Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial.
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/FiO2ratio 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/FiO2ratio 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. Apost hocanalysis 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).


CONCLUSIONS
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.


BACKGROUND
The study was registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) in October 2012 (UMIN000009082).
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Sho
S
Hayakawa
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Yasuo
0000-0001-7470-6303
Y
Matsuzawa
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Tamako
T
Irie
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Hagino
H
Rikitake
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Noriaki
N
Okada
Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, 564-1 Shimoshidu, Sakura City, Chiba 285-8741 Japan.
Yasuo
Y
Suzuki
Acute exacerbation; Idiopathic pulmonary fibrosis; Recombinant human soluble thrombomodulin