The study, “Thrombomodulin alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Randomized, Double-blind, Placebo-controlled Trial,” was published in the American Journal of Respiratory and Critical Care Medicine.
In IPF, acute exacerbations are characterized by rapid disease progression, leading to decreased lung function and ultimately death. Although the mechanisms underlying the onset of these episodes of rapid disease progression are unclear, scientists believe excessive coagulation and inflammation in the lungs to be the main triggers.
ART-123, developed by Asahi Kasei, is a recombinant (lab-made) version of the protein thrombomodulin, which has strong anti-coagulant and anti-inflammatory properties that could be beneficial to treat acute exacerbations among those with IPF.
“Several clinical studies have shown that ART-123 may improve the survival proportion in patients with AE [acute exacerbation]-IP,” the researchers wrote. “However, since these studies were small or retrospective clinical studies, a prospective, placebo-controlled, double-blind study was considered necessary.”
The Phase 3 trial (NCT02739165) was aimed at assessing the safety and efficacy of ART-123 in IPF patients experiencing acute exacerbations.
The trial, funded by Asahi Kasei, was conducted at 27 sites in Japan and enrolled 82 adults with IPF, ranging in age from 40 to 85.
Study participants were randomly assigned to receive either ART-123 or a placebo, both given at a dose of 380 U/kg/day for 14 days, delivered by an intravenous drip that took about half an hour to administer. All patients also received standard-of-care therapy with corticosteroids.
The trial’s main goal was to assess the percentage of patients who were still alive after 90 days of treatment.
Of the 82 patients enrolled in the study, 77 (40 treated with ART-123 and 37 with a placebo) completed the trial and were eligible for efficacy analysis.
By the 90th day, 29 of the 40 patients treated with ART-123 (72.5%) were still alive, as were 33 of the 37 participants receiving the placebo (89.2%). Differences in the survival rates between the two groups were not statistically significant, indicating that ART-123 failed to prolong the survival of IPF patients experiencing acute exacerbations.
The most common cause of death in both groups was the progression or recurrence of acute exacerbations.
Additional subgroup analyses failed to find a survival benefit associated with ART-123, and confirmed this was not due to potential baseline differences between the two groups prior to treatment.
All ART-123-treated participants reported adverse events, as did about three-quarters of participants given a placebo. The most common adverse events among those given the medication were insomnia, delirium, hyperglycemia (high blood sugar), diabetes mellitus, and constipation.
Bleeding, one of the major concerns since ART-123 is an anticoagulant (preventing blood clotting), occurred in 23.8% of participants treated with ART-123 and in 10.5% of those given a placebo.
Three serious adverse events were deemed related to the study drug. Two of these were bleeding events. In the case of one participant given ART-123, a cause-and-effect relationship between treatment-related bleeding and the patient’s death “could not be ruled out,” the researchers said.
Since no correlations were found between the levels of ART-123 in the blood and instances of bleeding or death, “it is unlikely that an excessive effect of ART-123 resulted in an increase in bleeding or death,” the researchers said.
“However, the possibility of an increased risk of death caused by ART-123 could not be completely ruled out. An appropriate additional clinical study would be needed to clarify this,” they said.
Overall, “the results of this study suggest that the use of ART-123 for the treatment of AE-IPF not be recommended,” they said.
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