Safety and Dose Escalation Study of Zinc Supplementation in Critically Ill Children

A Safety and Dose-escalation Study of Zinc Supplementation in Pediatric Critical Illness

The purpose of the study is 1) to determine whether administration of intravenous zinc to critically ill children is safe, and 2) to determine an appropriate dose of zinc supplementation.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Drug: Zinc sulfate

Detailed Description

Our recently published studies in children with septic shock demonstrated that pediatric septic shock is characterized by large scale repression of genes that either directly depend on normal zinc homeostasis or directly participate in zinc homeostasis. Functional validation studies demonstrated that nonsurvivors of pediatric septic shock have abnormally low serum zinc concentrations. A follow-up pilot study in a general population of critically ill children demonstrated that the presence of low plasma zinc concentrations is a prevalent problem in critically ill children. In addition, low plasma zinc concentrations correlate inversely with indices of inflammation and directly with the number of organ failures. These preliminary data, coupled with the expected safety of zinc supplementation, provided the rationale for a double blinded, prospective, placebo-controlled trial of zinc supplementation in critically ill children, with the two primary study endpoints to assess efficacy being highly clinically relevant: reduction of the lymphopenia rate and improvement of glucose homeostasis. Although the proposal was well-received, the primary concern precluding funding of this trial were lack of safety and dosing data for intravenous zinc. We have therefore developed a proposal for a Phase I/II study of safety and pharmacokinetics to address these concerns. It is anticipated that data generated through this proposal will provide the necessary preliminary data to re-submit our application for an interventional efficacy trial of zinc supplementation in critically ill children

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94611
      • Childrens' Hospital & Research Center Oakland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Admission to pediatric intensive care unit
• Age between 1 month and 10 years
• Pediatric Risk of Mortality III score > 5, OR presence of at least 1 new organ failure
• Anticipated pediatric intensive care unit length of stay > 3 days
• Ability of parent or legal guardian to provide informed consent

Exclusion Criteria:

• Known zinc deficiency
• Pre-existing bone marrow failure
• New or existing diagnosis of diabetes mellitus
• Limitation of care orders in place
• New diagnosis of brain injury, encephalopathy
• Clinical contraindication for zinc supplementation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; No intervention
Active Comparator: Low dose group; 250 mcg/kg/day supplemental IV zinc sulfate divided every 8 hours for 7 days	Drug: Zinc sulfate; Zinc sulfate 200 mcg/ml in Normal Saline
Active Comparator: Medium dose group; 500 mcg/kg/day supplemental IV zinc sulfate q8 hours for 7 days	Drug: Zinc sulfate; Zinc sulfate 200 mcg/ml in Normal Saline
Active Comparator: High dose group; 750 mcg/kg/day supplemental IV zinc sulfate q8 hrs for 7 days	Drug: Zinc sulfate; Zinc sulfate 200 mcg/ml in Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Zinc Concentration Over Time	Plasma Zinc levels were measured daily during the seven day study period in each group.	7 days
New Fever	Because of reports of fever in patients wiht zinc overdoses, we monitored patients for new fever while on supplementation	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Homeostasis	Patients were assigned a score based on glucose range to take into account the degree of hyperglycemia as well as the need for insulin over the course of the 7 day study period. This score is an ordinal scale ranging from 1 to 5, with a score of 1 indicating no hyperglycemia, and 5 indicating severe hyperglycemia despite insulin administration.	7 days

Collaborators and Investigators

• Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborators: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Natalie Z Cvijanovich, MD, UCSF Benioff Children's Hospital Oakland

Publications and helpful links

General Publications

• Cvijanovich NZ, King JC, Flori HR, Gildengorin G, Wong HR. Zinc homeostasis in pediatric critical illness. Pediatr Crit Care Med. 2009 Jan;10(1):29-34. doi: 10.1097/PCC.0b013e31819371ce.
• Wong HR, Shanley TP, Sakthivel B, Cvijanovich N, Lin R, Allen GL, Thomas NJ, Doctor A, Kalyanaraman M, Tofil NM, Penfil S, Monaco M, Tagavilla MA, Odoms K, Dunsmore K, Barnes M, Aronow BJ; Genomics of Pediatric SIRS/Septic Shock Investigators. Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiol Genomics. 2007 Jul 18;30(2):146-55. doi: 10.1152/physiolgenomics.00024.2007. Epub 2007 Mar 20.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: February 2, 2010
• First Submitted That Met QC Criteria: February 2, 2010
• First Posted (Estimate): February 4, 2010

Study Record Updates

• Last Update Posted (Actual): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 19, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Dermatologic Agents; Astringents; Zinc Sulfate
• Other Study ID Numbers: SPID 0876

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No