A Randomized, Placebo-Controlled Trial to determine the effect of Budesonide Orodispersible Tablets in patients with Eosinophilic Esophagitis.

Clinical Research 6 min 358

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Created On: 21/10/2020

A Randomized, Placebo-Controlled Trial to determine the effect of Budesonide Orodispersible Tablets in patients with Eosinophilic Esophagitis.

Eosinophilic Esophagitis (EoE) is a chronic disease, which causes esophageal dysfunction and eosinophil-predominant inflammation. Incidence of EoE has been increasing from the last two decades.

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Key take away

Budesonide orodispersible tablet (BOT) administered at a dose of 0.5 mg or 1.0 mg, twice daily is effective and well-tolerated for maintaining remission of Eosinophilic Esophagitis.

Background

Eosinophilic Esophagitis (EoE) is a chronic disease, which causes esophageal dysfunction and eosinophil-predominant inflammation. Incidence of EoE has been increasing from the last two decades. It is the common cause of food bolus impaction and esophageal dysphagia and if left untreated, can cause inflammation and persistent symptoms. Long-term eosinophilic inflammation can result in functional damage. EoE also has a negative impact on the health-related quality of life (HRQoL) as it causes emotional distress and restricted social activities.

The efficiency of swallowed topical corticosteroids (STCs) such as budesonide in controlling the symptoms and inflammation had been proved several times. Though the original formulations of these drugs are developed for airway administration in asthma, multiple trials have proved their efficacy in reducing inflammation and symptoms associated with EoE. The findings of a previous phase 3 trial have also demonstrated the therapeutic efficacy and safety of a new budesonide oro-dispersible tablet formulation in adult patients with active EoE achieving up to 85% histologic remission rate after 6 weeks of treatment.

Rationale behind research

Majority of patients with EoE suffers from a rapid relapse after the discontinuation of therapy, therefore, long-term management is needed. The efficacy of STCs has been evaluated in previous studies but the confirmatory maintenance trials to determine the efficacy of STCs for inducing remission are still missing. Therefore, the present study is conducted.

Objective

The objective of this study is to demonstrate the safety and efficiency outcomes of BOT for maintaining remission in patients with EoE.

Method

Study outcomes

The primary outcomes included evaluation of remission at week 48, defined by criteria of clinical relapse, histological relapse, food impaction involving endoscopic intervention, the requirement for dilation and early withdrawal for any cause
The secondary outcomes included evaluation of the rate of histological relapse, change in the peak eos/mm², rate of clinical relapse and rate of clinical remission at week 48
Other outcomes included change from baseline in the PatGA, time to clinical relapse, deep histological remission, changes in endoscopic alterations, deep endoscopic remission and HRQoL and patient’s global satisfaction with treatment

Result

Outcomes

Baseline: There were no significant differences reported at baseline

Study outcomes:

Significant remission was achieved in 73.5% of patients who received BOT 0.5 mg and 75% who received BOT 1.0 mg as compared with 4.4% of the patients in the placebo group. (Fig 2)

The patients receiving BOT 0.5mg twice daily and BOT 1.0mg twice daily showed a greater reduction in histological and clinical relapse rates as compared to patients in the placebo group
A significant improvement was observed in HRQoL overall and its subscores (disease anxiety, eating/diet impact, swallowing anxiety, social impact and emotional impact) from baseline to both BOT groups when compared to the placebo group
There were no significant adverse events reported after treatment with BOT. Both doses of BOT were well tolerated

Conclusion

This study shows the first multi-centre Phase 3 trial evaluating the safety and efficacy of the long-term treatment with BOT. In this study, BOT 0.5mg two times a day and BOT 1.0mg two times a day were efficient and superior to placebo for achieving remission in the adult EoE patients. Approximately three-quarters of patients achieve remission with BOT in the complete 48-week study period, irrespective of the dose. On the other side, 95% of patients in the placebo group experienced a relapse during this phase. Also, both doses of BOT were safe and well-tolerated. These findings demonstrated the efficacy of BOT as a maintenance treatment for EoE.

The assessment of relapse rates in patients with EoE also reported that both doses of BOT were effective in reducing relapse rates. These findings were consistent with the results of a previous retrospective study which illustrated that the loss of effectiveness overtime is not an expected concern for budesonide in the treatment of EoE. Clinic-histological estimates indicated stability in endoscopic remission in about 70% of patients after treatment with BOT 0.5mg or 1.0 mg. A significant improvement in Health-related quality of life (HRQoL) was also observed with BOT but it declined in the placebo group.

No dose-finding maintenance studies were conducted in EoE, therefore, in this study efficiency of two different BOT doses was compared. Remission rates after 48-week treatment were not different, so it is possible that dosing of 0.5mg two times a day might be enough to effectively sustain long-term remission for the adult EoE patient.

Adverse events were comparable between all the treatment groups. Though serious adverse events have not occurred, candidiasis occurred at a high rate under budesonide. However, it never interferes with the routine life activities of patients and was easy to treat. Further studies are still required to confirm and evaluate other treatment schedules, e.g., an easier to adhere once per day regimen, or an intermittent or even an on-demand treatment strategy.

Limitations

Minimum efficient dose regimen to continue for EoE in remission was not identified.
A large subgroup analysis was not done to find possible predictive factors for the future
Systematically, squamous epithelium thickness at baseline was not measured

Clinical take-away

This study supports the long term use of BOT for maintaining remission of Eosinophilic Esophagitis due to its established safety and tolerability data. It provides a better management option to clinicians.