A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer.

A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2).

Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome.

OBJECTIVES: To prospectively evaluate the performance of the Clinical Pulmonary Infection Score (CPIS) and its components to identify early in the hospital course of ventilator-associated pneumonia (VAP) which patients are responding to therapy. DESIGN: Prospective, multicenter, in a cohort of mechanically ventilated patients. SETTING: The intensive care unit of six hospitals located in the metropolitan area of Buenos Aires, Argentina. PATIENTS: Sixty-three patients, from a cohort of 472 mechanically ventilated patients hospitalized for >72 hrs, had clinical evidence of VAP and bacteriologic confirmation by bronchoalveolar lavage (BAL) or blood cultures. INTERVENTIONS: Bronchoscopy with BAL fluid culture and blood cultures after establishing a clinical diagnosis of VAP. All patients received antibiotics, 46 before bronchoscopy and 17 immediately after bronchoscopy. MEASUREMENTS AND RESULTS: CPIS was measured at 3 days before VAP (VAP-3); at the onset of VAP (VAP); and at 3 (VAP+3), 5 (VAP+5), and 7 (VAP+7) days after onset. CPIS rose from VAP-3 to VAP and then fell progressively in the population as a whole (p <.001), and the fall in CPIS was significant in 31 survivors, but not in 32 nonsurvivors. From the individual components of the CPIS, only the Pao /Fio ratio distinguished survivors from nonsurvivors, beginning at VAP+3. When CPIS was <6 at 3 or 5 days after VAP onset, mortality was lower than in the remaining patients (p =.018). These differences also related to the finding that those receiving adequate therapy had a slight fall in CPIS and a significant increase of Pao /Fio at VAP+3, whereas those getting inadequate therapy did not. CONCLUSIONS: Serial measurements of CPIS can define the clinical course of VAP resolution, identifying those with good outcome as early as day 3, and could possibly be of help to define strategies to shorten the duration of therapy.