A Randomized, Double-Blind, -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 Online Supplementary Data Appendix 1: Country distribution of the 233 centers Country Number of centers Number of patients randomized ART-123 Argentina 17 22 22 Australia 23 27 26 Belgium 10 45 44 Canada 7 11 10 Czech Republic 7 34 34 Hong Kong 2 0 0 India 26 97 98 Israel 15 16 16 Malaysia 3 3 3 Netherlands 7 8 8 New Zealand 4 9 8 Singapore 1 0 1 Spain 8 20 20 Taiwan 5 8 9 Thailand 7 11 12 United Kingdom 4 4 4 United States 87 60 60 1
Appendix 2: Full study exclusion criteria Patients were excluded from the study if any of the following criteria were present: Unable to obtain informed consent; pregnant or breastfeeding; previous treatment with ART-123; body weight 175 kg; prothrombin time prolongation or thrombocytopenia that was not due to sepsis; intra-thoracic, intra-abdominal, or intra-cranial surgery within the 12 hours prior to randomization, or ongoing impairment of hemostasis as a result of one of these procedures; a history of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to enrolment; cerebrovascular accident (CVA) within 3 months prior to enrolment; any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system; a history of congenital bleeding diatheses (e.g., hemophilia) or condition associated with hypercoagulable state; gastrointestinal bleeding within 6 weeks prior to enrolment unless a corrective interventional procedure had been performed; deep vein thrombosis or pulmonary embolism within 3 months prior to enrolment; known or suspected severe liver disease, as defined by a score of 10-15 (Class C) using the Child-Pugh Classification; portosystemic hypertension or known history of bleeding esophageal varices; history of solid organ, allogeneic bone marrow, or stem cell transplantation within 6 months of enrolment; acute pancreatitis where infection had not been documented by a positive blood or abdominal fluid culture; severe renal failure characterized by chronic or acute need of hemodialysis, hemofiltration or peritoneal dialysis; use or intended use of drotrecogin alfa (activated) within the 24 hours prior to enrolment; use or intended use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 24 hours prior to study dosing with the exception of heparin locks/flushes, deep vein thrombosis prophylaxis with either 2
unfractionated heparin or low molecular weight heparin (LMWH); platelet count <20,000 or platelet count <30,000/mm³ after platelet transfusion; life expectancy <90 days; current use of any chemotherapy agent. 3
Table S1. Mortality rates before and after Protocol Amendment 4 (increase in the cut-off for the mdic score from 2 to 3) ART 123 Subgroup (N=370) (N=371) Pre protocol amendment 4 Dead n (%) 43 (18%) 51 (21%) Alive n (%) 202 (82%) 197 (79%) Post protocol amendment 4 Dead n (%) 23 (18%) 29 (24%) Alive n (%) 102 (82%) 94 (76%) 4
Table S2. Summary of treatment-emergent adverse events experienced by at least 5% of patients Adverse event ART-123 (N = 371) (N = 370) Total (N = 741) Hypokalemia 71 (19.1%) 74 (20.0%) 145 (19.6%) Anemia 79 (21.3%) 56 (15.1%) 136 (18.4%) Pyrexia 56 (15.1%) 58 (15.7%) 114 (15.4%) Constipation 46 (12.4%) 54 (14.6%) 100 (13.5%) Diarrhea 48 (12.9%) 38 (10.3%) 86 (11.6%) Pleural effusion 38 (10.2%) 39 (10.5%) 77 (10.4%) Insomnia 27 (7.3%) 35 (9.5%) 62 (8.4%) Hypernatremia 37 (10.0%) 24 (6.5%) 61 (8.2%) Hypotension 36 (9.7%) 25 (6.8%) 61 (8.2%) Hypertension 31 (8.4%) 28 (7.6%) 59 (8.0%) Hypoglycemia 25 (6.7%) 29 (7.8%) 54 (7.3%) Thrombocytopenia 30 (8.1%) 22 (5.9%) 52 (7.0%) Atrial fibrillation 34 (9.2%) 17 (4.6%) 51 (6.9%) Hyperglycemia 30 (8.1%) 21 (5.7%) 51 (6.9%) Pneumonia 24 (6.5%) 24 (6.5%) 48 (6.5%) Septic shock 24 (6.5%) 23 (6.2%) 47 (6.3%) Hypophosphatemia 27 (7.3%) 16 (4.3%) 43 (5.8%) Respiratory failure 21 (5.7%) 22 (5.9%) 43 (5.8%) Nausea 28 (7.5%) 14 (3.8%) 42 (5.7%) Agitation 25 (6.7%) 17 (4.6%) 42 (5.7%) Hypomagnesemia 22 (5.9%) 19 (5.1%) 41 (5.5%) Decubitus ulcer 24 (6.5%) 16 (4.3%) 40 (5.4%) Hypoalbuminemia 23 (6.2%) 15 (4.1%) 38 (5.1%) Vomiting 17 (4.6%) 21 (5.7%) 38 (5.1%) 5
Table S3. Summary of adverse events leading to permanent discontinuation in 2 subjects Adverse event ART-123 (N = 371) (N = 370) Total (N = 741) Acute renal failure 4 (1.1%) 6 (1.6%) 10 (1.3%) Multi-organ failure 3 (0.8%) 4 (1.1%) 7 (0.9%) Gastrointestinal hemorrhage 0 6 (1.6%) 6 (0.8%) Septic shock 4 (1.1%) 2 (0.5%) 6 (0.8%) Renal failure 3 (0.8%) 1 (0.3%) 4 (0.5%) Thrombocytopenia 3 (0.8%) 0 3 (0.4%) Myocardial ischemia 2 (0.5%) 0 2 (0.3%) Hepatic failure 1 (0.3%) 1 (0.3%) 2 (0.3%) Brain edema 0 2 (0.5%) 2 (0.3%) Cerebral infarction 0 2 (0.5%) 2 (0.3%) Ischemic stroke 1 (0.3%) 1 (0.3%) 2 (0.3%) 6