Pilot Study of Goal-Directed Iron Supplementation +/- Oxandrolone for Functional Iron Deficiency of Critical Illness

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2014 by Denver Health and Hospital Authority
Sponsor:
Information provided by (Responsible Party):
Fredric Pieracci, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier:
NCT02047552
First received: January 26, 2014
Last updated: NA
Last verified: January 2014
History: No changes posted
  Purpose

The purpose of this trial is to determine if the combination of goal directed iron supplementation and hepcidin mitigation can safely eliminate both the serum and bone marrow iron debt of anemic, critically ill trauma patients with functional iron deficiency.


Condition Intervention Phase
Functional Iron Deficiency
Trauma
Anemia
Drug: Iron sucrose
Drug: Oxandrolone
Other: IV iron placebo
Other: Oxandrolone placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Pilot Study of Goal-directed Iron Supplementation of Anemic, Critically Ill Trauma Patients With Functional Iron Deficiency, With and Without Oxandrolone

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Serum iron debt (as measured by the transferrin saturation) [ Time Frame: One week ] [ Designated as safety issue: Yes ]
    The transferrin saturation will be measured at baseline and daily thereafter for one week


Secondary Outcome Measures:
  • Bone marrow iron debt (as measured by the zinc protoporphyrin) [ Time Frame: one week ] [ Designated as safety issue: No ]
    Zinc protoporphyrin will be measured at baseline and daily thereafter for one week

  • Serum ferritin concentration [ Time Frame: one week ] [ Designated as safety issue: Yes ]
    The serum ferritin concentration will be measured at baseline and daily thereafter for one week

  • serum hepcidin concentration [ Time Frame: one week ] [ Designated as safety issue: No ]
    The serum hepcidin concentration will be measured at baseline and daily thereafter for one week.

  • Liver function tests [ Time Frame: one week ] [ Designated as safety issue: Yes ]
    Liver function tests will be measured at baseline and daily thereafter for one week.

  • Erythropoeitin concentration [ Time Frame: one week ] [ Designated as safety issue: No ]
    The serum erythropoeitin concentration will be measured at baseline and daily thereafter for one week.

  • Red blood cell transfusion requirement [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    The incidence and number of red blood cell transfusions will be collected for 28 days.

  • Hemoglobin [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    The hemoglobin concentration will be measured at baseline and daily thereafter for 28 days.

  • Infections [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    The incidence, types, and number of infections will be collected for 28 days.

  • All cause mortality [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    All cause mortality will be collected for 28 days


Estimated Enrollment: 40
Study Start Date: April 2014
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Iron sucrose
Iron sucrose 100 mg IV will be dosed daily for up to seven days if, on morning laboratory analysis, (1) TSAT < 25%, (2) Serum iron concentration < 150 ug/mL, and (3) Serum ferritin concentration < 1,500 ng/mL. Thus, the maximum possible cumulative dose of iron sucrose over the one-week dosing period will be 700 mg.
Drug: Iron sucrose
Iron sucrose 100 mg IV will be dosed daily for up to seven days if, on morning laboratory analysis, (1) TSAT < 25%, (2) Serum iron concentration < 150 ug/mL, and (3) Serum ferritin concentration < 1,500 ng/mL. Thus, the maximum possible cumulative dose of iron sucrose over the one-week dosing period will be 700 mg.
Other: Oxandrolone placebo
similar color and size sugar pill
Active Comparator: Oxandrolone
Oxandrolone 10 mg PO q12 hours will be dosed for seven days.
Drug: Oxandrolone
10 mg PO Q12 hours for seven days
Other: IV iron placebo
100 mL normal saline.
Experimental: Iron sucrose + oxandrolone
Combination goal-directed iron sucrose (as described in the iron sucrose only arm) and oxandrolone (as described in the oxandrolone only arm) for seven days.
Drug: Iron sucrose
Iron sucrose 100 mg IV will be dosed daily for up to seven days if, on morning laboratory analysis, (1) TSAT < 25%, (2) Serum iron concentration < 150 ug/mL, and (3) Serum ferritin concentration < 1,500 ng/mL. Thus, the maximum possible cumulative dose of iron sucrose over the one-week dosing period will be 700 mg.
Drug: Oxandrolone
10 mg PO Q12 hours for seven days
Placebo Comparator: Control
IV placebo and PO placebo.
Other: IV iron placebo
100 mL normal saline.
Other: Oxandrolone placebo
similar color and size sugar pill

Detailed Description:

The inflammatory response associated with traumatic critical illness rapidly induces a functional iron deficiency, characterized by hypoferremia, decreased transferrin saturation (TSAT), hyperferritinemia, and iron-deficient erythropoiesis (IDE). These derangements in iron metabolism are primarily related to upregulation of the iron regulatory protein hepcidin, which inhibits ferroportin-mediated release of iron from both duodenal enterocytes and macrophages. The resultant functional iron deficiency both contributes to intensive care unit (ICU) anemia and increases the packed red blood cell (pRBCs) transfusion requirement.

Treatment strategies for functional iron deficiency in critically ill patients may be divided broadly into (1) iron supplementation and (2) mitigation of the effects of hepcidin. The goals of treatment are to reverse the serum iron debt, eliminate IDE, improve anemia, and ultimately decrease pRBCs transfusions. Given that approximately 90% of critically ill trauma patients with an ICU length of stay (LOS) ≥ 7 days receive at least one pRBCs transfusion, any strategy that has even a modest impact upon the transfusion requirement is likely to improve overall health outcomes substantially.

Issues surrounding iron supplementation of critically ill patients include formulation, dose, route of administration, hepcidin antagonism, and mitigation of the complications of iron overload, particularly infection. Our first 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, we compared intravenous iron sucrose 100 mg thrice weekly to placebo among critically ill trauma patients (NCT01180894, NTI-ICU-008-01) [8]. Iron supplementation using this generic dosing scheme did not impact the serum iron concentration, TSAT, IDE, anemia, or pRBCs transfusion requirement. Rather, iron supplementation accumulated as ferritin as evidenced by a significantly increased serum ferritin concentration in the iron as compared to the placebo group at all time points. Iron supplementation did not increase the risk of infection in either trial, despite a relatively high incidence of marked hyperferritinemia (serum ferritin concentration > 1,000 ng/mL) in the iron group.

The results of these trials suggest that iron supplementation alone, and using a generic dosing scheme, is ineffective. The current pilot trial aims to build upon the findings of the prior two RCTs by incorporating both goal-directed iron supplementation and hepcidin antagonism. The hypothesis is that the combination of goal directed iron supplementation and hepcidin mitigation will safely eliminate both the serum and bone marrow iron debt of anemic, critically ill trauma patients with functional iron deficiency.

  Eligibility

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

Inclusion Criteria:

  1. Informed consent from patient or patient representative.
  2. Trauma patient
  3. Anemia (hemoglobin < 12 g/dL).
  4. Functional iron deficiency:

    1. Serum iron concentration < 40 ug/dL
    2. TSAT < 25%
    3. Serum ferritin concentration > 28 ng/mL
  5. < 72 hours from ICU admission.
  6. Expected ICU length of stay ≥ 7 days.

Exclusion Criteria:

  1. Age < 18 years.
  2. Active bleeding requiring pRBCs transfusion.
  3. 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. Substantial levels of hyperferritinemia (serum ferritin 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.
  4. 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.
  5. Chronic inflammatory conditions (e.g., systemic lupus erythematosis, rheumatoid arthritis, ankylosing spondylitis).
  6. Pre-existing hematologic disorders (e.g., thalassemia, sickle cell disease, hemophilia, von Willibrand's disease, or myeloproliferative disease).
  7. Pre-existing hepatic dysfunction (cirrhosis, non-alcoholic steatohepatitis, hepatitis)
  8. Current or recent (within 30 days) use of immunosuppressive agents.
  9. Use of any recombinant human erythropoietin formulation within the previous 30 days.
  10. Known or suspected carcinoma of the breast or prostate.
  11. Nephrosis, the nephrotic phase of nephritis.
  12. Hypercalcemia (serum calcium concentration > 10.5 mg/dL).
  13. Pregnancy or lactation.
  14. Legal arrest or incarceration.
  15. Prohibition of pRBCs transfusion.
  16. Stay of ≥ 48 hours duration in the ICU of a transferring hospital.
  17. History of intolerance or hypersensitivity to either iron or oxandrolone.
  18. 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: NCT02047552

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   
Sponsors and Collaborators
Denver Health and Hospital Authority
Investigators
Principal Investigator: Fredric M Pieracci, MD, MPH Denver Health Medical Center
  More Information

No publications provided

Responsible Party: Fredric Pieracci, Assistant Professor of Surgery, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT02047552     History of Changes
Other Study ID Numbers: 14-0089
Study First Received: January 26, 2014
Last Updated: January 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Denver Health and Hospital Authority:
trauma
iron
anemia
red blood cell transfusion

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

ClinicalTrials.gov processed this record on August 21, 2014