Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial

Professor: Elisabeth Bendstrup 

Artikel link | DOI | PubMed | Journal: Am J Respir Crit Care Med I Dato: 2020 Maj

Se yderligere følgende artikel

Acute exacerbation of idiopathic pulmonary fibrosis: international survey and call for harmonisation

Kommentar til artiklen:

IPF er en irreversibel progredierende fibrotisk lungesygdom med høj mortalitet. Akut exacerbation af IPF (AE-IPF) er forbundet med 50% in-hospital mortalitet. Antifibrotisk behandling forlænger tiden til AE-IPF, men der er ingen direkte evidensbaseret behandling af AE-IPF. Kreuter et al. har undersøgt hvorledes læger (n = 509) behandler AE-IPF, og trods manglende evidens, benyttes corticosteroid af 94% af de adspurgte. Kondoh et al har gennemført et placebokontrolleret, dobbeltblindet randomiseret forsøg med Thrombomodulin Alfa i AE-IPF, desværre uden forbedret 90-dages overlevelse. Studiet understøtter endnu engang behovet for prospektive undersøgelser og viser samtidig, at sådanne studier, trods sygdommens sjældenhed og patienternes geografisk spredning, er mulig.

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).