Clinical trial NCT01573806: Pharmacology of Exenatide in Pediatric Sepsis
Official title: Phase 1-2 Study of the Pharmacology of Exenatide in Pediatric Sepsis
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Septic Shock
Inflammation
Glucose Homeostasis
Organ Dysfunction
Health-related Quality of Life
Keywords: sepsis
septic shock
children
incretins
exenatide
pharmacokinetics
pharmacodynamics
glucose homeostasis
inflammation
cytokines
health-related quality of life
functional status
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
First posted: 2012-04-10
Enrollment: 0
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Exenatide associated adverse event occurence
timeFrame: From PICU admission to PICU discharge, an average interval of 7.5 days
measure: Exenatide pharmacokinetics: Area under the exenatide concentration curve for 4 subcutaneous exenatide injections administered every 12 hours.
timeFrame: 48 hours following the first exenatide dose
Secondary outcomes:
measure: Exenatide pharmacodynamics: Effect of exenatide on glucose homeostasis
timeFrame: 60 hours following first exenatide dose
measure: Exenatide pharmacodynamics: Effect of exenatide on serum inflammatory cytokine concentrations.
timeFrame: 60 hours following first exenatide dose
measure: Exenatide clinical efficacy: Effect of exenatide on intensity and duration of organ dysfunctions.
timeFrame: From PICU admission to PICU discharge, an average interval of 7.5 days
measure: Exenatide clinical efficacy: Effect of exenatide on intensity and duration of hemodynamic instability.
timeFrame: From onset to discontinuation of vasoactive-inotropic support, an average interval of 4 days
measure: Exenatide clinical efficacy: Effect of exenatide on intensity and duration of pulmonary failure.
timeFrame: From onset to discontinuation of mechanical ventilator support, an average interval of 4.5 days
measure: Exenatide clinical efficacy: Effect of exenatide on intensity and duration of renal failure
timeFrame: From PICU admission to PICU discharge, an average interval of 7.5 days
measure: Exenatide clinical efficacy: Effect of exenatide on magnitude of sepsis-associated change in functional status.
timeFrame: 2 measurements: baseline and PICU discharge, the latter occuring on average at 7.5 days
measure: Exenatide clinical efficacy: Effect of exenatide on magnitude of sepsis-associated change in health-related quality of life
timeFrame: 2 measurements: baseline and PICU discharge, the latter occuring on average at 7.5 days
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
References:
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citation: Malloy J, Capparelli E, Gottschalk M, Guan X, Kothare P, Fineman M. Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: a randomized, placebo-controlled, single-blind, dose-escalation, crossover study. Clin Ther. 2009 Apr;31(4):806-15. doi: 10.1016/j.clinthera.2009.04.005.
citation: Deane AM, Chapman MJ, Fraser RJ, Summers MJ, Zaknic AV, Storey JP, Jones KL, Rayner CK, Horowitz M. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med. 2010 May;38(5):1261-9. doi: 10.1097/CCM.0b013e3181d9d87a.