Pharmacology of Exenatide in Pediatric Sepsis

Study Overview
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Brief Summary
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Pharmacology of Exenatide in Pediatric Sepsis, PEPS is a phase 1-2 research study that will examine drug safety, drug metabolism, drug action and preliminary drug clinical effects of four does of exenatide injected every 12 hours to children with shock from infection (septic shock). The investigators hypothesize that exenatide can be safely dosed to children with sepsis to achieve blood levels of drug similar to that achieved in teenagers with type 2 diabetes. The investigators further hypothesize that injection of exenatide to children with septic shock will normalize blood glucose levels and decrease levels of inflammation proteins in the blood during the early course of sepsis.

Detailed Description
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Pharmacology of Exenatide in Pediatric Sepsis, PEPS is a phase 1-2 investigation that will examine safety, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy of 4 subcutaneous doses of exenatide administered every 12 hours to children with newly diagnosed septic shock. The investigators' long term goal is to explore the potential benefit of exenatide on: early immunomodulation and glucose homeostasis, organ dysfunction, and clinically meaningful outcomes associated with pediatric sepsis. The current study objectives are to conduct a 3+3 dose escalation study, and then examine a best exenatide allometric dose to generate safety, pharmacokinetic, pharmacodynamic, and initial efficacy data in a larger cohort. In Phase 1 (three allometric doses; three age strata)the investigators will identify an exenatide dosing regimen that mimics area under the exenatide concentration curve for exenatide dosing among adolescents with type 2 diabetes with minimal or no adverse events. A total of 18 subjects are expected to be enrolled in Phase 1. In Phase 2 the investigators will utilize this best exenatide allometric dose to further clarify exenatide safety (adverse event occurence: e.g. nausea, abdominal pain, delayed gastric emptying, hypoglycemia, pancreatitis, renal dysfunction), pharmacokinetics, pharmacodynamics (glucose homeostasis; inflammatory cytokine serum concentrations), and effect on clinical outcomes (AUC of Saturation Index, AUC Vasoactive-Inotropic Score, AUC RIFLE Criteria, Pediatric Logistic Organ Dysfunction Score; changes in health-related quality of life and functional status). In Phase 2, 30 subjects in each age strata in the ratio of 4:1, exenatide: vehicle, are expected to be enrolled.

Official Title
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Phase 1-2 Study of the Pharmacology of Exenatide in Pediatric Sepsis

Conditions
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Septic Shock, Inflammation, Glucose Homeostasis, Organ Dysfunction, Health-related Quality of Life

Intervention / Treatment
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* Drug: Exenatide
* Drug: Exenatide vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 44 weeks estimated gestational age to 18 years AND Admitted to the PICU for the sepsis event AND Vascular catheter capable of providing serial blood samples in place AND Diagnosis of septic shock = sepsis with cardiovascular organ dysfunction AND Parents speak English or Spanish Exclusion Criteria: Greater than 12 hours from admission to PICU to enrollment OR Chronic or acute dialytic therapy, history of renal impairment or renal transplantation OR History of pancreatitis OR History of hypersensitivity to Byetta OR History of severe gastrointestinal disease or gastroparesis OR History of diabetes mellitus, type I or type II OR History of insulin, sulfonyl urea drugs, or coumarin use OR History of hypoglycemia OR History of active pregnancy (effect of exenatide on the fetus is unknown) OR Inability to collect serial blood samples OR Previously enrolled in the PEPS study OR Lack of commitment to aggressive sepsis therapy OR Expectation to succumb from the sepsis event OR Patient is a foster child and/or ward of the state OR Sepsis event associated with a PICU-acquired nosocomial infection OR Patient is enrolled in another interventional investigation that might obscure the potential effects of exenatide dosing.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Exenatide<br>Subjects dosed with exenatide in Phase 2 | Drug: Exenatide<br>* Exenatide, dosed subcutaneously every 12 hours for 4 doses<br>|
| Placebo Comparator: Exenatide vehicle<br>Subjects dosed with exenatide vehicle in Phase 2 | Drug: Exenatide vehicle<br>* Exenatide vehicle, dosed subcutaneously every 12 hours for 4 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exenatide associated adverse event occurence | Potential adverse events associated with exenatide: nausea, abdominal pain, hypoglycemia, delayed gastric emptying, pancreatitis, renal dysfunction, reactions at injection site. Adverse event occurence will be tabulated while the subject remains in the PICU. | From PICU admission to PICU discharge, an average interval of 7.5 days | 
| Exenatide pharmacokinetics: Area under the exenatide concentration curve for 4 subcutaneous exenatide injections administered every 12 hours. | Delineation of the pharmacokinetics of subcutaneously dosed exenatide among children with de novo septic shock. | 48 hours following the first exenatide dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exenatide pharmacodynamics: Effect of exenatide on glucose homeostasis | Delineation of exenatide pharmacodynamics among children with de novo septic shock: AUC of all serum glucose values or results of continuous glucose monitoring obtained during the 60 hours following the first dose of exenatide (or drug vehicle). | 60 hours following first exenatide dose | 
| Exenatide pharmacodynamics: Effect of exenatide on serum inflammatory cytokine concentrations. | Delineation of exenatide pharmacodynamics among children with de novo septic shock: AUC of serial serum inflammatory cytokine concentrations. | 60 hours following first exenatide dose | 
| Exenatide clinical efficacy: Effect of exenatide on intensity and duration of organ dysfunctions. | AUC of daily Pediatric Logistic Organ Dysfunction (PELOD) scores while the subject remains in the PICU | From PICU admission to PICU discharge, an average interval of 7.5 days | 
| Exenatide clinical efficacy: Effect of exenatide on intensity and duration of hemodynamic instability. | AUC of daily Vasoactive-Inotropic Scores while the subject remains on vasoactive-inotropic support. | From onset to discontinuation of vasoactive-inotropic support, an average interval of 4 days | 
| Exenatide clinical efficacy: Effect of exenatide on intensity and duration of pulmonary failure. | AUC of daily Saturation Indices ([FiO2*MAP]/SpO2) | From onset to discontinuation of mechanical ventilator support, an average interval of 4.5 days | 
| Exenatide clinical efficacy: Effect of exenatide on intensity and duration of renal failure | AUC of daily RIFLE criteria | From PICU admission to PICU discharge, an average interval of 7.5 days | 
| Exenatide clinical efficacy: Effect of exenatide on magnitude of sepsis-associated change in functional status. | Determination per parent report of declination from baseline to PICU discharge of, Pediatric Overall Performance Category Score and Functional Status Score | 2 measurements: baseline and PICU discharge, the latter occuring on average at 7.5 days | 
| Exenatide clinical efficacy: Effect of exenatide on magnitude of sepsis-associated change in health-related quality of life | Determination per parent report of declination from baseline to PICU discharge of, Pediatric Quality of Life Inventory, Generic Core Scales, 4.0 (PedsQL) | 2 measurements: baseline and PICU discharge, the latter occuring on average at 7.5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock, children, incretins, exenatide, pharmacokinetics, pharmacodynamics, glucose homeostasis, inflammation, cytokines, health-related quality of life, functional status