Abstract
BackgroundA recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma. To compare the efficacy and safety of AT gamma to plasma-derived AT (pAT), we conducted a randomized, open-label, multicenter trial in patients with sepsis-induced disseminated intravascular coagulation (DIC).MethodsEligible patients, recruited at 30 clinical sites, had been diagnosed with sepsis-induced DIC (by the Japanese Association for Acute Medicine [JAAM] DIC criteria) and AT activity at 70% or below. Patients were randomized 1:1 to either 36 IU/kg/day AT gamma (n = 110) or 30 IU/kg/day pAT (n = 112), both administered intravenously for 5 days. The primary endpoint was recovery from DIC at day 6 or early study withdrawal. DIC recovery was defined as a DIC score of less than four. Secondary endpoints were DIC score, outcome on day 28, sequential organ failure assessment score, acute physiology and chronic health evaluation II score (APACHE II), and plasma AT activity. Adverse events and adverse drug reactions were recorded using MedDRA/J version 16.0.ResultsBaseline patient demographics and clinical features were similar in the two treatment groups. On day 6 (or at withdrawal), DIC recovery had occurred in 62 of 110 (56.4%; 95% confidence interval, 46.6–65.8%) patients in the AT gamma group and 59 of 112 (52.7%; 95% confidence interval, 43.0–62.2%) patients in the pAT group. In both treatment groups, DIC recovery rate values tended to be higher when stratified by baseline AT activity rates. All changes in other secondary endpoints were similar in both treatment groups. Safety was also similar in the two treatment groups. Adverse events occurred in 89 of 108 (82.4%) patients in the AT gamma group and 99 of 113 (87.6%) patients in the pAT group.ConclusionsSafety and efficacy were similar for 36 IU/kg/day AT gamma and 30 IU/kg/day pAT. These results confirm that AT gamma is an excellent alternative to pAT for improving outcomes for patients with DIC.Trial registrationClinicalTrials.gov identifier: NCT01384903; June 2011.
Highlights
A recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma
The following patients were excluded from the study: patients with drug allergies; patients with serious hepatic dysfunction; patients unlikely to survive long enough to provide efficacy and safety data; patients who were pregnant, breastfeeding, or who may have been pregnant; patients who had participated in another clinical study in the previous 4 months; patients who had previously received AT gamma; patients who had received prohibited concomitant medications or therapies between informed consent and enrollment; and patients judged to be ineligible by the investigator
Of the 112 patients assigned to the plasma-derived AT (pAT) group and 110 patients assigned to the AT gamma group, one patient (0.9%) in the AT gamma group withdrew from the study before the start of study treatment
Summary
A recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma. To compare the efficacy and safety of AT gamma to plasma-derived AT (pAT), we conducted a randomized, open-label, multicenter trial in patients with sepsis-induced disseminated intravascular coagulation (DIC). Antithrombin (AT), a major coagulation inhibitor in humans, is a single-chain glycoprotein with 432 amino acids and a molecular weight of approximately 58 kDa [1, 2]. Acquired AT deficiency can result from either decreased production or increased degradation of AT and is often associated with disseminated intravascular coagulation (DIC) [6], a life-threatening condition characterized by activated coagulation pathways, decreased anticoagulant activity, and altered activity of fibrinolytic pathways [6, 7]. DIC is typically secondary to other conditions such as sepsis and trauma [6]
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