Decreased organ failure in patients with severe SIRS and septic shock treated with the platelet-activating factor antagonist TCV-309: A prospective, multicenter, double-blind, randomized phase II trial

Sepsis and organ failure remain the main cause of death on the ICU. Sepsis is characterized by a severe inflammatory response, in which platelet-activ ating factor (PAF) is considered to play an important role. This study inve stigated whether treatment with the PAF-antagonist TCV-309 reduces morbidit y and mortality in patients with septic shock. The study was conducted as a double-blind, randomized, placebo controlled multicenter study. The includ ed patients had to fulfill the SIRS criteria with a clinical suspicion of i nfection, an admission APACHE II score greater than 15, and shock, defined as a mean arterial pressure <70 mmHg and/or a decrease <greater than or equ al to>40 mmHg despite adequate fluid resuscitation. Patients received 1.0 m g/kg TCV-309 or placebo, twice daily, intravenously during 14 days. The pro spectively set goals were MOF score, recovery from shock, mortality, and as sessment of the safety of the medication. A total of 98 patients were inclu ded of which 97 were analyzed on an intention-to-treat basis. The overall s urvival at day 56 of TCV-309 treated patients was similar compared to place bo treated patients (51.0% vs. 41.7%, P = 0.47). In contrast, the mean perc entage of failed organs per patient present after 14 days in the TCV-309 tr eated patients was significantly lower compared to the placebo treated pati ents (11.9% vs. 25.1%, P = 0.04), leading to a reduced need for vasopressor s, dialysis, and ventilatory support. Furthermore, the mean APACHE-II score during treatment with TCV-309 was significantly lower and the number of pa tients recovered from shock after day 14 was significantly higher in the TC V-309 treated patient group (2/32 vs. 9/29, P = 0.01). The number of advers e events was not significantly different between the TCV-309 and placebo tr eated patients. TCV-309 did not change overall mortality of septic shock, h owever a substantial reduction in organ dysfunction and morbidity, frequent ly associated with septic shock was achieved, without significant adverse e vents.