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Pharmacokinetic and Biomarker Study of Pioglitazone in Adolescents With Severe Sepsis and Septic Shock

Primary Purpose

Severe Sepsis, Septic Shock

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pioglitazone hydrochloride
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Sepsis

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Weight range between 30 to less than or equal to 90kg
  • Have a known or suspected infection and meet criteria for severe sepsis or septic shock as defined according to the International Pediatric Sepsis Consensus Conference guidelines

Exclusion Criteria:

  • Are in a moribund state in which death is perceived as imminent
  • Have an advanced directive or do not resuscitate order to withhold life-sustaining
  • Have a history of cyanotic heart disease or congestive heart failure
  • Have a serum transaminase level (ALT) that exceeds about 2.5 times the upper limit of normal (>112 unit/L)
  • Are or become pregnant
  • Are already on or have a history of taking pioglitazone or rosiglitazone
  • Have type 1 or 2 diabetes
  • Have total body weight below 30 kg or above 90 kg
  • Have a serious condition, in addition to sepsis, which in the opinion of the investigator would compromise the participant

Sites / Locations

  • Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Pioglitazone hydrochloride

Normal standard care

Arm Description

Pioglitazone hydrochloride treatment group

Normal standard care control group

Outcomes

Primary Outcome Measures

Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events
The number of hypoglycemic events in pioglitazone vs standard care. Hypoglycemia was defined as blood glucose level that remains <40mg/dl despite dextrose bolus treatment.
Safety Labs - Blood Urea Nitrogen (BUN)
BUN levels in blood from subject on the final day of enrollment
Safety Labs - Creatinine
Creatinine levels in blood from subject on the final day of enrollment
Safety Labs - Alanine Aminotransferase (ALT)
ALT levels in blood from subject on the final day of enrollment
Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration
Pioglitazone concentration as the total area under curve divided by the number of days receiving the drug in subjects who took the drug by mouth versus by naso-gastric tube

Secondary Outcome Measures

Effect of Pioglitazone Area Under the Curve on Changes in IL-6
We examined the effect of pioglitazone Area under the curve on IL-6 in patients receiving pioglitazone only. (Control subjects did not receive pioglitazone). The pharmacokinetic endpoint was area under the curve (AUC) total/days of pioglitazone administration

Full Information

First Posted
February 23, 2011
Last Updated
August 18, 2020
Sponsor
Children's Hospital Medical Center, Cincinnati
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1. Study Identification

Unique Protocol Identification Number
NCT01352182
Brief Title
Pharmacokinetic and Biomarker Study of Pioglitazone in Adolescents With Severe Sepsis and Septic Shock
Official Title
Pharmacokinetic Characteristics of Pioglitazone and Preliminary Biomarker Response in Adolescents Aged 12 to 17 Years With Severe Sepsis and Septic Shock
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
January 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the pharmacokinetics of pioglitazone and to determine the effect on inflammatory biomarkers for pioglitazone in patients with severe sepsis and septic shock.
Detailed Description
Severe sepsis is a major cause of morbidity and mortality among adults and children. Few clinical trials have demonstrated clinical benefit in sepsis. Severe sepsis is a systemic inflammatory syndrome in response to infection that is associated with acute organ dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARg) is involved in the regulation of the sepsis-induced inflammatory response. The central hypothesis is that pioglitazone reduces the inflammatory responses in children with severe sepsis and septic shock.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Sepsis, Septic Shock

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
InvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pioglitazone hydrochloride
Arm Type
Experimental
Arm Description
Pioglitazone hydrochloride treatment group
Arm Title
Normal standard care
Arm Type
No Intervention
Arm Description
Normal standard care control group
Intervention Type
Drug
Intervention Name(s)
Pioglitazone hydrochloride
Other Intervention Name(s)
Actos
Intervention Description
Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.
Primary Outcome Measure Information:
Title
Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events
Description
The number of hypoglycemic events in pioglitazone vs standard care. Hypoglycemia was defined as blood glucose level that remains <40mg/dl despite dextrose bolus treatment.
Time Frame
Assessement over five days
Title
Safety Labs - Blood Urea Nitrogen (BUN)
Description
BUN levels in blood from subject on the final day of enrollment
Time Frame
Final day of study
Title
Safety Labs - Creatinine
Description
Creatinine levels in blood from subject on the final day of enrollment
Time Frame
Final day of study
Title
Safety Labs - Alanine Aminotransferase (ALT)
Description
ALT levels in blood from subject on the final day of enrollment
Time Frame
Final day of study
Title
Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration
Description
Pioglitazone concentration as the total area under curve divided by the number of days receiving the drug in subjects who took the drug by mouth versus by naso-gastric tube
Time Frame
five days
Secondary Outcome Measure Information:
Title
Effect of Pioglitazone Area Under the Curve on Changes in IL-6
Description
We examined the effect of pioglitazone Area under the curve on IL-6 in patients receiving pioglitazone only. (Control subjects did not receive pioglitazone). The pharmacokinetic endpoint was area under the curve (AUC) total/days of pioglitazone administration
Time Frame
Evaluation of inflammatory biomarkers will be obtained prior to dosing for the first five days of the study

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Weight range between 30 to less than or equal to 90kg Have a known or suspected infection and meet criteria for severe sepsis or septic shock as defined according to the International Pediatric Sepsis Consensus Conference guidelines Exclusion Criteria: Are in a moribund state in which death is perceived as imminent Have an advanced directive or do not resuscitate order to withhold life-sustaining Have a history of cyanotic heart disease or congestive heart failure Have a serum transaminase level (ALT) that exceeds about 2.5 times the upper limit of normal (>112 unit/L) Are or become pregnant Are already on or have a history of taking pioglitazone or rosiglitazone Have type 1 or 2 diabetes Have total body weight below 30 kg or above 90 kg Have a serious condition, in addition to sepsis, which in the opinion of the investigator would compromise the participant
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jennifer M. Kaplan, M.D., M.S.
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19760394
Citation
Kaplan JM, Denenberg A, Monaco M, Nowell M, Wong H, Zingarelli B. Changes in peroxisome proliferator-activated receptor-gamma activity in children with septic shock. Intensive Care Med. 2010 Jan;36(1):123-30. doi: 10.1007/s00134-009-1654-6. Epub 2009 Sep 17.
Results Reference
background
PubMed Identifier
21667139
Citation
Sherwin CM, Ding L, Kaplan J, Spigarelli MG, Vinks AA. Optimal study design for pioglitazone in septic pediatric patients. J Pharmacokinet Pharmacodyn. 2011 Aug;38(4):433-47. doi: 10.1007/s10928-011-9202-8. Epub 2011 Jun 11.
Results Reference
background
PubMed Identifier
30255316
Citation
Kaplan JM, Zingarelli B, Krallman K, Tang Girdwood S, Lagory D, Mizuno T, Fei L, Wong HR, Vinks AA. Phase 1 safety and pharmacokinetic study on the use of pioglitazone in critically ill patients with sepsis: a randomized clinical trial. Intensive Care Med. 2018 Nov;44(11):2006-2008. doi: 10.1007/s00134-018-5374-7. Epub 2018 Sep 25. No abstract available.
Results Reference
result
Links:
URL
http://www.cincinnatichildrens.org/research/divisions/c/critical/labs/Kaplan/default/
Description
Kaplan Lab Page

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Pharmacokinetic and Biomarker Study of Pioglitazone in Adolescents With Severe Sepsis and Septic Shock

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