Randomised Clinical Trial

The Safety and Tolerability of Fluticasone Propionate Orally Disintegrating Tablets Versus Placebo for Eosinophilic Oesophagitis

Ikuo Hirano; Ekaterina Safroneeva; Marie C. Roumet; Gail M. Comer; Gina Eagle; Alain Schoepfer; Gary W. Falk


Aliment Pharmacol Ther. 2020;51(8):750-759. 

In This Article


Prior studies of fluticasone in EoE have relied on oral administration of preparations that are designed for airway delivery in the treatment of asthma. Despite the length of time from completion to its publication, this phase 1b/2a, double-blind, placebo-controlled, proof-of-concept trial represents a novel evaluation of an orally disintegrating tablet formulation of fluticasone, called APT-1011, which was specifically designed for the treatment of EoE. As the primary end point of this proof-of-concept study, there were no safety issues noted with either dose of APT-1011 compared with placebo. In addition, 75% and 63% of participants receiving APT-1011 at 1.5 mg BID and APT-1011 at 3.0 mg QD, respectively, achieved a reduction in inflammation to <15 eosinophils/HPF compared with only 13% of participants treated with placebo. We observed a greater improvement in maximal oesophageal eosinophilia, EREFS, Patient Global Assessment and EEsAI PRO (trend) in APT-1011 treatment groups compared with placebo. No participants had complete resolution of dysphagia as assessed by EEsAI PRO in the placebo group, whereas six participants (38%) in APT-1011–treated groups achieved complete resolution of dysphagia symptoms. Given the small sample size and imbalances in symptom severity at baseline, particularly as some subjects experienced no dysphagia at randomisation, the data on clinical remission should be interpreted with caution.

APT-1011 was well tolerated, without demonstrable safety concerns with dosing at 1.5 mg BID and 3.0 mg QD for 8 weeks in adolescents and adults with EoE. Specifically, no participant who received active drug developed clinical manifestations of adrenal suppression or oral/oesophageal candidiasis in this small phase 1b/2a study. This safety profile is particularly relevant as the dose of fluticasone studied is higher than those currently used in clinical practice for EoE with swallowed asthma formulations of fluticasone (440–880 μg BID).[22] Measurable systemic side effects of oral fluticasone propionate therapy are not expected because the absolute systemic bioavailability of orally administered fluticasone propionate is negligible (<1%) compared with inhaled fluticasone propionate (16.6%).[23,24] Ongoing clinical trials of swallowed topical corticosteroids are examining multiple aspects of safety, including adrenal function, in the context of long-term maintenance therapy.

Swallowed topical corticosteroids are the most commonly used medical therapy for the management of children and adults with EoE. Previous double-blind, placebo-controlled trials have demonstrated histologic improvement in oesophageal mucosal eosinophil density.[3,4,25] Three trials evaluated fluticasone using an inhaler formulation of fluticasone propionate designed for asthma, and two trials were performed in children with EoE. One trial of fluticasone in adults identified a significant reduction in eosinophil inflammation, but not in symptom improvement, compared with placebo over a 6-week treatment period.[26] Recently, use of fluticasone powder extracted from the diskus formation of fluticasone for asthma was reported as an effective alternative to the metered-dose formulation in an uncontrolled study of 40 adults with EoE.[27] While topical corticosteroid preparations have not yet been approved by the US FDA, budesonide in an orally disintegrating tablet formulation was recently approved by the European Medicines Agency for the treatment of EoE.[28]

Disparate histologic definitions of therapeutic response were reported in prior studies of topical corticosteroids. On the basis of a histologic threshold of <15 eosinophils/HPF, response rates were highly variable, ranging from 50% to 90% of participants.[26,29] Reasons for this variation are being studied, but they may be related to differences in the phenotypic severity of EoE, use of concomitant medications, different doses of corticosteroids or use of corticosteroid formulations that are optimised for oesophageal delivery. Potential genetic variation in corticosteroid metabolism and patient adherence are additional factors that may impact efficacy. In this study, APT-1011 achieved a histologic response <15 eosinophils/HPF in 75% of participants, which supports the effectiveness of the novel delivery system, especially when combined with the observed improvement in endoscopic outcomes.

Although a small number of participants were recruited in this proof-of-concept study to assess the short-term safety of APT-1011, study results show improvements in histology and endoscopy outcomes. The results should be interpreted with a number of considerations in mind. The diagnostic threshold of 24 eosinophils/HPF used in the study exceeded the guideline-based criteria of ≥15 eosinophils/HPF. At the time of this trial, uniform inclusion criteria for EoE trials had not been established. Higher-than-diagnostic-threshold criteria were followed in this trial to reduce the chance of including patients with borderline EoE activity. While we excluded patients with PPI-responsive oesophageal eosinophilia (PPI-REE), a large percentage of patients (66.7%) continued PPIs. The continued use of PPIs in this group of patients may have reflected the presence of concomitant gastro-oesophageal reflux disease. The role of dual therapy is still unclear in the management of EoE and is an area of active investigation. Dysphagia was not a required symptom for the purposes of study inclusion. For entry into this trial, no validated PRO instrument for assessment of EoE symptoms in adolescents and adults was used, as no such instrument was available when the trial was designed. The EEsAI PRO instrument used in this study was in an early stage of development for adult use. One participant in the placebo group violated the study protocol by taking exogenous corticosteroids for lumbar disc disease; this participant exhibited a profound decrease in oesophageal eosinophilia and severity of endoscopic findings from baseline to end of treatment. Finally, patients with PPI-REE were excluded based on 2007 and 2011 consensus guidelines for the diagnosis of EoE.[30,31] The recently published AGREE (A Working Group on PPI-REE) statement removed the PPI response criterion for EoE diagnosis, making PPI-REE part of the EoE spectrum.[4] It remains unclear whether the revised criteria will alter the therapeutic efficacy of medical therapies, as prior trials have excluded patients with PPI-REE.

In conclusion, APT-1011, a novel, orally disintegrating tablet formulation of fluticasone, was safe and well tolerated in adolescents and adults with EoE. Exploratory efficacy outcomes demonstrated improvement in both endoscopic and histologic findings as well as symptoms. The results of this study support the continued development of APT-1011 for the treatment of EoE.