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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Severe Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Pioglitazone hydrochloride


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |