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

Disclosures

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

In This Article

Results

The study was performed between October 2011 and October 2012. Twenty-four participants were randomised and 22 participants completed the study (Figure 1). Demographic and baseline characteristics were largely similar between the treatment groups (Table 1); however, there was a higher percentage of participants in the placebo group who experienced continuous dysphagia. More than half of the participants continued to use PPI therapy during the study.

Figure 1.

Study flow diagram. Abbreviations: BID, twice daily; QD, once daily

Safety and Tolerability

There were no deaths, serious TEAEs, severe TEAEs or discontinuations from the study related to a TEAE. A total of 41 TEAEs were reported by 18 participants: 12 participants receiving APT-1011 reported 26 TEAEs and 6 participants receiving placebo reported 15 TEAEs. Two participants on placebo discontinued due to TEAEs. A total of three TEAEs were considered by a treatment-blinded investigator to be possibly related to the study drug: two participants receiving APT-1011 at 3.0 mg QD and one participant receiving placebo reported a TEAE of decreased blood cortisol (Table 2). Two participants had an adverse event of special interest, adrenal suppression: one participant receiving placebo and one participant receiving APT-1011 at 1.5 mg BID. In the participant receiving APT-1011 at 1.5 mg BID, serum cortisol levels were 27.7 μg/dL at baseline and 4.8 μg/dL at Day 27. The participant did not report any associated symptoms or signs of adrenal insufficiency, and results of a subsequent adrenocorticotropic hormone stimulation test were within normal limits. The adverse event was reported due to low cortisol value, but no adrenal insufficiency was present. The participant receiving placebo who had adrenal suppression had used systemic steroid therapy, in violation of the study protocol, and had a serum cortisol of 2.6 μg/dL; this participant was diagnosed with adrenal insufficiency unrelated to study drug.

There were no reports of oral or oesophageal candidiasis in either APT-1011 treatment group or the placebo group. Besides the changes in cortisol levels described above, there were no clinically meaningful changes in laboratory values, vital signs or findings of physical examination during the 8-week study.

Efficacy

Histology. Pre-specified Analyses: The mean/median eosinophil counts in the proximal and distal oesophagus and changes in these values from baseline to Week 8 in the ITT population are shown in Table 3. The median peak eosinophils/HPF in patients who received APT-1011 at 1.5 mg BID was reduced by 92% in the distal oesophagus and by 100% in the proximal oesophagus from screening to Week 8 (Distal eosinophils/HPF: screening = 39.0, Week 8 = 3.0; proximal eosinophils/HPF: screening = 47.0, Week 8 = 0). The median peak eosinophils/HPF in participants who received APT-1011 at 3.0 mg QD was reduced by 63% in the distal oesophagus and by 97% in the proximal oesophagus from screening to Week 8 (Distal eosinophils/HPF: screening = 65.5, Week 8 = 24.5; proximal eosinophils/HPF: screening = 29.5, Week 8 = 1.0). With placebo treatment, reductions in eosinophil counts over 8 weeks were less than in the active treatment groups (12% reduction in median eosinophils/HPF in the distal oesophagus and 0% reduction in the proximal oesophagus). Histologic response rates based on a reduction from ≥24 eosinophils/HPF at screening to ≤15 eosinophils/HPF at Week 8 and a complete histologic response (0 eosinophils/HPF) at Week 8 are shown in Figure 2A.

Figure 2.

Per cent of participants with treatment response from >24 to <15 eosinophils/HPF and >24 to 0 eosinophilic per HPF (A), median maximum peak oesophageal eosinophils/HPF in the oesophagus overall (B), and median total EREFS in patients treated with placebo, APT-1011 at 1.5 mg BID and APT-1011 at 3.0 mg QD (C). Abbreviations: BID, twice daily; HPF, high-power field; QD, once daily

Post hoc Analyses. The maximal peak eosinophils/HPF in the oesophagus overall at baseline and Week 8 is shown in Figure 2B (baseline values are shown in Table S1). When comparing each of the APT-1011–treated groups with placebo, differences in changes in maximal eosinophils/HPF from baseline to end of treatment were observed. Participants treated with APT-1011 at 1.5 mg BID had a greater reduction in eosinophils/HPF from baseline than placebo-treated participants (coefficient, −47.05; 95% confidence interval [CI]: −82.67, −1.02; P = 0.012). Participants treated with APT-1011 at 3.0 mg QD had a greater reduction in eosinophils/HPF from baseline than placebo-treated participants (coefficient, −38.2; 95% CI: −73.94, −1.02; P = 0.037).

The results of linear regression analyses for changes in maximal peak eosinophils/HPF in combined APT-1011–treated groups relative to the placebo-treated group are shown in Table S2.

Endoscopic Appearance. Pre-specified Analyses: Endoscopic features reflecting acute inflammation (including oedema, exudates and furrowing) demonstrated the greatest differences between placebo- and APT-1011–treated participants, as shown in Table S3. Whereas oedema and furrowing were unchanged from baseline to Week 8 in the placebo-treated participants, these endoscopic features were less likely to be present among APT-1011–treated participants at Week 8 compared with baseline. Study participants were less likely to have white exudates at week 8 compared with baseline; white exudates were absent in APT-1011–treated participants at Week 8.

Post hoc Analyses: Median EREFS values observed in the different groups and at different visits are presented in Figure 2C (baseline values are shown in Table S1). When comparing each of the APT-1011–treated groups with placebo, differences in EREFS from baseline to end of treatment were observed (on average, a decrease of 2.92 points [95% CI: −4.68, −0.88] in the APT-1011 at 1.5 mg BID group relative to placebo [P = 0.002] and a decrease of 2.74 points [95% CI: −4.5 to −0.88] in the APT-1011 at 3.0 mg QD group relative to placebo [P = 0.004]). The results of linear regression analysis for changes in EREFS in the combined APT-1011–treated group relative to the placebo-treated group are shown in Table S2.

Symptoms. Pre-specified Analyses: Dysphagia was not a required symptom for entry into the study (patients were eligible if they had at least one of the following symptoms: chest pain or discomfort [58%], dysphagia [84%] or food impaction [33%]) at baseline. The data on participants' symptoms, as measured by the Patient Global Assessment of EoE symptom severity, are shown in Figure 3A (baseline values are shown in Table S1).

Figure 3.

Patient Global Assessment of Symptom Severity (A), percentage of patients in remission based on EEsAI PRO <20 (B) and percentage of patients free of dysphagia in the past 7 d (C). Abbreviations: BID, twice daily; EEsAI PRO, Eosinophilic Esophagitis Activity Index patient-reported outcomes; QD, once daily

Post hoc Analyses. When comparing each of the APT-1011–treated groups with placebo, differences in changes in Patient Global Assessment of EoE symptom severity from baseline to end of treatment were observed (on average, a decrease of 2.4 points [95% CI: −4.04, −1.21] in the APT-1011 at 1.5 mg BID group relative to placebo [P = 0.006] and a decrease of 1.55 points [95% CI: −3.17, −1.21] in the APT-1011 at 3.0 mg QD group relative to placebo [P = 0.061]).

EEsAI PRO symptom scores were calculated in 23 patients (one placebo patient was missing frequency of dysphagia information at end of treatment) (baseline values are shown in Table S1). Trends towards significant changes in EEsAI PRO in the drug-treated group relative to the placebo group were observed (on average, a decrease of 15.13 points [95% CI: −33.5 to −1.07] in the APT-1011 at 1.5 mg BID group relative to placebo [P = 0.1] and a decrease of 13.27 points [95% CI: −29.87 to −1.07] in the APT-1011 at 3.0 mg QD group relative to placebo [P = 0.11]).

The data on the percentage of patients in clinical remission (based on EEsAI PRO <20) and patients free of dysphagia over the last 7 days are shown in Figure 3B,C. Compared with baseline, an additional four patients in the APT-1011 at 1.5 mg BID group (in addition to three patients with no dysphagia at baseline) and two patients in the APT-1011 at 3.0 mg QD group (in addition to one patient with no dysphagia at baseline) were free of dysphagia in the 7 days prior to the endoscopy visit. No patient had complete resolution of dysphagia as assessed by EEsAI PRO in the placebo group (one patient had no dysphagia at baseline) compared with six patients in the APT-1011–treated groups. Although the percentage of participants without trouble swallowing during the week prior to the end of treatment was greater in participants treated with APT-1011, these data should be interpreted with caution given the variability in dysphagia frequency/symptoms severity between the different groups at baseline.

Data from the Gastrointestinal Symptom Rating Scale Questionnaire and Mayo Dysphagia Questionnaire did not demonstrate any meaningful changes (data not shown).

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