Ketotifen for Children With Functional Dyspepsia in Association With Duodenal Eosinophilia

Study Overview
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Brief Summary
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Acid reduction remains the most common treatment prescribed empirically by pediatric gastroenterologists for children with functional dyspepsia (FD). When acid reduction therapy fails to provide patients with a therapeutic effect, ketotifen and cromolyn, mast cell stabilizers, represent an attractive potential therapy given data implicating mast cells in the generation of dyspeptic symptoms. Although there have been no adult or pediatric studies on the use of mast cell stabilizers in patients with FD, benefit has been demonstrated in adults with IBS and children with eosinophilic gastroenteritis. Additionally, previous studies show mucosal eosinophilia is highly correlated with functional dyspepsia. Our usual current treatment pathway for functional dyspepsia in association with duodenal mucosal eosinophilia is as follows: acid-reducing medication/montelukast → addition of H1 antagonist → addition of budesonide → addition of oral cromolyn. If ketotifen is effective, it offers the advantage of being able to replace both the H1 antagonist and the oral cromolyn at a substantially reduced cost (approximately 10% of the cost of cromolyn alone). This study aims to introduce ketotifen earlier in the treatment pathway to examine its efficacy on children with functional dyspepsia in association with duodenal eosinophilia.

Detailed Description
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This study is a double-blind, placebo-controlled, cross-over trial of ketotifen in children ages 8 through 17 inclusive that have a diagnosis of functional dyspepsia and have had continued abdominal pain despite acid reduction therapy in combination with montelukast. The primary aim is to assess the symptomatic response to ketotifen as compared to placebo in children with functional dyspepsia in association with duodenal eosinophilia who have previously had worsening, no clinical change, or only a partial response to acid-reduction therapy in combination with montelukast. The study lasts 147 days for subjects responsive to ketotifen and 63 days for those who are not. For those who respond to ketotifen, there are 4 clinic visits and 3 phone interviews. Clinic visits include a physical, blood draws, questionnaires, review of medical history and medications; phone interviews involve answering a few questions. For those who do not respond to ketotifen, there are 3 clinic and 2 phone visits. Subjects who enroll in the study are randomly assigned to Group A or Group B. The subject, subject's parents, and study staff will not know to which group the subject is assigned. Group A will be given a placebo, an inactive pill with no medication in it, for days 1-28, and switched to ketotifen for days 36-63. Group B will be given ketotifen for days 1-28 and switched to placebo for days 36-63. The group assignment will be unblinded at day 63, at which point initial ketotifen responders will undergo an open-label twelve week trial of ketotifen to assess sustainability. Secondary aims of this study include assessing the impact of ketotifen on quality of life, state and trait anxiety, and whether baseline trait anxiety is predictive of clinical response to ketotifen. The study will also assess whether functional dyspepsia subtype is predictive of response to ketotifen, the sustainability of response to ketotifen in initial responders, and the pharmacokinetics of ketotifen in this patient population.

Official Title
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Double-blind, Placebo-controlled, Cross-over Trial of Ketotifen in Children and Adolescents With Functional Dyspepsia in Association With Duodenal Eosinophilia

Conditions
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Functional Dyspepsia

Intervention / Treatment
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* Drug: Ketotifen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: between the ages of 8 and 17 years, inclusive abdominal pain of at least 8 weeks duration and fulfilling symptom-based criteria for functional dyspepsia(5); previous endoscopy with biopsies demonstrating >20 eosinophils/high powered field on duodenal mucosal biopsies; previous treatment with acid-reduction therapy and montelukast with a level 3 (as defined below)or lesser response; evidence of written parental permission (consent) and subject assent; Negative pregnancy screening for females of child bearing potential. Exclusion Criteria: previous treatment with ketotifen; treatment with corticosteroids or oral cromolyn sodium in the four weeks prior to enrollment; any prior history of diabetes mellitus, cancer, chronic cardiac disease, respiratory disease, or renal disease requiring routine medical care; Pregnant/planning to become pregnant; Post-menarche females unwilling to use highly-efficacious contraception to prevent pregnancy; Epilepsy or history of seizures; Liver disease or elevation of liver enzymes; Use of oral hypoglycemic medications, antipsychotics, benzodiazepines, tricyclic antidepressants, barbiturates, or opioids; Allergy to ketotifen or other products in capsule Refusal of Urine pregnancy test in post-menarchal females.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cross-over of Ketotifen<br>Patients will begin the active ketotifen treatment first and cross over to placebo. | Drug: Ketotifen<br>* Ketotifen is an anti-histamine approved by the U.S. FDA to prevent and treat itching of the eyes caused by allergies.<br>|
| Placebo Comparator: cross-over of Placebo<br>Patients will begin the placebo treatment first and cross over to the active ketotifen. | Drug: Placebo<br>* The placebo tablet looks identical to the ketotifen tablet, but does not contain ketotifen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Physical | The study physician will check all systems and ask questions about pain and symptoms. This is a comprehensive system check to ensure safety. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Blood pressure | A trained professional will measure blood pressure to ensure value is within normal range and ensure safety of patient. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Liver Functioning Test (a test ran from a blood sample to check a patients liver functioning) | A blood sample is collected and tested by a certified laboratory for liver function. This will be completed and verified to be within normal ranges by the study physician to ensure patient safety. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| State-Trait Inventory for Cognitive and Somatic Anxiety - Child Version | Anxiety score testing assessed with questionnaires. Anxiety scores are correlated with pain. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Pediatric Quality of Life Inventory | Quality of life survey for pediatrics to ensures maintenance of quality of life throughout study. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Heart Rate | A trained professional will measure heart rate to ensure value is within normal range and patient safety. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Respiratory Rate | A trained professional will measure respiratory rate to ensure value is within normal range and patient safety. Change is assessed from each time period. | day 0, day 28, day 63, and day 147 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Sampling (Area under the plasma concentration versus time curve - AUC) | Pharmacokinetic sampling allows for evaluation of the entire process of the drug breakdown by the body and ensures long term efficacy and safety. Change is being assessed from each time period. | day 0, day 28, day 63, and day 147 | 
| Pharmacokinetics Sampling (Peak Plasma Concentration - Cmax) | Pharmacokinetic sampling allows for evaluation of the entire process of the drug breakdown by the body and ensures long term efficacy and safety. Change is being assessed from each time period. | day 0, day 28, day 63, and day 147 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, eosinophilia, duodenal, ketotifen, functional dyspepsia