Functional Dyspepsia (FD) - Clinical Response to Montelukast in Children
15 de mayo de 2019 actualizado por: Craig A. Friesen, MD, Children's Mercy Hospital Kansas City
Predictors of Clinical Response to Montelukast in Children With Functional Dyspepsia
Duodenal eosinophilia has been associated with dyspepsia in adults and the investigators have previously described the finding of duodenal mucosal eosinophilia in 71-79% of children undergoing diagnostic endoscopy. Previous studies in children have shown positive response to montelukast with approximately 50% finding complete relief and 20-30 percent showing no response.
There are a number of factors that have the potential to contribute to the observed variability in response to montelukast. These include variability in:
- systemic drug exposure (drug absorption, biotransformation and/or elimination)
- regulation of leukotriene biosynthesis
- cysteinyl leukotriene receptors and downstream mediators
- patient disease phenotype (e.g. Functional Gastrointestinal Disorder (FGID) disease classification, psychologic profile)
In this study, the investigators propose to utilize biopsy specimens stratified by drug response to identify candidate gene expression modules that will be validated in a prospective study design. The overall goal of this program is to develop a signature of montelukast response that can be applied not only to eosinophilic gastroenteritis, but more generally to other diseases, such as asthma, where the drug is widely used with variable success.
Descripción general del estudio
Estado
Terminado
Condiciones
Tipo de estudio
De observación
Inscripción (Actual)
18
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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Missouri
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Kansas City, Missouri, Estados Unidos, 64108
- Children's Mercy
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-
Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
8 años a 17 años (Niño)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Método de muestreo
Muestra no probabilística
Población de estudio
Up to 50 subjects (allowance of 20 additional subjects for screen fails and those who will not complete Phase 3 of the study) will be recruited from a cohort of patients referred to the Abdominal Pain Clinic at Children's Mercy Hospitals and Clinics and enrolled prior to routine initial endoscopy.
Descripción
Inclusion Criteria:
- Ages 8 - 17 years, inclusive
- Abdominal pain of at least 8 weeks duration and fulfilling symptom- based criteria for functional dyspepsia
- Scheduled for endoscopy following failure to respond to acid-reduction therapy
- Evidence of written parental permission (consent) and subject assent
Exclusion Criteria:
- Previous treatment with montelukast
- Treatment with corticosteroids or oral cromolyn sodium in the four weeks prior to enrollment
- Prior history or clinical signs/symptoms of chronic disease requiring regular medical care (e.g., diabetes mellitus, juvenile idiopathic arthritis, cystic fibrosis or cancer)
- Exposure within the past two weeks to drugs or natural products that induce CYP2C8/9 or CYP3A4, including amprenavir, carbamazepine, lopinavir/ritonavir, nafcillin, nevirapine, oxcarbazepine, phenobarbital, phenytoin, rifampin, St. John's Wort, or that inhibit CYP2C8/9 or CYP3A4, such as ciprofloxacin, clarithromycin, erythromycin, fluconazole, fluvoxamine, grapefruit juice, paroxetine, sertraline, sulfamethoxazole, trimethoprim
- A Body Mass Index of 30 or greater
- Non-English speaking
- Those patients who will turn 18 during the duration of the study
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
Cohortes e Intervenciones
Grupo / Cohorte |
|---|
|
Peds/Adol Pts w/ FD - CMH GI APT clinic
Phase 1. Standard-of-Care Endoscopy to establish baseline data and immunohistochemistry studies. Additional biopsies taken for DNA and microarray analysis. If participant biopsies meet criteria (> or = 20/hpf) and no nodularity or tumors, s/he will be eligible to move to second phase. Phase 2. Standard of care treatment of 3 mg/kg ranitidine bid and 20 mg. montelukast each AM for three weeks. Based on response to global assessment score, participants will be placed in non-responder or responder group. Participants from the responder group will move to final phase of the study. Phase 3: Research endoscopy to measure response to montelukast therapy. Biopsies taken for cell density counts and immunohistochemistry studies. Additional biopsies taken for DNA and microarray analysis. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Identification of a signature of montelukast response using gene expression patterns in biopsy samples from clinical responders and non-responders to montelukast.
Periodo de tiempo: Approximately 7-8 weeks
|
Identification of patients who will benefit from montelukast therapy , allowing more efficient, and possibly more effective, care.
|
Approximately 7-8 weeks
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Characterization a signature of montelukast response using comparison gene expression patterns in biopsy samples obtained before and after montelukast therapy in children with a positive clinical response to the drug.
Periodo de tiempo: 7-8 weeks.
|
Identification and development of a signature of montelukast response applied to eosinophilic gastroenteritis, and more generally to other diseases, such as asthma, where the drug is widely used with variable success.
|
7-8 weeks.
|
Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Investigadores
- Investigador principal: Craig A. Friesen, MD, Children's Mercy, Division of Gastroenterlogy, Hepatology, and Nutrition
- Investigador principal: Steven Leeder, PharmD, PhD, Children's Mercy, Division of Clinical Pharmacology and Medical Toxicology
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
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- Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ. Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics. 2009 Feb;19(2):129-38. doi: 10.1097/FPC.0b013e32831bd98c.
- Mougey EB, Lang JE, Wen X, Lima JJ. Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. J Clin Pharmacol. 2011 May;51(5):751-60. doi: 10.1177/0091270010374472. Epub 2010 Oct 25.
- Lima JJ. Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers. Mol Diagn Ther. 2007;11(2):97-104. doi: 10.1007/BF03256228.
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- Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, Stanghellini V. Functional gastroduodenal disorders. Gastroenterology. 2006 Apr;130(5):1466-79. doi: 10.1053/j.gastro.2005.11.059. Erratum In: Gastroenterology. 2006 Jul;131(1):336.
- Schurman JV, Singh M, Singh V, Neilan N, Friesen CA. Symptoms and subtypes in pediatric functional dyspepsia: relation to mucosal inflammation and psychological functioning. J Pediatr Gastroenterol Nutr. 2010 Sep;51(3):298-303. doi: 10.1097/MPG.0b013e3181d1363c.
- Hall W, Buckley M, Crotty P, O'Morain CA. Gastric mucosal mast cells are increased in Helicobacter pylori-negative functional dyspepsia. Clin Gastroenterol Hepatol. 2003 Sep;1(5):363-9. doi: 10.1053/s1542-3565(03)00184-8.
- Friesen CA, Lin Z, Singh M, Singh V, Schurman JV, Burchell N, Cocjin JT, McCallum RW. Antral inflammatory cells, gastric emptying, and electrogastrography in pediatric functional dyspepsia. Dig Dis Sci. 2008 Oct;53(10):2634-40. doi: 10.1007/s10620-008-0207-0. Epub 2008 Mar 5.
- Friesen CA, Neilan NA, Schurman JV, Taylor DL, Kearns GL, Abdel-Rahman SM. Montelukast in the treatment of duodenal eosinophilia in children with dyspepsia: effect on eosinophil density and activation in relation to pharmacokinetics. BMC Gastroenterol. 2009 May 11;9:32. doi: 10.1186/1471-230X-9-32.
- Friesen CA, Sandridge L, Andre L, Roberts CC, Abdel-Rahman SM. Mucosal eosinophilia and response to H1/H2 antagonist and cromolyn therapy in pediatric dyspepsia. Clin Pediatr (Phila). 2006 Mar;45(2):143-7. doi: 10.1177/000992280604500205.
- Talley NJ, Walker MM, Aro P, Ronkainen J, Storskrubb T, Hindley LA, Harmsen WS, Zinsmeister AR, Agreus L. Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol. 2007 Oct;5(10):1175-83. doi: 10.1016/j.cgh.2007.05.015. Epub 2007 Aug 7.
- Friesen CA, Andre L, Garola R, Hodge C, Roberts C. Activated duodenal mucosal eosinophils in children with dyspepsia: a pilot transmission electron microscopic study. J Pediatr Gastroenterol Nutr. 2002 Sep;35(3):329-33. doi: 10.1097/00005176-200209000-00017.
- Friesen CA, Kearns GL, Andre L, Neustrom M, Roberts CC, Abdel-Rahman SM. Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia. J Pediatr Gastroenterol Nutr. 2004 Mar;38(3):343-51. doi: 10.1097/00005176-200403000-00021.
- Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10.
- Erjefalt JS, Greiff L, Andersson M, Adelroth E, Jeffery PK, Persson CG. Degranulation patterns of eosinophil granulocytes as determinants of eosinophil driven disease. Thorax. 2001 May;56(5):341-4. doi: 10.1136/thorax.56.5.341.
- Muijsers RB, Noble S. Montelukast: a review of its therapeutic potential in asthma in children 2 to 14 years of age. Paediatr Drugs. 2002;4(2):123-39. doi: 10.2165/00128072-200204020-00005.
- Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):506. doi: 10.1016/s0091-6749(99)70404-5. No abstract available.
- Schwartz DA, Pardi DS, Murray JA. Use of montelukast as steroid-sparing agent for recurrent eosinophilic gastroenteritis. Dig Dis Sci. 2001 Aug;46(8):1787-90. doi: 10.1023/a:1010682310928.
- Vanderhoof JA, Young RJ, Hanner TL, Kettlehut B. Montelukast: use in pediatric patients with eosinophilic gastrointestinal disease. J Pediatr Gastroenterol Nutr. 2003 Feb;36(2):293-4. doi: 10.1097/00005176-200302000-00027. No abstract available.
- Chiba M, Xu X, Nishime JA, Balani SK, Lin JH. Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist, in humans. Drug Metab Dispos. 1997 Sep;25(9):1022-31.
- Karonen T, Filppula A, Laitila J, Niemi M, Neuvonen PJ, Backman JT. Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast. Clin Pharmacol Ther. 2010 Aug;88(2):223-30. doi: 10.1038/clpt.2010.73. Epub 2010 Jun 30.
- Filppula AM, Laitila J, Neuvonen PJ, Backman JT. Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. Drug Metab Dispos. 2011 May;39(5):904-11. doi: 10.1124/dmd.110.037689. Epub 2011 Feb 2.
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- Rodriguez-Antona C, Niemi M, Backman JT, Kajosaari LI, Neuvonen PJ, Robledo M, Ingelman-Sundberg M. Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism. Pharmacogenomics J. 2008 Aug;8(4):268-77. doi: 10.1038/sj.tpj.6500482. Epub 2007 Oct 9.
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- Duroudier NP, Tulah AS, Sayers I. Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy. 2009 Jun;64(6):823-39. doi: 10.1111/j.1398-9995.2009.02015.x. Epub 2009 Mar 26.
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- Sampson AP, Pizzichini E, Bisgaard H. Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation. J Allergy Clin Immunol. 2003 Jan;111(1 Suppl):S49-59; discussion S59-61. doi: 10.1067/mai.2003.24.
- Bizzintino JA, Khoo SK, Zhang G, Martin AC, Rueter K, Geelhoed GC, Goldblatt J, Laing IA, Le Souef PN, Hayden CM. Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma. Prostaglandins Leukot Essent Fatty Acids. 2009 Jul;81(1):9-15. doi: 10.1016/j.plefa.2009.05.022. Epub 2009 Jun 12.
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- Maeba S, Ichiyama T, Ueno Y, Makata H, Matsubara T, Furukawa S. Effect of montelukast on nuclear factor kappaB activation and proinflammatory molecules. Ann Allergy Asthma Immunol. 2005 Jun;94(6):670-4. doi: 10.1016/S1081-1206(10)61326-9.
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Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio
1 de agosto de 2014
Finalización primaria (Actual)
1 de agosto de 2016
Finalización del estudio (Actual)
1 de agosto de 2016
Fechas de registro del estudio
Enviado por primera vez
3 de septiembre de 2014
Primero enviado que cumplió con los criterios de control de calidad
5 de febrero de 2015
Publicado por primera vez (Estimar)
11 de febrero de 2015
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
16 de mayo de 2019
Última actualización enviada que cumplió con los criterios de control de calidad
15 de mayo de 2019
Última verificación
1 de mayo de 2019
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- 13100348
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .