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Thrombomodulin alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Randomized, Double-blind, Placebo-controlled Trial.

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 anti-inflammatory 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/day for 14 days 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 proportion on Day 90 was 72.5% (29/40) in the thrombomodulin alfa group and 89.2% (33/37) in the placebo group, a difference of -16.7 percentage points (95% CI, -33.8% to 0.4%, p=0.0863). In the safety population (N=80), bleeding adverse events occurred in the thrombomodulin alfa group (10/42, 23.8%) and the placebo group (4/38, 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 registration available at www.clinicaltrials.gov, ID: NCT02739165.