Program Directorfl'rincipal Investigator (Last, First, Middle): Rothenberg, Marc E.2. AbstractEosinophilic esophagitis (EE) is an emerging vyorldwide disease that mimics gastroesophageal reflux disease(GERD) and can lead to esophageal narrowing and stricture (1-4). EE is differentiated from GERD by themagnitude of mucosal eosinophilia and epithelial thickening, its association with atopy, its much lowerincidence (~1:10,000) and the lack of response to add suppression. Attention has been drawn toimderstanding the; etiology and. treatment of EE because there has been a recent surge of newly recognizedcases. Over the past decade, the mechanisms and treatment of eosinophil accumulation in the gastrointestinal(Gi) tract, with special attention on the esophagus have begun to be characterized. We have established thatthe esophagus is normally devoid of eosinophils, and that esophageal eosinophilia occurs in association with Thelper type 2 (Th2) allergic responses in the lung and GI tract (5, 6). Employing genome wide microarrayexpression profile analysis, we recently identified an EE transcriptome that includes the eosinophilchemoattractant and activating factor eotaxin-3 as the single most dysregulated gene in the esophagus of EEpatients (7). Furthermore, levels of eotaxin-3 strongly correlated with disease severity and a single nucleotidepolymorphism in the eotaxin-3 gene was associated with disease susceptibility. In addition, we have recentlycompleted the first double-blind-plaCebo controlled cHnical trial for EE (8) demonstrating that 880 meg of dailyswallowed fluticasone (delivered via an asthma inhaler) induces a complete remission (including reductions inesophageal eotaXin-3 expression) in approximately 50% of patients compared with remission rates of less than10% in patients randomized to placebo (8, 9). Notably, we have identified factors that correspond withglucocorticoid-resistance induding atopic status and increasing patient age, weight, and height. These andother findings have led us to hypothesize that 1760 meg of daily swallowed fluticasone induces diseaseremission in EE (compared with placebo). Accordingly/ as part of our RESC-RDCRC grant, we propose amulti-center dinical trial that will test this hypothesis in the following two related aims.
Aim 1. Efficacy of fluticasone vs. placebo at inducing disease remission. In preliminary studies, we havedetermined that swallowed fluticasone (at a daily dose of 880 meg) induces disease remission in ~50% ofindividuals whereas placebo has an ~9% effect (8). Based on these encoiuraging results, we will test theefficacy of a higher dose of swallowed fluticasone (1760 meg daily dose) compared with placebo during athree-month double-blind trial. The primary endpoint of the study will be disease remission defined bycomplete normalization of the esophagus (eosinophil levels <l / hpf).
Aim 2. Effect of fluticasone on secondary endpoints. In preliminary studies we have found that swallowedfluticasone at a daily dose of 880 meg is well tolerated and responsiveness appears to be assodated withpatient age, weight, height, and atopic status (8). We will extend these preliminary findings by examining theeffect of the higher dose of swallowed fluticasone on a.series of related secondary endpoints including safetyparameters as determined by the occurrence of adverse events and changes in Cortisol levels. In addition, wewill determine the effect of patient phenotype and compliance with medidne usage on responsiveness tofluticasone. In addition, in an open-label extension phase of this trial, we will change the dose of swallowedfluticasone and monitor responsiveness.At present, there is no drug specifically approved by the FDA for the treatment of EE. Based on ourpreliminary studies demonstrating the efficacy and safety of a relatively low dose of swallowed fluticasone forthe treatment of EE, we have designed the current study aimed at developing critical information concerningthe efficacy and safety of a relatively higher dose of swallowed fluticasone compared with placebo. Inaddition, we aim to gain critical insignt into the mechanism of drug action, as well as factors that influencedrug responsiveness. These studies are timely, given the recent attention that EE is receiving in the medicalcommuruty, the emergence of a range of new anti-inflammatory agents that are entering the clinic, and thepotential of these results to lead to me development of a topical glucocorticoid that is specifically developed(and FDA approved) for the treatment of EE.This trial is consistent with the goals of the RDCRC as it studies the rare disease EE, aims to optimize thetherapy for this urmiet medical disease, will provide insight into basic disease characteristics including thenatural history of disease over the course of a 28 week period of observation, uncovers the factors assodatedwith drug responsiveness as well as placebo responses; the latter will provide a basis for the design of futuredinical trials with a variety of anti-iitflammatory agents currently being developed (please see the Pilot StudiesPHS 398/2590 (Rev. 11/07) Page 255 Gontinualion Format Page I Program Director/Principal Investigator (Last, First, Middle): Rothenberg, Marc E.section for examples of future clinical studies). Furthermore, as a multi-site study, faster patient recruitmentwill be obtained and the generality of the results across centers will be examined. The advantage associatedwith multi-center patient recruitment will be particularly important since the study's inclusion criteria isparticularly strict in order to rule out underlying GERD (requiring long term therapy with a proton pumpinhibitor prior to enrollment).PHS 398/2590 (Rev, 11/07) Page 256 Continuation Format PageProgram Director/Principal Investigator (Last, First, Middle): Rothenberg, MarcDETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLYPERSONNEL (Applicant organization only) Months Devoted to Proiect ROLE ON Cal. Acad. Summer INST.BASE NAME PROJECT Mnths Mnths Mnths SALARY PrincipalMarc Rothenberg 1.2 196,700 InvestigatorBridget Bucknneier CRCIV 6 48,392TBN Coordinator 1.8 38,000SUBTOTALS CONSULTANT COSTSEQUIPMENT (Itemize)SUPPLIES (Itemize by category)Study Medication $53,310Placebo Cost $20,000Saliva kits and laboratory cost $1,800TRAVELVisit to each site ensuring proper compliancePATIENT CARE COSTS INPATIENT / OUTPATIENTALTERATIONS AND RENOVATIONS (Itemize by category)OTHER EXPENSES (Itemize by category)Patient Travel $30,000Fee for Service - 27 patients (g$7,646 per patient =$206,442Patient Incentive $13,500Purchase Services (DMSB) $15,240 V.CONSORTIUM/CONTRACTUAL COSTSE.FROM THROUGH07/01/09 06/30/10 DOLLAR AMOUNT REQUESTED (omit cents) SALARY FRINGEREQUESTED BENEFITS TOTAL 19,670 5,311 24,98124,196 6,533 30,7295,700 1,539 7,23949,566 13,383 62,94975,1106,000265,182DIRECT COSTSSUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (/tem 7a, Face Page) $ 409,241 1CONSORTIUM/CONTRACTUAL COSTS <' FACILITIES AND ADMINISTRATIVE COSTSTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 409,241PHS 398 (Rev. 11/07) Page. Form Page 4
| Butz, Bridget K; Wen, Ting; Gleich, Gerald J et al. (2014) Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology 147:324-33.e5 |
| Fulkerson, Patricia C; Rothenberg, Marc E (2013) Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 12:117-29 |
| Simon, Dagmar; Wardlaw, Andrew; Rothenberg, Marc E (2010) Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract. J Allergy Clin Immunol 126:3-13; quiz 14-5 |
| Brown-Whitehorn, Terri F; Spergel, Jonathan M (2010) The link between allergies and eosinophilic esophagitis: implications for management strategies. Expert Rev Clin Immunol 6:101-9 |
