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

INDIGO Study Group

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Abstract

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/).

Original languageEnglish
Pages (from-to)935-947
Number of pages13
JournalGastroenterology
Volume154
Issue number4
DOIs
Publication statusPublished - 01-03-2018

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Indigo Carmine
Ulcerative Colitis
Randomized Controlled Trials
Placebos
Pulmonary Hypertension
Hemorrhage
Aryl Hydrocarbon Receptors

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

@article{e513038e216643de98909c276f3e823c,
title = "Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis",
abstract = "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/).",
author = "{INDIGO Study Group} and Makoto Naganuma and Shinya Sugimoto and Keiichi Mitsuyama and Taku Kobayashi and Naoki Yoshimura and Hidehisa Ohi and Shinji Tanaka and Akira Andoh and Naoki Ohmiya and Keiichiro Saigusa and Takayuki Yamamoto and Yuichi Morohoshi and Hitoshi Ichikawa and Katsuyoshi Matsuoka and Tadakazu Hisamatsu and Kenji Watanabe and Shinta Mizuno and Wataru Suda and Masahira Hattori and Shinji Fukuda and Akiyoshi Hirayama and Takayuki Abe and Mamoru Watanabe and Toshifumi Hibi and Yasuo Suzuki and Takanori Kanai and Makoto Naganuma and Shinta Mizuno and Yoshihiro Nakazato and Tomohiro Fukuda and Toshiaki Teratani and Haruhiko Ogata and Yasushi Iwao and Takanori Kanai and Hiroshi Yamasaki and Keiichi Mitsuyama and Taku Kobayashi and Takahiko Toyonaga and Masaru Nakano and Toshifumi Hibi and Naoki Yoshimura and Yoichi Sameshima and Hidehisa Ohi and Ryohei Hayashi and Yoshitaka Ueno and Shinji Tanaka and Shigeki Bamba and Akira Andoh and Katsuyoshi Matsuoka and Mamoru Watanabe",
year = "2018",
month = "3",
day = "1",
doi = "10.1053/j.gastro.2017.11.024",
language = "English",
volume = "154",
pages = "935--947",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis. / INDIGO Study Group.

In: Gastroenterology, Vol. 154, No. 4, 01.03.2018, p. 935-947.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis

AU - INDIGO Study Group

AU - Naganuma, Makoto

AU - Sugimoto, Shinya

AU - Mitsuyama, Keiichi

AU - Kobayashi, Taku

AU - Yoshimura, Naoki

AU - Ohi, Hidehisa

AU - Tanaka, Shinji

AU - Andoh, Akira

AU - Ohmiya, Naoki

AU - Saigusa, Keiichiro

AU - Yamamoto, Takayuki

AU - Morohoshi, Yuichi

AU - Ichikawa, Hitoshi

AU - Matsuoka, Katsuyoshi

AU - Hisamatsu, Tadakazu

AU - Watanabe, Kenji

AU - Mizuno, Shinta

AU - Suda, Wataru

AU - Hattori, Masahira

AU - Fukuda, Shinji

AU - Hirayama, Akiyoshi

AU - Abe, Takayuki

AU - Watanabe, Mamoru

AU - Hibi, Toshifumi

AU - Suzuki, Yasuo

AU - Kanai, Takanori

AU - Naganuma, Makoto

AU - Mizuno, Shinta

AU - Nakazato, Yoshihiro

AU - Fukuda, Tomohiro

AU - Teratani, Toshiaki

AU - Ogata, Haruhiko

AU - Iwao, Yasushi

AU - Kanai, Takanori

AU - Yamasaki, Hiroshi

AU - Mitsuyama, Keiichi

AU - Kobayashi, Taku

AU - Toyonaga, Takahiko

AU - Nakano, Masaru

AU - Hibi, Toshifumi

AU - Yoshimura, Naoki

AU - Sameshima, Yoichi

AU - Ohi, Hidehisa

AU - Hayashi, Ryohei

AU - Ueno, Yoshitaka

AU - Tanaka, Shinji

AU - Bamba, Shigeki

AU - Andoh, Akira

AU - Matsuoka, Katsuyoshi

AU - Watanabe, Mamoru

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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/).

AB - 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/).

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U2 - 10.1053/j.gastro.2017.11.024

DO - 10.1053/j.gastro.2017.11.024

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JF - Gastroenterology

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