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

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Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis
Gastroenterology ( IF 29.4 ) Pub Date : 2017-11-22 , DOI: 10.1053/j.gastro.2017.11.024
Makoto Naganuma , Shinya Sugimoto , Keiichi Mitsuyama , Taku Kobayashi , Naoki Yoshimura , Hidehisa Ohi , Shinji Tanaka , Akira Andoh , Naoki Ohmiya , Keiichiro Saigusa , Takayuki Yamamoto , Yuichi Morohoshi , Hitoshi Ichikawa , Katsuyoshi Matsuoka , Tadakazu Hisamatsu , Kenji Watanabe , Shinta Mizuno , Wataru Suda , Masahira Hattori , Shinji Fukuda , Akiyoshi Hirayama , Takayuki Abe , Mamoru Watanabe , Toshifumi Hibi , Yasuo Suzuki , Takanori Kanai , Makoto Naganuma , Shinya Sugimoto , Shinta Mizuno , Yoshihiro Nakazato , Tomohiro Fukuda , Toshiaki Teratani , Haruhiko Ogata , Yasushi Iwao , Takanori Kanai , Hiroshi Yamasaki , Keiichi Mitsuyama , Taku Kobayashi , Takahiko Toyonaga , Masaru Nakano , Toshifumi Hibi , Naoki Yoshimura , Yoichi Sameshima , Hidehisa Ohi , Ryohei Hayashi , Yoshitaka Ueno , Shinji Tanaka , Shigeki Bamba , Akira Andoh , Katsuyoshi Matsuoka , Mamoru Watanabe , Keiichiro Saigusa , Atsushi Nakazawa , Yuichi Morohoshi , Yuji Koike , Jin Imai , Hitoshi Ichikawa , Takahiro Shimoyama , Takayuki Yamamoto , Ken Takeuchi , Yasuo Suzuki , Mitsuo Nagasaka , Naoki Ohmiya , Atsuo Kitano , Shinya Ashizuka , Haruhiko Inatsu , Kei Onodera , Hiroshi Nakase , Kazuya Kitamura , Kentaro Ikeya , Hiroyuki Hanai , Chikako Watanabe , Ryota Hokari , Fumihito Hirai , Yuji Naito , Namiko Hoshi , Fukunori Kinjo , Yo Ishiguro , Makoto Sasaki , Takayuki Matsumoto , Kenji Watanabe , Tadakazu Hisamatsu , Fumiya Sano , Rachel Roberts , Takayuki Abe , Wataru Suda , Masahira Hattori , Shinji Fukuda , Akiyoshi Hirayama

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/).

中文翻译：

靛蓝在溃疡性结肠炎患者多中心随机对照试验中的疗效

背景与目标

靛蓝（IN）是一种传统中药，其中包含芳烃受体的配体，并通过诱导白介素22的产生促进粘膜的再生。IN可以诱导溃疡性结肠炎（UC）患者的粘膜愈合。我们进行了一项随机对照试验，以研究IN在UC患者中的安全性和有效性。

方法

我们进行了一项多中心，双盲试验，评估了2016年3月30日至2016年12月27日在日本活动的UC（Mayo评分为6或更高）的86例患者的安全性。将患者随机分组并给予每日剂量服用0.5、1.0或2.0 g IN或安慰剂（1：1：1：1比例），持续8周。主要终点指标是第8周的临床缓解率，定义为Mayo评分降低了3分，较基线降低了至少30％，直肠出血评分或绝对分值降低了至少1分直肠出血评分为0-1。主要的次要终点是第8周时的临床缓解率，定义为Mayo评分或≤2，且无评分> 1。在第8周也评估了粘膜愈合。

结果

该试验由于以下外部原因而终止：一名使用自行购买的IN治疗6个月的患者发生肺动脉高压的报告。在意向治疗分析中，我们观察到有临床反应的患者比例呈显着的剂量依赖性线性趋势（对安慰剂有临床反应的患者为13.6％；对0.5 g IN的患者为69.6％；对g为75.0％的患者；对安慰剂为75.0％的患者；对安慰剂为65.0％的患者）。（2.0 g IN为81.0％）（Cochran-Armitage趋势检验P <.0001与安慰剂相比）。1.0 g IN组（55.0％，P = .0004）和2.0 g IN组（38.1％，（P = .0093）高于安慰剂组（4.5％）。安慰剂组粘膜愈合的患者比例为13.6％，IN组0.5g，56.5％，IN组1.0g，60.0％，IN组2.0g，47.6％（与安慰剂相比，P = .0278）。尽管在接受IN的10例患者中观察到轻度肝功能不全，但未观察到严重的不良事件。