Recombinant Human Soluble Thrombomodulin in Patients With Sepsis
Recombinant Human Soluble Thrombomodulin in Patients With Sepsis
A total of 750 patients were randomized: 371 received ART-123 and 370 received placebo (nine patients [four in the ART-123 group and five in the placebo group] were randomized but did not receive any of the allocated study treatment; Fig. 1). One patient randomized to placebo was incorrectly given ART-123. Under the intent-to-treat principle, this patient was included in the placebo group for the efficacy analyses (full analysis set) but in the ART-123 group for the safety analyses (safety analysis set). A total of 145 patients (19.6%) did not complete the study (66 [17.8%] patients in the ART-123 group; 79 [19.5%] patients in the placebo group), but mortality data were available for all but three patients.
Baseline demographic characteristics are shown in Table 3. The mean patient age was 57 years (range, 18–93). There were no meaningful differences between ART-123 and placebo groups in any of the baseline variables. Slightly more patients in the ART-123 group were receiving heparin or low–molecular weight heparin at baseline than in the placebo group (55 [14.9%] vs 45 [12.1%]). The lung was the most common site of infection in both groups (Table 3). Eighty-three percent (n = 587) of patients had microbiological evidence of infection; the most commonly isolated organism was Escherichia coli (77 patients [17%] in the ART-123 group and 92 patients [20%] in the placebo group). At baseline, 30% of patients had no organ dysfunction; 134 patients (36.2%) in the ART-123 group and 127 patients (34.2%) in the placebo group had two or more organ dysfunctions at baseline. On day 28, 22 patients (7.8%) in the ART-123 group and 15 patients (5.4%) in the placebo group had some organ dysfunction. Overt DIC (ISTH score ≥ 5) was present at baseline in 98 patients (13.2%): 45 (12.2%) in the ART-123 group and 53 (14.3%) in the placebo group.
Twenty-eight-day mortality was 17.8% (n = 66) in the ART-123 group and 21.6% (n = 80) in the placebo group; Kaplan–Meier survival curves are shown in Figure 2 and gave a one-sided log-rank p value of 0.17. A Cochran–Mantel–Haenszel test stratified by baseline mDIC and pooled country resulted in a two-sided p value of 0.273 (0.137 one sided) in favor of the ART-123 group, which met the predefined statistical test for evidence suggestive of efficacy (0.15 one-sided alpha level). In the 248 patients admitted after amendment 4 of the protocol, in which the mDIC score required for entry was increased from 2 to 3 and the DIC score needed to be confirmed 4 hours prior to randomization, there was an increase in placebo mortality (24% vs 21%) and in the absolute reduction in mortality with ART-123 (6% vs 3%) compared with patients admitted before this amendment (Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/A674).
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Figure 2.
Kaplan–Meier plots of survival time for the two treatment arms: 28-d survival was 82.2% (95% CI, 77.9%, 85.7%) for the ART-123 group and 79.4% (95% CI, 74.9%, 83.2%) for the placebo group (one-sided logrank p value = 0.17). Observations occurring after day 28 were censored at day 28.
In subgroup analyses for the primary endpoint, the largest treatment effect was seen in patients receiving baseline prophylactic heparin (Table 4): 28-day mortality rate 18% (10/55) in the ART-123 group compared with 40% (18/45) in the placebo group (chi-squared p = 0.016 based upon post hoc analysis without multiplicity adjustment). There was no difference in mortality among groups in patients with overt DIC. A series of post hoc analyses were conducted to identify populations that benefited from ART-123 therapy by stratifying subjects according to comorbidities, types of organ dysfunction, and severity of inflammation or coagulopathy based on the biomarker values at baseline. The greatest survival benefit was seen in patients with respiratory or cardiac dysfunction and coagulopathy characterized by PT-INR greater than 1.4 at baseline with a platelet count between 30 and 150 × 10/L: mortality rate of ART-123 was 26.3% (21/80) and placebo was 38.2% (29/76).
There were no statistically significant differences in the event-free and alive days between two groups (Table 5). The comparison of resolution of overt DIC between two treatment groups was tested using a stratified Cochran–Mantel–Haenszel test. At day 1, the difference in percentage of patients with resolution of overt DIC (28.9% ART-123 group vs 18.9% placebo group) reached the suggestive level of statistical evidence (p = 0.175).
D-dimer, F1.2, and TAT complex (TATc) concentrations were lower in the ART-123 treatment group than in the placebo group (Fig. 3). No differences were seen with regard to platelets or PT. There were no significant differences between the groups in any of the measured inflammatory markers.
(Enlarge Image)
Figure 3.
Median d-dimer, F1.2, and TAT complex concentrations over time in the two groups. *p < 0.05, p < 0.001. p values from Wilcoxon test using change from baseline and imputing a change of zero for subjects who died.
The pharmacokinetics of ART-123 were similar to those reported in previous studies and were not affected by sex, race/nationality, age, or hematocrit. Mean ART-123 concentrations in patients receiving active product increased throughout the study with highest values recorded on day 3 (1031.8 + 430.6 ng/mL). Although ART-123 is mostly excreted by the kidneys, renal dysfunction did not appear to have a major impact on ART-123 volume of distribution or clearance over a large range of creatinine clearances (from 7 to over 400 mL/min).
Overall, 681 patients (92%) experienced at least one treatment-emergent adverse event (AE): 339 patients (91.4%) in the ART-123 group and 342 patients (92.4%) in the placebo group. The most commonly occurring AEs were hypokalemia, anemia, and pyrexia (Table S2, Supplemental Digital Content 1, http://links.lww.com/CCM/A674). Anemia, thrombocytopenia, and postprocedural hemorrhage were more common in the ART-123-treated patients than in the placebo patients. Overall, 265 patients (35.8%) experienced at least one treatment-emergent SAE: 139 (37.5%) patients in the ART-123 group and 126 patients (34.1%) in the placebo group. Nineteen patients (5.1%) in the ART-123 group and 17 patients (4.6%) in the placebo group experienced an on-treatment serious major bleeding event; four patients (1.1%) in each group had a serious major bleeding event that was fatal. There were no differences between the groups in the prevalence of thromboembolic complications (deep-vein thrombosis, pulmonary embolism, ischemic stroke, acute coronary syndrome). Overall, 71 patients (9.6%) experienced AEs leading to permanent discontinuation of the study drug: 33 patients (8.9%) in the ART-123 group and 38 patients (10.3%) in the placebo group (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/A674). There were no differences between the groups in the development of new infections: 158 patients (43%) in the ART-123 group and 154 patients (42%) in the placebo group. Hematology and biochemistry results were comparable across the study treatments, with no discernible differences between the groups in the number of patients with laboratory results outside of the normal range at any time point.
Eleven patients (six in the ART-123 group and five in the placebo group) had positive results for anti-ART-123 antibody at day 28. No neutralizing antibodies were detected, and no adverse events potentially related to antidrug antibodies were reported.
Results
A total of 750 patients were randomized: 371 received ART-123 and 370 received placebo (nine patients [four in the ART-123 group and five in the placebo group] were randomized but did not receive any of the allocated study treatment; Fig. 1). One patient randomized to placebo was incorrectly given ART-123. Under the intent-to-treat principle, this patient was included in the placebo group for the efficacy analyses (full analysis set) but in the ART-123 group for the safety analyses (safety analysis set). A total of 145 patients (19.6%) did not complete the study (66 [17.8%] patients in the ART-123 group; 79 [19.5%] patients in the placebo group), but mortality data were available for all but three patients.
Baseline demographic characteristics are shown in Table 3. The mean patient age was 57 years (range, 18–93). There were no meaningful differences between ART-123 and placebo groups in any of the baseline variables. Slightly more patients in the ART-123 group were receiving heparin or low–molecular weight heparin at baseline than in the placebo group (55 [14.9%] vs 45 [12.1%]). The lung was the most common site of infection in both groups (Table 3). Eighty-three percent (n = 587) of patients had microbiological evidence of infection; the most commonly isolated organism was Escherichia coli (77 patients [17%] in the ART-123 group and 92 patients [20%] in the placebo group). At baseline, 30% of patients had no organ dysfunction; 134 patients (36.2%) in the ART-123 group and 127 patients (34.2%) in the placebo group had two or more organ dysfunctions at baseline. On day 28, 22 patients (7.8%) in the ART-123 group and 15 patients (5.4%) in the placebo group had some organ dysfunction. Overt DIC (ISTH score ≥ 5) was present at baseline in 98 patients (13.2%): 45 (12.2%) in the ART-123 group and 53 (14.3%) in the placebo group.
Efficacy
Twenty-eight-day mortality was 17.8% (n = 66) in the ART-123 group and 21.6% (n = 80) in the placebo group; Kaplan–Meier survival curves are shown in Figure 2 and gave a one-sided log-rank p value of 0.17. A Cochran–Mantel–Haenszel test stratified by baseline mDIC and pooled country resulted in a two-sided p value of 0.273 (0.137 one sided) in favor of the ART-123 group, which met the predefined statistical test for evidence suggestive of efficacy (0.15 one-sided alpha level). In the 248 patients admitted after amendment 4 of the protocol, in which the mDIC score required for entry was increased from 2 to 3 and the DIC score needed to be confirmed 4 hours prior to randomization, there was an increase in placebo mortality (24% vs 21%) and in the absolute reduction in mortality with ART-123 (6% vs 3%) compared with patients admitted before this amendment (Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/A674).
(Enlarge Image)
Figure 2.
Kaplan–Meier plots of survival time for the two treatment arms: 28-d survival was 82.2% (95% CI, 77.9%, 85.7%) for the ART-123 group and 79.4% (95% CI, 74.9%, 83.2%) for the placebo group (one-sided logrank p value = 0.17). Observations occurring after day 28 were censored at day 28.
In subgroup analyses for the primary endpoint, the largest treatment effect was seen in patients receiving baseline prophylactic heparin (Table 4): 28-day mortality rate 18% (10/55) in the ART-123 group compared with 40% (18/45) in the placebo group (chi-squared p = 0.016 based upon post hoc analysis without multiplicity adjustment). There was no difference in mortality among groups in patients with overt DIC. A series of post hoc analyses were conducted to identify populations that benefited from ART-123 therapy by stratifying subjects according to comorbidities, types of organ dysfunction, and severity of inflammation or coagulopathy based on the biomarker values at baseline. The greatest survival benefit was seen in patients with respiratory or cardiac dysfunction and coagulopathy characterized by PT-INR greater than 1.4 at baseline with a platelet count between 30 and 150 × 10/L: mortality rate of ART-123 was 26.3% (21/80) and placebo was 38.2% (29/76).
There were no statistically significant differences in the event-free and alive days between two groups (Table 5). The comparison of resolution of overt DIC between two treatment groups was tested using a stratified Cochran–Mantel–Haenszel test. At day 1, the difference in percentage of patients with resolution of overt DIC (28.9% ART-123 group vs 18.9% placebo group) reached the suggestive level of statistical evidence (p = 0.175).
D-dimer, F1.2, and TAT complex (TATc) concentrations were lower in the ART-123 treatment group than in the placebo group (Fig. 3). No differences were seen with regard to platelets or PT. There were no significant differences between the groups in any of the measured inflammatory markers.
(Enlarge Image)
Figure 3.
Median d-dimer, F1.2, and TAT complex concentrations over time in the two groups. *p < 0.05, p < 0.001. p values from Wilcoxon test using change from baseline and imputing a change of zero for subjects who died.
Pharmacokinetics
The pharmacokinetics of ART-123 were similar to those reported in previous studies and were not affected by sex, race/nationality, age, or hematocrit. Mean ART-123 concentrations in patients receiving active product increased throughout the study with highest values recorded on day 3 (1031.8 + 430.6 ng/mL). Although ART-123 is mostly excreted by the kidneys, renal dysfunction did not appear to have a major impact on ART-123 volume of distribution or clearance over a large range of creatinine clearances (from 7 to over 400 mL/min).
Safety
Overall, 681 patients (92%) experienced at least one treatment-emergent adverse event (AE): 339 patients (91.4%) in the ART-123 group and 342 patients (92.4%) in the placebo group. The most commonly occurring AEs were hypokalemia, anemia, and pyrexia (Table S2, Supplemental Digital Content 1, http://links.lww.com/CCM/A674). Anemia, thrombocytopenia, and postprocedural hemorrhage were more common in the ART-123-treated patients than in the placebo patients. Overall, 265 patients (35.8%) experienced at least one treatment-emergent SAE: 139 (37.5%) patients in the ART-123 group and 126 patients (34.1%) in the placebo group. Nineteen patients (5.1%) in the ART-123 group and 17 patients (4.6%) in the placebo group experienced an on-treatment serious major bleeding event; four patients (1.1%) in each group had a serious major bleeding event that was fatal. There were no differences between the groups in the prevalence of thromboembolic complications (deep-vein thrombosis, pulmonary embolism, ischemic stroke, acute coronary syndrome). Overall, 71 patients (9.6%) experienced AEs leading to permanent discontinuation of the study drug: 33 patients (8.9%) in the ART-123 group and 38 patients (10.3%) in the placebo group (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/A674). There were no differences between the groups in the development of new infections: 158 patients (43%) in the ART-123 group and 154 patients (42%) in the placebo group. Hematology and biochemistry results were comparable across the study treatments, with no discernible differences between the groups in the number of patients with laboratory results outside of the normal range at any time point.
Eleven patients (six in the ART-123 group and five in the placebo group) had positive results for anti-ART-123 antibody at day 28. No neutralizing antibodies were detected, and no adverse events potentially related to antidrug antibodies were reported.
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