P564 Indigo naturalis induces mucosal healing in patients with ulcerative colitis: A multicentre randomised controlled trial

Abstract

Background: Indigo naturalis (IN) contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa, by inducing production of interleukin 22. Therefore, IN may be effective for inducing mucosal healing (MH) in ulcerative colitis (UC). However, there have been no study to confirm whether IN induce MH in UC patients receiving IN. We performed a randomised controlled trial to investigate clinical and endoscopic efficacy of IN in UC patients. Methods: We performed a multicentre, double‐blind trial in Japan with active UC (Mayo scores of 6 or more). Patients were randomly assigned to groups give a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1: 1: 1: 1 ratio) for 8 weeks. The rate of clinical response, clinical remission, MH (Mayo endoscopic score (MES) of 0‐1 at 8 weeks) and complete MH (MES of 0) at 8 weeks of treatment were assessed in the intention to treat analysis. The on‐site investigators and endoscopic central reviewer evaluated Mayo endoscopic score (MES) and the reviewer assured the reliability of the evaluation by the on‐site investigators. Results: A total of 86 patients were enrolled. The trial was terminated due to an external reason: a report of a pulmonary arterial hypertension in a patient who used self‐purchased IN for 6 months. Mean Mayo score, MES and the proportion of patients with steroid‐dependent disease at the Week 0 was comparable among the 4 groups. For clinical response rates, a significant dose‐dependent linear trend for IN was confirmed (placebo: 13.6% (3 of 22), 0.5 g IN: 69.6% (16 of 23; p < 0.001), 1.0 g: 75.0% (15 of 20; p < 0.001), 2.0 g: 81.0% (17 of 21; p < 0.001). Similar clinical response rates were confirmed when the endoscopic central reviewer independently evaluated the MES. The rates of clinical remission were significantly higher in patients who received daily doses of 1.0 g (55.0%, p < 0.001) or 2.0 g (38.1%, p = 0.009) of IN compared with patients who received the placebo (4.5%). The MH rates were 13.6%, 56.5% (p = 0.005), 60.0% (p = 0.003) and 47.6% (p = 0.021) in placebo and 0.5, 1.0, and 2.0 g group, respectively. The rate of complete MH was 4.5% (1 of 22) in placebo group and 14.1% (9 of 64) in all IN group (p = 0.214). The κ value validating the interobserver agreement on the MES at Week 0 and 8 was 0.58 and 0.52, respectively. Although mild liver dysfunction was observed in 10 patients who received IN, no PAH were observed in our study. Conclusions: In a randomised, placebo‐controlled trial, we found 8 weeks of IN to be effective in inducing a clinical response and MH in UC patients. Although PAH was not observed in our study, further product development and elucidation of the mechanisms underlying the adverse events is necessary to avoid the occurrence of PAH and other adverse effects.