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

Pharmacokinetic Characteristics of Pioglitazone and Preliminary Biomarker Response in Adolescents Aged 12 to 17 Years With Severe Sepsis and Septic Shock

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: Drug: Pioglitazone hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone hydrochloride; Pioglitazone hydrochloride treatment group	Drug: Pioglitazone hydrochloride; Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.; Other Names: Actos
No Intervention: Normal standard care; Normal standard care control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Assessement over five days
Safety Labs - Blood Urea Nitrogen (BUN)	BUN levels in blood from subject on the final day of enrollment	Final day of study
Safety Labs - Creatinine	Creatinine levels in blood from subject on the final day of enrollment	Final day of study
Safety Labs - Alanine Aminotransferase (ALT)	ALT levels in blood from subject on the final day of enrollment	Final day of study
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	five days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Evaluation of inflammatory biomarkers will be obtained prior to dosing for the first five days of the study

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Jennifer M. Kaplan, M.D., M.S., Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Kaplan Lab Page

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: February 23, 2011
• First Submitted That Met QC Criteria: May 10, 2011
• First Posted (Estimate): May 11, 2011

Study Record Updates

• Last Update Posted (Actual): September 2, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: PIOSEPSIS1217