Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study.

BACKGROUND: We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness. METHODS: In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5-2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8. RESULTS: The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8. CONCLUSIONS: In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS: We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS: The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).