Yasuhiro Kondoh1, Arata Azuma2, Yoshikazu Inoue3, Takashi Ogura4, Susumu Sakamoto5, Kenji Tsushima6, Takeshi Johkoh7, Kiminori Fujimoto8, Kazuya Ichikado9, Yasuo Matsuzawa10, Takefumi Saito11, Kazuma Kishi5, Keisuke Tomii12, Noriho Sakamoto13, Masahiro Aoshima14, Jun Araya15, Shinyu Izumi16, Machiko Arita17, Mitsuhiro Abe18, Hiroyoshi Yamauchi19, Joe Shindoh20, Takafumi Suda21, Masaki Okamoto22, Masahito Ebina23, Yoshihito Yamada24, Yuji Tohda25, Tetsuji Kawamura26, Yoshio Taguchi27, Hiroshi Ishii28, Naozumi Hashimoto29, Shinji Abe30, Hiroyuki Taniguchi1, Jun Tagawa31, Koji Bessho31, Natsuki Yamamori31, Sakae Homma32. 1. Department of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan. 2. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. 3. Clincal Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan. 4. Division of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan. 5. Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan. 6. Department of Pulmonary Medicine, School of Medicine, International University of Health and Welfare, Chiba, Japan. 7. Department of Radiology, Kansai Rosai Hospital, Hyogo, Japan. 8. Department of Radiology and. 9. Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan. 10. Department of Respiratory Medicine, Toho University Medical Center-Sakura Hospital, Chiba, Japan. 11. Department of Respiratory Medicine, National Hospital Organization, Ibarakihigashi National Hospital, Ibaraki, Japan. 12. Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan. 13. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 14. Department of Pulmonology, Kameda Medical Center, Chiba, Japan. 15. Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. 16. Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan. 17. Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan. 18. Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. 19. Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan. 20. Department of Respiratory Medicine, Ogaki Municipal Hospital, Gifu, Japan. 21. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan. 22. Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan. 23. Department of Respiratory Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, Japan. 24. Department of Respiratory Medicine, Japan Railway Tokyo General Hospital, Tokyo, Japan. 25. Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kindai University, Osaka, Japan. 26. Department of Respiratory Medicine, National Hospital Organization Himeji Medical Center, Hyogo, Japan. 27. Department of Respiratory Medicine, Tenri Hospital, Nara, Japan. 28. Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Japan. 29. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan. 30. Department of Respiratory Medicine, Tokyo Medical University Hospital, Tokyo, Japan. 31. Asahi-Kasei Pharma Corporation, Tokyo, Japan; and. 32. Department of Advanced and Integrated Interstitial Lung Diseases Research, School of Medicine, Toho University, Tokyo, Japan.
Abstract
Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation. Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis. Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).
RCT Entities:
Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation. Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis. Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).
Authors: Anna J Podolanczuk; Alyson W Wong; Shigeki Saito; Joseph A Lasky; Christopher J Ryerson; Oliver Eickelberg Journal: Am J Respir Crit Care Med Date: 2021-06-01 Impact factor: 21.405