Montelukast in the Treatment of Duodenal Eosinophilia
|First Submitted Date ICMJE||September 6, 2005|
|First Posted Date ICMJE||September 8, 2005|
|Last Update Posted Date||December 29, 2011|
|Start Date ICMJE||September 2005|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00148603 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Montelukast in the Treatment of Duodenal Eosinophilia|
|Official Title ICMJE||Montelukast in the Treatment of Duodenal Eosinophilia in Children With Dyspepsia: Effect on Eosinophil Density and Activation in Relation to Pharmacokinetics|
|Brief Summary||This is a single site study of the effect of montelukast on eosinophil and mast cell counts and activation in the lining of the duodenum in 24 children with dyspepsia in association with duodenal eosinophilia in association with measuring the concentration of the medication in the lining of the duodenum. Patients will be endoscoped with biopsies obtained from the duodenum as part of routine clinical care. Participants in the study will then receive montelukast daily and the endoscopy with biopsies will be repeated on day 21 to measure cell counts and activation and tissue montelukast levels. Cell counts and measures of activation will be compared to pre-treatment levels.|
Recurrent abdominal pain is a common complaint among school-age children, being present in up to 15% at any given time. It represents the most common chronic pain entity in pediatric patients. These patients frequently have dyspepsia defined as upper abdominal pain or discomfort. (1) Eighty-three percent of children referred to our institution for recurrent pain have dyspepsia. Shaffer, et al, found dyspepsia to be present in 73% of 154 children with recurrent abdominal pain. (2)
We have found mucosal eosinophilia in 71% of children undergoing endoscopy with mucosal biopsy for dyspepsia. However, eosinophil density does not necessarily correlate with eosinophil activation and many eosinophil-derived mediators are bioactive in a concentration-dependent fashion. (3) In previous investigations, we have found evidence of moderate to extensive eosinophil degranulation in the biopsies of dyspeptic children who had normal mucosal eosinophil densities. (4)
Montelukast is a competitive antagonist of the cys LT1 receptor with an affinity that is similar, but lower than that of leukotriene D4. (5) We and others have previously reported good clinical response to montelukast in patients with eosinophilic gastroenteritis. (6-9) Recently, Vanderhoof and Young (8) reported eight patients with dysphagia, diarrhea, and/or constipation associated with tissue eosinophilia who had prolonged remission of symptoms with montelukast therapy. This experience prompted us to undertake a double-blinded placebo-controlled cross-over trial of montelukast in dyspeptic children with duodenal eosinophilia. We were able to demonstrate the superiority of montelukast as compared to placebo in the relief of pain. (9) Despite an average duration of pain of nearly 22 months prior to study enrollment, approximately one-half of the patients became pain free or nearly pain-free during the two week course of therapy with montelukast. Also of interest from this particular study was the finding that montelukast pharmacokinetics, and thus exposure, were different than previously observed in children receiving the drug. Specifically, the average population elimination t-1/2 for montelukast in our subjects (1.8 hours) was substantially shorter than mean values for this parameter (3.4 hours) determined from children without concurrent intestinal disease. (5, 10) While the reasons for this apparent disparity are not clear, it is possible that local montelukast metabolism (ie., in the small intestine) may vary as a consequence of disease state. Nonetheless, what remains to be determined is whether there is a link between systemic and tissue levels and whether an exposure-response relation can be established for montelukast in pediatric patients with eosinophilic duodenitis.
Finally, the mechanism responsible for the demonstrated clinical efficacy of montelukast in this disorder has not been established. It is possible that the therapeutic effect might result consequent to a lowering in eosinophil density, alteration of the eosinophil activation state, blocking leukotrienes released by eosinophils (or other cells) at their site of action, or any combination of the aforementioned effects. The clinical effectiveness of medications for eosinophilic esophagitis has been previously found to be associated with a decrease in eosinophil density, but the activation state was not assessed. (11-12) As well, no previous investigations of therapeutic interventions for this disorder have addressed exposure-response relationships.
The beneficial therapeutic effect of montelukast in patients with eosinophilic duodenitis is determined by the activation state and local density of eosinophils, and by attainment of sufficient systemic and local exposure.
III. Objectives / Specific Aims
A. To determine the effect of montelukast on mucosal eosinophil density and activation state in pediatric patients with eosinophilic duodenitis presenting as dyspepsia.
B. To evaluate the relationship between clinical response, systemic drug exposure, local tissue drug concentration, and the eosinophil density and activation state.
A. Study Population
A total of 24 patients evaluated at the Children's Mercy Hospitals and Clinics will be enrolled in the study.
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
|Intervention ICMJE||Drug: montelukast|
|Study Arms||Not Provided|
|Publications *||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.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Enrollment ICMJE||24|
|Completion Date||December 2006|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
A subject will be eligible for inclusion in this study if all of the following criteria are met:
Subjects will not be eligible for inclusion in this study if any of the following criteria apply:
|Ages||8 Years to 17 Years (Child)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00148603|
|Other Study ID Numbers ICMJE||05 01-009|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||Children's Mercy Hospital Kansas City|
|Collaborators ICMJE||Merck Sharp & Dohme Corp.|
|PRS Account||Children's Mercy Hospital Kansas City|
|Verification Date||December 2011|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP