Ketotifen for Children With Functional Dyspepsia in Association With Duodenal Eosinophilia

Official title

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

Overview

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

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 include: 1) assessing the impact of ketotifen as compared to placebo on quality of life; 2) assessing the sustainability of response to ketotifen in initial responders, and 3) assessing the pharmacokinetics of ketotifen in this patient population.

Interventions

• Drug Ketotifen
  Ketotifen is an anti-histamine approved by the U.S. FDA to prevent and treat itching of the eyes caused by allergies.
• Drug Placebo
  The placebo tablet looks identical to the ketotifen tablet, but does not contain ketotifen.

Primary outcome measures

• Complete Physical [Time frame: day 0, day 28, day 63, and day 147]
• Blood pressure [Time frame: 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) [Time frame: day 0, day 28, day 63, and day 147]
• State-Trait Inventory for Cognitive and Somatic Anxiety - Child Version [Time frame: day 0, day 28, day 63, and day 147]
• Pediatric Quality of Life Inventory [Time frame: day 0, day 28, day 63, and day 147]
• Heart Rate [Time frame: day 0, day 28, day 63, and day 147]
• Respiratory Rate [Time frame: day 0, day 28, day 63, and day 147]

Secondary outcome measures (2)

• Pharmacokinetic Sampling (Area under the plasma concentration versus time curve - AUC) [Time frame: day 0, day 28, day 63, and day 147]
• Pharmacokinetics Sampling (Peak Plasma Concentration - Cmax) [Time frame: day 0, day 28, day 63, and day 147]

Eligibility criteria

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 oral corticosteroids or oral cromolyn sodium in the 6 months 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• The Children's Mercy Hospital — Kansas City

Publications

• McFadyen ML, Miller R, Ludden TM. Ketotifen pharmacokinetics in children with atopic perennial asthma. Eur J Clin Pharmacol. 1997;52(5):383-6. doi: 10.1007/s002280050305. PMID 9272408
• Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21. doi: 10.1136/gut.2010.213108. Epub 2010 Jul 21. PMID 20650926
• 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. PMID 20479684
• 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. PMID 15017654
• 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. PMID 18320315
• 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. PMID 19432972
• Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR. Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology. 1998 Apr;114(4):640-8. doi: 10.1016/s0016-5085(98)70577-3. PMID 9516384
• Stefanini GF, Saggioro A, Alvisi V, Angelini G, Capurso L, di Lorenzo G, Dobrilla G, Dodero M, Galimberti M, Gasbarrini G, et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol. 1995 Jun;30(6):535-41. doi: 10.3109/00365529509089786. PMID 7569760

Identifiers

NCT: NCT02484248 · 14110467

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗