Makoto Naganuma1, Shinya Sugimoto1, Keiichi Mitsuyama2, Taku Kobayashi3, Naoki Yoshimura4, Hidehisa Ohi5, Shinji Tanaka6, Akira Andoh7, Naoki Ohmiya8, Keiichiro Saigusa9, Takayuki Yamamoto10, Yuichi Morohoshi11, Hitoshi Ichikawa12, Katsuyoshi Matsuoka13, Tadakazu Hisamatsu14, Kenji Watanabe15, Shinta Mizuno1, Wataru Suda16, Masahira Hattori17, Shinji Fukuda18, Akiyoshi Hirayama18, Takayuki Abe19, Mamoru Watanabe13, Toshifumi Hibi3, Yasuo Suzuki20, Takanori Kanai21. 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. 2. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. 3. Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan. 4. Department of Internal Medicine, Division of IBD, Tokyo Yamate Medical Center, Tokyo, Japan. 5. Department of Gastroenterology, Imamura Hospital, Kagoshima, Japan. 6. Department of Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima, Japan. 7. Department of Medicine, Shiga University of Medical Science, Otsu, Japan. 8. Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan. 9. Department of Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan. 10. IBD Center, Yokkaichi Hazu Medical Center, Yokkaichi, Japan. 11. Department of Medicine, Yokohama Municipal Citizen's Hospital, Yokohama, Japan. 12. Department of Gastroenterology, Tokai University Hachioji Hospital, Hachioji, Japan. 13. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan. 14. The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan. 15. Division of Gastroenterology, Osaka City General Hospital, Osaka, Japan; Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan. 16. Department of Immunology, Keio University School of Medicine, Tokyo, Japan; Laboratory of Metagenomics, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. 17. Laboratory of Metagenomics, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan; Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan. 18. Institute for Advanced Biosciences, Keio University, Yamagata, Japan. 19. Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan. 20. Department of Gastroenterology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan. 21. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address: takagast@keio.jp.
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/).
RCT Entities:
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/).