Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial
Yasuhiro Kondoh, Arata Azuma, Yoshikazu Inoue, Takashi Ogura, Susumu Sakamoto, Kenji Tsushima, Takeshi Johkoh, Kiminori Fujimoto, Kazuya Ichikado, Yasuo Matsuzawa, Takefumi Saito, Kazuma Kishi, Keisuke Tomii, Noriho Sakamoto, Masahiro Aoshima, Jun Araya, Shinyu Izumi, Machiko Arita, Mitsuhiro Abe, H. Yamauchi, Joe Shindoh, Takafumi Suda, Masaki Okamoto, Masahito Ebina, Yoshihito Yamada, Yuji Tohda, Tetsuji Kawamura, Yoshio Taguchi, Hiroshi Ishii, Naozumi Hashimoto, Shinji Abe, Hiroyuki Taniguchi, Jun Tagawa, Koji Bessho, Natsuki Yamamori, Sakae Homma
Abstract
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).