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. 2016 Nov 7:11:38.
doi: 10.1186/s40248-016-0074-z. eCollection 2016.

Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial

Sho Hayakawa  1 , Yasuo Matsuzawa  1 , Tamako Irie  1 , Hagino Rikitake  1 , Noriaki Okada  1 , Yasuo Suzuki  1
Affiliations

Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial

Sho Hayakawa et al. Multidiscip Respir Med. .

Abstract

Background: Coagulation abnormalities are involved in the pathogenesis of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). The administration of recombinant human soluble thrombomodulin (rhTM), which has both anti-inflammatory and anticoagulant activities, improves outcomes and respiratory function in patients with acute respiratory distress syndrome. Therefore, we conducted a prospective clinical study to examine the effects of rhTM on respiratory function, coagulation markers, and outcomes for patients with AE-IPF.

Methods: After registration of the protocol, the patients with AE-IPF who satisfied the study inclusion criteria were treated daily with 380 U/kg of rhTM for 7 days and steroid pulse therapy. The concomitant administration of immunosuppressants and polymyxin B-immobilized fiber column treatment was prohibited. The sample size was 10 subjects. The primary study outcome was the improvement of PaO2/FiO2 ratio a week after treatment initiation. Secondary outcomes were change in D-dimer level over time and 28-day survival rate in patients without intubation. Study data were compared with historical untreated comparison group, including 13 patients with AE-IPF who were treated without rhTM before the registration.

Results: The mean PaO2/FiO2 ratio for the rhTM treatment group (n = 10) on day 8 significantly improved compared with that on day one (two-way analysis of variance, p = 0.01). The mean D-dimer level tended to decrease in the rhTM group on day 8, but the change was not significant. The 28-day survival rate was 50 % higher in the rhTM group than in the historical untreated comparison group, but the difference was not significant. A post hoc analysis showed that overall survival time was significantly longer in the treated group compared with that of the historical untreated comparison group (p = 0.04, log-rank test).

Conclusion: rhTM plus steroid pulse therapy improves respiratory functions in patients with AE-IPF and is expected to improve overall patient survival without using other combination therapies.

Trial registration: The study was registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) in October 2012 (UMIN000009082).

Keywords: Acute exacerbation; Idiopathic pulmonary fibrosis; Recombinant human soluble thrombomodulin.

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Figures

Fig. 1
Fig. 1
Flow diagram of the patients of two groups. rhTM: recombinant human soluble thrombomodulin
Fig. 2
Fig. 2
Serial changes in coagulation markers and HMGB1 levels of the patients in the rhTM group (n = 10). There were no significant changes between the serial change in D-dimer, TAT, PIC and HMGB1 (one-way repeated ANOVA). Data are expressed as the group means ± standard deviation. HMGB1: high mobility group box 1; TAT: thrombin-antithrombin complex; PIC: plasmin-α2 plasmin inhibitor complex. *n = 7, †n = 5
Fig. 3
Fig. 3
Kaplan–Meier distribution for the probability of survival without tracheal intubation. The solid line represents patients in the recombinant human soluble thrombomodulin (rhTM) group, and the dotted line represents patients in the untreated group. Survival was significantly better in the rhTM group than in the untreated group at 1 year (p = 0.04, log-rank test). rhTM: recombinant human soluble thrombomodulin
See this image and copyright information in PMC

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