Full Text Link (courtesy of AGA twitter feed):Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial AJ Lucendo et al. Gastroenterol 2019; 157: 74-86. https://doi.org/10.1053/j.gastro.2019.03.025
Background & Aims
Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE.
We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0–10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily).
At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P< .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent.
In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.
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A recent study (ES Dellon et al Clin Gastroenterol Hepatol 2019; 17: 666-73) prospectively followed patients in a 24 week open-label extension of a randomized, double-blind, placebo-controlled trial of budesonide oral suspension (BOS) for eosinophilic esophagitis (EoE). The authors defined histologic response as ≤6 eos/hpf. During the extension, the dosage of BOS was reduced from 2 mg twice daily to 2 mg once a day.
- No new safety signals. One patient in placebo/BOS arm (n=37) developed oral candidiasis and one patient in the BOS/BOS arm (n=45) did as well. In addition, four patients in placebo/BOS developed esophageal candidiasis. No clinically relevant changes in morning serum cortisol levels were identified.
- Histologic response was observed in 49% (16/33) in placebo/BOS arm and 23% (9/39) of BOS/BOS arm. 58% of placebo/BOS and 28% of BOS/BOS patients had ≤15 eos/hpf.
- Mean peak eosinophil count decreased in placebo/BOS arm from 119 to 29 and increased in BOS/BOS arm from 38 to 72.
- Overall, only 42% of patients who responded to BOS during double-blind 12 week study maintained a histologic response.
While this study shows that BOS is effective for many patients with EoE, it also shows that many lose a response. In addition, most patients who “did not respond to treatment during the double-blind phase did not gain a histologic or endoscopic response with longer-term treatment.” Only 1 of 26 patients (4%) gained a response. This has several important implications:
- Some patients may develop corticosteroid resistance
- In patients who respond to induction, it may be prudent to continue with the same induction dose rather than reducing the dosage
- In patients who do not respond to induction, further treatment is not beneficial
My take: Though the response to BOS was not very high in this study, the population studied was highly symptomatic and had histologically-severe EoE. Thus, in a more typical population of patients with EoE, the response rate is likely to be more favorable. Also, many patients will not maintain a response to BOS at a lowered dose.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
A recent study (ES Dellon et al Gastroenterol 2017; 152: 776-86) provides more data indicating that a premixed solution of budesonide improves eosinophilic esophagitis (EoE). This study complements a recent report highlighted in a blog post earlier this year:
A Better Budesonide for Eosinophilic Esophagitis
In the present study by Dellon et al, the authors performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial of 93 EoE patients (ages 11-40). All patients had dysphagia and active EoE. The active treatment group received 2 mg twice daily.
- Dysphagia symptom questionnnaire (DSQ) scores improved more in the active treatment group compared to placebo. At baseline, the DSQ scores were 29.3 and 29.0 respectively. After 12 weeks, the the scores were 15.0 and 21.5 respectively.
- Similarly, the active treatment group peak eosinophil counts improved more. At baseline, the treatment group had a count (per hpf) of 156 and this dropped to 39; in contrast, the placebo group started at 130 and dropped to 113.
- The overall histologic response (≤6 eos/hpf) was 39% for the treatment group and 3% for the placebo group.
- No significant adverse effects could be attributed to budesonide. There was 1 case of esohageal candidiasis. “There were no notable differences between the groups in cortisol levels.”
My take: Budesonide suspension is useful for EoE but not effective in all patients. A reliable composition from a manufacturer, if not too expensive, would be a big improvement for many kids with EoE. Higher doses of budesonide may be warranted in some cases of EoE.
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A recent study (S Olivia et al. JPGN 2017; 64: 218-24) examines a preprepared viscous budesonide (PVB) for eosinophilic esophagitis (EoE).
The authors used higher doses than in previous studies: 1 mg twice a day if height <150 cm and 2 mg twice a day if height >150 cm. Treatment period was 12 weeks.
- 32 of 36 (89%) showed macroscopic remission at 12 weeks and median eosinophils count in histology dropped from 42.2 to 2.9 cells/hpf. 46.7% maintained remission (off therapy) at 36 weeks.
- 89% achieved eosinophil count <20 cells/hpf at 12 weeks.
- In this short study, the authors did not identify any changes in cortisol levels.
My take: A reliable composition from a manufacturer, if not too expensive, would be a big improvement for many kids with EoE. Higher doses of budesonide may be warranted in some cases of EoE.
Related article: “How I Approach the Management of Eosinophilic Esophagitis in Adults” I Hirano. Am J Gastroenterol 2017; 112: 197-99. (Thanks to Seth Marcus for this reference). The author states that he prefers to perform a baseline assessment prior to PPI initiation. After diagnosis, he will use PPI and if no response, advance to either a dietary approach or topical steroids (he prefers fluticasone using the diskus formulations). His goals for therapy include: elimination of esophageal eosinophilia (<5-15 eos/hpf), resolution of dysphagia, and maintenance of esophageal diameter ≥16 mm. He does advocate annual testing for adrenal insufficiency for those taking long-term topical steroids.
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A recent study (MC Golekoh et al. J Pediatr 2016; 170: 240-5) shows that adrenal insufficiency developed in 10% of patients on chronic (>6 months) swallowed corticosteroid therapy for Eosinophilic Esophagitis (EoE).
Background: 58 patients with 67% receiving fluticasone and 33% receiving budesonide. Median age: 13.7, median fluticasone dose 1320 mcg/day, median treatment duration: 4 yrs. For budesonide, median dose was 1000 mcg/day and median age 10.7 yrs.
Key findings with low-dose ACTH stimulation:
- Abnormal peak cortisol (≤ 20 mcg/dL) present in 15% and adrenal insufficiency (< 18 mcg/dL) (n=6) noted in 10%
- Only patients receiving >440 mcg/day of fluticasone had adrenal insufficiency
- No patients taking budesonide had an abnormal cortisol level
- Higher doses of fluticasone, particularly early in treatment, has been shown to have an improved inflammatory response. However, as with asthma therapy, higher doses increase the risk of adrenal insufficiency.
- Adrenal insufficiency can be asymptomatic but pose a risk for life-threatening adrenal crisis.
- Strengths of study: Fairly large cohort, endoscopic/pathologic reports available, and ACTH stimulation testing which has better sensitivity than random cortisol.
- Limitations: Lower number of patients receiving budesonide, particularly at a higher dose. No indication of adherence.
My take: If higher doses of fluticasone are needed for prolonged period, consider screening (endocrinology consultation) for adrenal insufficiency.
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J Jimenez et al. (JPGN 2015; 61: 208-11) provide more data that gastric acid suppression is associated with an increase risk of Clostridium difficile infection (CDI). This was a retrospective case-control study with 138 children with CDI and 276 controls. After adjustment, acid-suppression therapy had a 1.8 Odds Ratio association with CDI.
S Harel et al. (JPGN 2015; 61: 190-3) in this retrospective ‘pilot’ study of patients receiving topical budesonide for eosinophilic esophagitis, 6 of 14 (43%) had mild biochemical evidence of adrenal suppression, as measured by ACTH testing. Bottomline: a prospective study is likely needed to confirm or refute these findings. In the meanwhile, stress steroid coverage could be considered in patients on prolonged budesonide.
A recent study (Sandborn WJ, et al. Gastroenterol 2015; 148: 740-50, editorial 701-4) shows that budesonide foam can be helpful for patients with ulcerative proctitis and ulcerative proctosigmoiditis.
Design: Two identical randomized, double-blind, placebo-controlled trials examined the use of budesonide foam in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis. Patients had at least 5 cm of involved mucosa but no more than 40 cm. Dosing: 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks. The primary endpoint of remission was defined as an endoscopy subscore of ≤1, rectal bleeding subscore of 0, and improvement or no change from baseline in stool frequency subscore of the Mayo score. It is noted that about 90% of patients had moderate Mayo endoscopy subscore at baseline.
- Combining the results of the studies, 41.2% achieved the primary end point of remission at the end of 6 weeks, compared with 24.0% of placebo patients.
- There were 10 patients (3.7%) with low morning cortisol (compared with 0.7% of placebo-treated patients) and 14% who had abnormal ACTH testing at 6 weeks (compared with 4% of placebo-treated patients), though there no reported signs/symptoms of adrenal suppression present.
The associated editorial suggests that budesonide could be implemented in patients who did not respond to 5-ASA topical therapy (suppository for proctitis and enema for proctosigmoiditis). In addition, the editorial questions whether a single night-time administration may be more effective by maximizing adherence.
Bottomline: Budesonide foam was superior to placebo in this study and may eliminate the need for systemic steroid use. As the editorial suggests, 5-ASA topical therapy likely should be considered as first-line treatment.
Related blog post: Budesonide for Ulcerative Colitis