Pharmacology of Exenatide in Pediatric Sepsis

NCT ID: NCT01573806

Last Updated: 2017-10-05

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2014-10-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Exenatide

Subjects dosed with exenatide in Phase 2

Group Type: ACTIVE_COMPARATOR

Exenatide

Intervention Type: DRUG

Exenatide, dosed subcutaneously every 12 hours for 4 doses

Exenatide vehicle

Subjects dosed with exenatide vehicle in Phase 2

Group Type: PLACEBO_COMPARATOR

Exenatide vehicle

Intervention Type: DRUG

Exenatide vehicle, dosed subcutaneously every 12 hours for 4 doses

Interventions

Exenatide

Exenatide, dosed subcutaneously every 12 hours for 4 doses

Intervention Type: DRUG

Exenatide vehicle

Exenatide vehicle, dosed subcutaneously every 12 hours for 4 doses

Intervention Type: DRUG

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.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Seattle Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Jerry Zimmerman

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Seattle Children's Hospital

Seattle, Washington, United States

Countries

United States

References

Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010 Mar 15;16(6):1726-36. doi: 10.1158/1078-0432.CCR-09-1961. Epub 2010 Mar 9.

Reference Type: BACKGROUND

PMID: 20215542 (View on PubMed)

Mecott GA, Herndon DN, Kulp GA, Brooks NC, Al-Mousawi AM, Kraft R, Rivero HG, Williams FN, Branski LK, Jeschke MG. The use of exenatide in severely burned pediatric patients. Crit Care. 2010;14(4):R153. doi: 10.1186/cc9222. Epub 2010 Aug 11.

Reference Type: BACKGROUND

PMID: 20701787 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19446153 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20228679 (View on PubMed)

Other Identifiers

PEPS-SCH-001

Identifier Type: -

Identifier Source: org_study_id