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

INDIGO Study Group

    Research output: Contribution to journalArticle

    19 Citations (Scopus)

    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 - 2018 Mar 1

    Fingerprint

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

    Keywords

    • Aryl Hydrocarbon Receptor
    • IBD
    • Mucosal Healing
    • Qing-Dai

    ASJC Scopus subject areas

    • Gastroenterology

    Cite this

    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

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    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/).",
    keywords = "Aryl Hydrocarbon Receptor, IBD, Mucosal Healing, Qing-Dai",
    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 Shinya Sugimoto 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",
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    month = "3",
    day = "1",
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    language = "English",
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    pages = "935--947",
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    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 - Sugimoto, Shinya

    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

    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/).

    KW - Aryl Hydrocarbon Receptor

    KW - IBD

    KW - Mucosal Healing

    KW - Qing-Dai

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    UR - http://www.scopus.com/inward/citedby.url?scp=85043260143&partnerID=8YFLogxK

    U2 - 10.1053/j.gastro.2017.11.024

    DO - 10.1053/j.gastro.2017.11.024

    M3 - Article

    VL - 154

    SP - 935

    EP - 947

    JO - Gastroenterology

    JF - Gastroenterology

    SN - 0016-5085

    IS - 4

    ER -