hematologic Diseases
Iron Metabolism Disorders
Metabolic Diseases
Disease Attributes
Pathologic Processes
Iron
Ferric oxide, saccharated
Ferric Compounds
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Hematinics
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 22, 2014