PEPS: Pharmacology of Exenatide in Pediatric Sepsis

Sponsor

Seattle Children's Hospital (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01573806

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Septic Shock Inflammation Glucose Homeostasis Organ Dysfunction Health-related Quality of Life	Drug: Exenatide Drug: Exenatide vehicle	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2012

Anticipated Primary Completion Date :

Oct 1, 2014

Anticipated Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Exenatide Subjects dosed with exenatide in Phase 2	Drug: Exenatide Exenatide, dosed subcutaneously every 12 hours for 4 doses
Placebo Comparator: Exenatide vehicle Subjects dosed with exenatide vehicle in Phase 2	Drug: Exenatide vehicle Exenatide vehicle, dosed subcutaneously every 12 hours for 4 doses

Arm

Intervention/Treatment

Active Comparator: Exenatide

Subjects dosed with exenatide in Phase 2

Drug: Exenatide

Exenatide, dosed subcutaneously every 12 hours for 4 doses

Placebo Comparator: Exenatide vehicle

Subjects dosed with exenatide vehicle in Phase 2

Drug: Exenatide vehicle

Exenatide vehicle, dosed subcutaneously every 12 hours for 4 doses

Outcome Measures

Primary Outcome Measures

Exenatide associated adverse event occurence [From PICU admission to PICU discharge, an average interval of 7.5 days]
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.
Exenatide pharmacokinetics: Area under the exenatide concentration curve for 4 subcutaneous exenatide injections administered every 12 hours. [48 hours following the first exenatide dose]
Delineation of the pharmacokinetics of subcutaneously dosed exenatide among children with de novo septic shock.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.