Zinc Therapy in Critical Illness

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Vermont
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Renee Stapleton, University of Vermont
ClinicalTrials.gov Identifier:
NCT01162109
First received: July 8, 2010
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

Sepsis is a clinical syndrome often caused by a bloodstream infection that results in a common set of symptoms termed systemic inflammatory response syndrome (SIRS). Severe sepsis (sepsis with organ failure) is the leading cause of death in critically ill patients in the US. Most patients with severe sepsis need to be treated in the intensive care unit with mechanical ventilation and intravenous antibiotics. Between 30 to 50% of all severe sepsis patients die and quality of life in survivors is substantially reduced. New therapies are needed to improve clinical outcomes in patients with sepsis.

A new area of interest in the treatment of critical illness is pharmaconutrition, in which micronutrients (like zinc) are studied and administered to determine if they affect the inflammatory response or immunologic processes in critical illness. The FDA does not regulate micronutrients and does not require rigorous pharmacokinetic (the study of how a drug or nutrient is metabolized in the body) testing so it is not clear how to dose micronutrients in critically ill patients. It is also not clear if critically ill patients would metabolize these micronutrients differently than healthy people and would need different dosing levels. This is true of zinc, the focus of this research study.

Zinc is essential for normal immune function, oxidative stress response, and wound healing, and its homeostasis is tightly regulated. Zinc deficiency occurs in >10% of Americans and leads to loss of innate and adaptive immunity and increased susceptibility to infections. The symptoms of zinc deficiency are similar to many of the symptoms of SIRS and there is strong biologic rationale to suggest that the zinc deficiency seen in nearly all sepsis patients may contribute to the development of sepsis syndrome and to the "immunoparalysis" common in sepsis patients

This study has three specific aims, 1) to perform a phase I dose-finding study of intravenous zinc in mechanically ventilated patients with severe sepsis; 2) to define the pharmacokinetic of intravenous zinc in mechanically ventilated patients with severe sepsis compared to healthy controls; and 3) to investigate the impact of zinc on inflammation, immunity, and oxidant defense in patients with severe sepsis.

A total of 40 critically ill patients from the FAHC intensive care units and 15 healthy controls will be enrolled in the study. The critically ill patient population will be divided into 4 dosing groups of 10 subjects (7 randomized to zinc and 3 to saline placebo). Group 1 will receive 500mcg/kg IBW/day elemental zinc in divided doses every 8 hours. If the 50th percentile of the normal plasma zinc range (110mcg/dL) has not been achieved in all patients by 7 days and there are no safety concerns, sequential groups of patients will receive increasing doses in 250mcg increments to the ceiling dose. Groups 2 through 4 will receive 750, 1000, and 1250mcg/kgIBW/day elemental zinc, respectively. Each participant will receive the intravenous zinc or placebo for a total of 7 days unless they die or leave the ICU earlier. Pharmacokinetic testing will be obtained from 40 of the critically ill subjects and in 15 healthy controls. Additional blood will be drawn during the infusion protocol to investigate the impact of zinc on inflammation, immunity, and oxidant defense.


Condition Intervention Phase
Severe Sepsis
Dietary Supplement: Zinc sulfate
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Pharmaconutrients as Therapies for Critical Illness: Zinc in Severe Sepsis

Resource links provided by NLM:


Further study details as provided by University of Vermont:

Primary Outcome Measures:
  • Pharmacokinetics/pharmacodynamics [ Time Frame: Several time points over one week during critical illness ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Production of TNF-alpha by circulating monocytes [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Production of IL-1beta by circulating monocytes [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Production of IL-6 by circulating monocytes [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Production of IL-8 by circulating monocytes [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Plasma TNF-alpha [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Plasma IL-1beta [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Plasma IL-6 [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Plasma IL-8 [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Serum malondialdehyde (MDA) [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Serum 8-hydroxydeoxyguanine (8-OHdG) [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]
  • Neutrophil phagocytosis [ Time Frame: Study days 1, 3, and 7 ] [ Designated as safety issue: No ]

Estimated Enrollment: 55
Study Start Date: September 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Severe sepsis without zinc
Mechanically ventilated patients with severe sepsis will be randomized to receive IV zinc or placebo
Dietary Supplement: Zinc sulfate

A group of 10 mechanically ventilated patients with severe sepsis will be randomized to receive 500mcg/kg IBW elemental zinc (IV) or placebo. The dose will be escalated by 250mcg/kg IBW every 10 subjects to ceiling dose of 1250 mcg/kg IBW or until toxicity develops.

A group of healthy volunteers will also receive IV zinc (as a single dose) and the PK will be compared to that in patients with sepsis.

Experimental: Zinc in severe sepsis
Mechanically ventilated patients with severe sepsis will be randomized to receive IV zinc or placebo
Dietary Supplement: Zinc sulfate

A group of 10 mechanically ventilated patients with severe sepsis will be randomized to receive 500mcg/kg IBW elemental zinc (IV) or placebo. The dose will be escalated by 250mcg/kg IBW every 10 subjects to ceiling dose of 1250 mcg/kg IBW or until toxicity develops.

A group of healthy volunteers will also receive IV zinc (as a single dose) and the PK will be compared to that in patients with sepsis.

Experimental: Healthy Volunteers receiving zinc
Cohort of healthy volunteers will receive a single dose of 500 mcg/kg IBW IV zinc and pharmacokinetics will be measured for 8 hours. PK in sepsis patients and healthy volunteers will be compared.
Dietary Supplement: Zinc sulfate

A group of 10 mechanically ventilated patients with severe sepsis will be randomized to receive 500mcg/kg IBW elemental zinc (IV) or placebo. The dose will be escalated by 250mcg/kg IBW every 10 subjects to ceiling dose of 1250 mcg/kg IBW or until toxicity develops.

A group of healthy volunteers will also receive IV zinc (as a single dose) and the PK will be compared to that in patients with sepsis.


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Severe sepsis
  • Requiring mechanical ventilation
  • 18 years or older

Exclusion Criteria:

  • >36 hours since meeting severe sepsis criteria4
  • Expected ICU length of stay <72 hours
  • Pre-existing gastrointestinal disease*
  • Post-cardiac arrest with significant anoxic brain injury
  • Creatinine clearance <40mL/min*
  • Taking zinc supplement during past month*
  • Has received zinc supplementation while hospitalized
  • Pregnant or lactating*
  • AIDS with CD4<200*
  • Previous bone marrow or solid organ transplant*
  • Receiving TPN with added zinc
  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: NCT01162109

Contacts
Contact: Sara S Ardren, PA 802-656-7953 sara.ardren@vtmednet.org
Contact: Renee D Stapleton, MD, PhD 802-656-7975 renee.stapleton@uvm.edu

Locations
United States, Vermont
University of Vermont College of Medicine Recruiting
Burlington, Vermont, United States, 05405
Contact: Sara S Ardren, PA    802-656-7953    sara.ardren@vtmednet.org   
Contact: Renee D Stapleton, MD, PhD    802-656-7975    renee.stapleton@uvm.edu   
Principal Investigator: Renee D Stapleton, MD, PhD         
Sponsors and Collaborators
University of Vermont
Investigators
Principal Investigator: Renee D Stapleton, MD, PhD University of Vermont
  More Information

No publications provided

Responsible Party: Renee Stapleton, Assistant Professor of Medicine, University of Vermont
ClinicalTrials.gov Identifier: NCT01162109     History of Changes
Other Study ID Numbers: Zinc1017, 1K23HL105654
Study First Received: July 8, 2010
Last Updated: July 23, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Vermont:
Zinc
sepsis
critical illness
mechanical ventilation
ICU

Additional relevant MeSH terms:
Critical Illness
Sepsis
Disease Attributes
Infection
Inflammation
Pathologic Processes
Systemic Inflammatory Response Syndrome
Zinc
Zinc Sulfate
Astringents
Dermatologic Agents
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on October 22, 2014