A Phase 2B Randomised Trial of Hyperbaric Oxygen Therapy for Ulcerative Colitis Patients Hospitalised for Moderate to Severe Flares

Parambir S. Dulai; Laura E. Raffals; David Hudesman; Michael Chiorean; Raymond Cross; Tasneem Ahmed; Michael Winter; Shannon Chang; David Fudman; Charlotte Sadler; Ernest L. Chiu; Frank L. Ross; Gary Toups; M. Hassan Murad; Kinjal Sethuraman; James R. Holm; Renie Guilliod; Benjamin Levine; Jay C. Buckey Jr; Corey A. Siegel

Disclosures

Aliment Pharmacol Ther. 2020;52(6):955-963. 

In This Article

Abstract and Introduction

Abstract

Background: Hyperbaric oxygen has been reported to improve disease activity in hospitalised ulcerative colitis (UC) patients.

Aim: To evaluate dosing strategies with hyperbaric oxygen for hospitalised UC patients.

Methods: We enrolled UC patients hospitalised for acute flares (Mayo score 6–12). Initially, all patients received 3 days of hyperbaric oxygen at 2.4 atmospheres (90 minutes with two air breaks) in addition to intravenous steroids. Day 3 responders (reduction of partial Mayo score ≥ 2 points and rectal bleeding score ≥ 1 point) were randomised to receive a total of 5 days vs 3 days of hyperbaric oxygen.

Results: We treated 20 patients with hyperbaric oxygen (75% prior biologic failure). Day 3 response was achieved in 55% (n = 11/20), with significant reductions in stool frequency, rectal bleeding and CRP (P < 0.01). A more significant reduction in disease activity was observed with 5 days vs 3 days of hyperbaric oxygen (P = 0.03). Infliximab or colectomy was required in only three patients (15%) despite a predicted probability of 80% for second-line therapy. Day 3 hyperbaric oxygen responders were less likely to require re-hospitalisation or colectomy by 3 months vs non-responders (0% vs 66%, P = 0.002). No treatment-related adverse events were observed.

Conclusion: Hyperbaric oxygen appears to be effective for optimising response to intravenous steroids in UC patients hospitalised for acute flares, with low rates of re-hospitalisation or colectomy at 3 months. An optimal clinical response is achieved with 5 days of hyperbaric oxygen. Larger phase 3 trials are needed to confirm efficacy and obtain labelled approval.

Introduction

Ulcerative colitis (UC) patients hospitalised for acute flares represent a population at greatest risk for disease-related complications. A substantial proportion of these patients will fail to respond to intravenous steroids and require progression to second-line therapies such as infliximab, ciclosporin or colectomy. These second-line therapies, although effective, are associated with substantial costs and can be associated with significant burden and adverse events.[1] Novel therapies that optimise response to intravenous steroids early in the hospitalisation for these patients are needed.

Hyperbaric oxygen involves breathing 100% oxygen under increased atmospheric pressure. The increased oxygenation of tissues has been used to treat various inflammatory conditions, including UC, with a favourable safety profile.[2] In a phase 2A multi-centre, double-blind, sham controlled, randomised trial it was demonstrated that the use of hyperbaric oxygen in addition to intravenous steroids for UC patients hospitalised for acute flares resulted in a significantly higher rate of clinical response and remission, and a significantly lower rate of progression to infliximab or colectomy during hospitalisation.[3]

This pilot trial helped to establish the potential role of hyperbaric oxygen in these high-risk patients; however, several important considerations remained that required further exploration. First, the trial included only 10 hyperbaric oxygen-treated hospitalised UC patients; which means that the reported estimates are imprecise. Estimates with higher certainty to confirm the effectiveness of hyperbaric oxygen are needed. Such estimates require larger randomised controlled trials. Second, the trial protocol was modified during recruitment for feasibility purposes. The original plan of providing 10 days of hyperbaric oxygen proved to be too long and patients were often not willing to return after being discharged. Within the modified 5-day protocol, it was observed that the maximal reduction in disease activity was seen in the first 3 days with only a subset of patients experiencing further improvements from day 3 to day 5. Therefore, a comparison of 3 vs 5 days of hyperbaric oxygen is needed to provide the optimal duration of treatment that maximises benefits, feasibility and reduce costs. To address these points we conducted an exploratory phase 2B dose-finding trial comparing 3 vs 5 days of hyperbaric oxygen. We anticipate that the results will further support the use of hyperbaric oxygen in a particularly high-risk population and provide more confidence in the expected response rates and dosing strategies. The results will also inform the design of future larger randomised trials with adequate power to evaluate long-term patient-important outcomes.

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