Coagulopathy, Severe Sepsis
Conditions
Keywords
sepsis
Brief summary
The purpose of the study is to evaluate if ART-123 given to patients who have severe sepsis can decrease mortality.
Detailed description
Study is to evaluate if ART-123 given to patients who have severe sepsis complicated by at least one organ dysfunction and coagulopathy can decrease mortality.
Interventions
DRUGART-123
Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
DRUGPlacebo
Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days.
Sponsors
Asahi Kasei Pharma America Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR) * Clinical objective evidence of bacterial infection and a known site of infection. * Cardiovascular dysfunction or Respiratory Failure due to sepsis. * Coagulopathy characterized by an INR \>1.40 without other known causes.
Exclusion criteria
* Subject or Authorized Representative is unable to provide informed consent. * Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study. * Subject is of childbearing potential and does not have a negative pregnancy test. * Subject is \< 18 years of age. * Subject has a known allergy to ART-123 or any components of the drug product. * Subject is unwilling to allow transfusion of blood or blood products. * Subject has an advance directive to withhold life-sustaining treatment. * Subject has had previous treatment with ART-123. * Body weight ≥ 175 kg. * Platelets \< 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis. * Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or non-traumatic orthopedic surgery of the femur or pelvis) that is completed within 12 hours prior to first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures * History of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent. * Cerebral Vascular Accident (CVA) within 3 months prior to consent. * Any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system. * History of congenital bleeding diathesesor anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia). * Significant gastrointestinal bleeding within 6 weeks prior to consent. * Subject is diagnosed with a known medical condition associated with a hypercoagulable state. * Child-Pugh score of 10-15 (Class C) * Portosystemic hypertension or known history of bleeding esophageal varices. * History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent. * Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or gram stain consistent with bacterial infection. * Subjects with renal dysfunction defined as (a) Chronic renal failure requiring renal replacement therapy (RRT), or (b) Acute renal failure with onset of oliguria (urine output \< 0.3 ml/kg/hr) \> 48 hours prior to first dose of study drug whether receiving RRT or not * Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug. * Life expectancy \< 90 days. * Current use of any chemotherapy agent likely to cause myeloablation (severe or complete depletion of bone marrow). * Participation in another research study involving an investigational agent within 30 days prior to consent or projected study participation during the 28 days post study randomization. * Confirmed or suspected endocarditis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 28-Day All-cause Mortality | 28 days | 28-Day All-cause Mortality |
| Number of Participants With On-Treatment Serious Major Bleeding Events | Through Study Day 28 | On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Follow up All-cause Mortality at 3 Months | 3 months | Follow up all-cause mortality at 3 months |
| Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | 28 days | Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days. |
| Number of Participants With Anti-drug Antibodies | 18 months | Presence of Anti-drug antibodies up to 18 months |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, India, Israel, Netherlands, New Zealand, Peru, Russia, Serbia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 319 sites in 27 countries; of these, 159 study sites (in 26 countries) assigned participants to study drug treatment. First participant was randomized on Oct 29, 2012 and the last participant was randomized on Mar 8, 2018. Last participant completed long term follow-up (survival only) on Feb 28, 2019.
Pre-assignment details
Of 946 consented participants, 816 randomized to study treatment, 800 received at least 1 dose of study treatment.
Participants by arm
| Arm | Count |
|---|---|
| ART-123 ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days | 395 |
| Placebo Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days | 405 |
| Total | 800 |
Baseline characteristics
| Characteristic | Placebo | Total | ART-123 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 174 Participants | 338 Participants | 164 Participants |
| Age, Categorical Between 18 and 65 years | 231 Participants | 462 Participants | 231 Participants |
| Age, Continuous | 60.5 years STANDARD_DEVIATION 15.94 | 60.7 years STANDARD_DEVIATION 15.89 | 61.0 years STANDARD_DEVIATION 15.87 |
| APACHE II (mean, SD) | 22.10 Total Score STANDARD_DEVIATION 8.025 | 22.22 Total Score STANDARD_DEVIATION 8.043 | 22.34 Total Score STANDARD_DEVIATION 8.071 |
| Arterial Lactate >55mg/dl (mean, SD) | 52 Participants | 105 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 42 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 285 Participants | 575 Participants | 290 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 98 Participants | 183 Participants | 85 Participants |
| Height | 168.02 cm STANDARD_DEVIATION 9.619 | 167.71 cm STANDARD_DEVIATION 9.19 | 167.39 cm STANDARD_DEVIATION 8.729 |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 58 Participants | 114 Participants | 56 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 34 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 16 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 308 Participants | 620 Participants | 312 Participants |
| Region of Enrollment Argentina | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Australia | 19 Participants | 38 Participants | 19 Participants |
| Region of Enrollment Belgium | 34 Participants | 68 Participants | 34 Participants |
| Region of Enrollment Brazil | 8 Participants | 19 Participants | 11 Participants |
| Region of Enrollment Bulgaria | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Canada | 24 Participants | 46 Participants | 22 Participants |
| Region of Enrollment Colombia | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Croatia | 5 Participants | 11 Participants | 6 Participants |
| Region of Enrollment Czechia | 11 Participants | 21 Participants | 10 Participants |
| Region of Enrollment Finland | 19 Participants | 37 Participants | 18 Participants |
| Region of Enrollment France | 74 Participants | 149 Participants | 75 Participants |
| Region of Enrollment Germany | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Greece | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Hungary | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment India | 44 Participants | 85 Participants | 41 Participants |
| Region of Enrollment Israel | 10 Participants | 19 Participants | 9 Participants |
| Region of Enrollment Netherlands | 27 Participants | 49 Participants | 22 Participants |
| Region of Enrollment New Zealand | 5 Participants | 11 Participants | 6 Participants |
| Region of Enrollment Peru | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Russia | 57 Participants | 111 Participants | 54 Participants |
| Region of Enrollment Serbia | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment South Korea | 2 Participants | 6 Participants | 4 Participants |
| Region of Enrollment Spain | 11 Participants | 20 Participants | 9 Participants |
| Region of Enrollment Taiwan | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment United States | 37 Participants | 71 Participants | 34 Participants |
| Sex: Female, Male Female | 184 Participants | 363 Participants | 179 Participants |
| Sex: Female, Male Male | 221 Participants | 437 Participants | 216 Participants |
| Weight | 75.74 kg STANDARD_DEVIATION 19.266 | 75.38 kg STANDARD_DEVIATION 19.191 | 75.01 kg STANDARD_DEVIATION 19.131 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 141 / 395 | 148 / 405 |
| other Total, other adverse events | 271 / 396 | 264 / 404 |
| serious Total, serious adverse events | 206 / 396 | 202 / 404 |
Outcome results
Primary
Number of Participants With 28-Day All-cause Mortality
28-Day All-cause Mortality
Time frame: 28 days
Population: Full Analysis Set - All randomized and dosed subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ART-123 | Number of Participants With 28-Day All-cause Mortality | 106 Participants |
| Placebo | Number of Participants With 28-Day All-cause Mortality | 119 Participants |
p-value: 0.31895% CI: [-3.68, 8.77]Cochran-Mantel-Haenszel
Primary
Number of Participants With On-Treatment Serious Major Bleeding Events
On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.)
Time frame: Through Study Day 28
Population: Safety population: all subjects who received at least 1 dose of study drug (analyzed according to study drug received; any subjects receiving both ART-123 and placebo were to be included in the ART-123 group)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ART-123 | Number of Participants With On-Treatment Serious Major Bleeding Events | 23 Participants |
| Placebo | Number of Participants With On-Treatment Serious Major Bleeding Events | 16 Participants |
Secondary
Follow up All-cause Mortality at 3 Months
Follow up all-cause mortality at 3 months
Time frame: 3 months
Population: Full Analysis Set - All randomized and dosed subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ART-123 | Follow up All-cause Mortality at 3 Months | 126 Participants |
| Placebo | Follow up All-cause Mortality at 3 Months | 136 Participants |
Secondary
Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction
Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days.
Time frame: 28 days
Population: Full Analysis Set - All randomized and dosed subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ART-123 | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Shock-free and alive | 17.6 Days | Standard Deviation 10.5 |
| ART-123 | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Ventilation-free and alive | 15.8 Days | Standard Deviation 11.75 |
| ART-123 | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Dialysis-free and alive | 20.2 Days | Standard Deviation 11.05 |
| Placebo | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Shock-free and alive | 17.6 Days | Standard Deviation 10.56 |
| Placebo | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Ventilation-free and alive | 14.5 Days | Standard Deviation 11.9 |
| Placebo | Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Dialysis-free and alive | 19.6 Days | Standard Deviation 11.21 |
Secondary
Number of Participants With Anti-drug Antibodies
Presence of Anti-drug antibodies up to 18 months
Time frame: 18 months
Population: Safety population: all subjects who received at least 1 dose of study drug (analyzed according to study drug received; any subjects receiving both ART-123 and placebo were to be included in the ART-123 group)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ART-123 | Number of Participants With Anti-drug Antibodies | 0 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies | 0 Participants |
Post Hoc
Day 28 Mortality in Subjects With INR > 1.4 at Baseline and PLT > 30K at Baseline
Post-Hoc analysis of Day 28 Mortality in Subjects with INR \> 1.4 at Baseline and PLT \> 30K at Baseline
Time frame: Day 28
Population: Full Analysis Set - All randomized and dosed subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ART-123 | Day 28 Mortality in Subjects With INR > 1.4 at Baseline and PLT > 30K at Baseline | 82 Participants |
| Placebo | Day 28 Mortality in Subjects With INR > 1.4 at Baseline and PLT > 30K at Baseline | 105 Participants |