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

Phase 1

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Pioglitazone hydrochloride	Pioglitazone hydrochloride	Pioglitazone hydrochloride treatment group

Primary Outcome Measures

Name	Time	Method
Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events	Assessement over five days	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 - Creatinine	Final day of study	Creatinine levels in blood from subject on the final day of enrollment
Safety Labs - Blood Urea Nitrogen (BUN)	Final day of study	BUN levels in blood from subject on the final day of enrollment
Safety Labs - Alanine Aminotransferase (ALT)	Final day of study	ALT levels in blood from subject on the final day of enrollment
Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration	five days	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

Name	Time	Method
Effect of Pioglitazone Area Under the Curve on Changes in IL-6	Evaluation of inflammatory biomarkers will be obtained prior to dosing for the first five days of the study	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