E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe sepsis and coagulopathy |
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E.1.1.1 | Medical condition in easily understood language |
severe sepsis and coagulopathy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate whether ART-123, when administered to subjects with bacterial infection complicated by at least one organ dysfunction (septic shock and/or respiratory failure) and coagulopathy, can reduce mortality.
2. To evaluate the safety of ART-123 in this patient population. |
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E.2.2 | Secondary objectives of the trial |
1. Assessment of the efficacy of ART-123 in resolution of organ dysfunction in this population.
2. Assessment of anti-drug antibody development in subjects with coagulopathy due to bacterial infection treated with ART-123. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
This study targets critically ill subjects with severe sepsis requiring the level of care that is normally associated with treatment in an ICU setting. The inclusion criteria for organ dysfunction and coagulopathy must be met within a 24 hour period.
1) Subjects must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR)
2)Subjects with:
a. Clinical objective evidence of bacterial infection and a known site of infection
b. Current treatment with intravenous antibiotics
c. White Blood Cell (WBC) count greater than (>) 12,000/mm3 or less than (<) 4,000/mm3 or Bandemia greater than (>) 10%.
d. Temperature of <36°C or fever >38°C. For hypothermia, a core reading is preferred.
Note 1: If a subject has a Gram stain consistent with bacterial infection, positive culture from blood or an otherwise sterile body fluid, observed peritonitis, positive urinary antigen, clinical presentation of meningococcemia, or otherwise compelling evidence of infection as determined by the CCC, only one of the two inclusion criteria # 2c (WBC) or 2d (temperature) is required.
Note 2: The presence of concurrent fungal or viral infection is allowed for the study entry, provided that the primary reason for treatment is bacterial infection.
3) Subjects with sepsis associated organ dysfunction defined by at least one of the following:
a) Cardiovascular Dysfunction defined as requiring both adequate fluid resuscitation and vasopressors* to maintain Mean Arterial Pressure (MAP) greater than or equal to (>) 65 mmHg (implies fluid resuscitation alone does not raise MAP to ≥ 65 mmHg). Adequate fluid resuscitation is defined as:
o Intravenous administration of at least 20 mL/kg crystalloid or 10 mL/kg colloid infusion within 6 hours.
OR
o Central Venous Pressure (CVP) greater than (>) 8 mmHg or Pulmonary Artery Wedge Pressure (PAWP) greater than (>) 12 mmHg.
* If dopamine is the only vasopressor used, the infusion rate must be greater than (>) 5 µg/kg/min (i.e., must be prescribed to support cardio-pulmonary perfusion). If vasopressin is used, it must be given in conjunction with another vasopressor.
b) Respiratory Dysfunction is defined as the acute need for mechanical ventilation and PaO2/FiO2 ratio of <250 (or < 200 when the lung is the site of infection). For the purposes of this protocol, mechanical ventilation is defined as any type of ventilation administered via an endotracheal tube or nasotracheal intubation. A simple administration of supplemental oxygen is NOT considered to be mechanical ventilation for the purposes of this study.
4)Subjects with coagulopathy characterized by an INR >1.40 without other known etiology (e.g., anticoagulant therapy, chronic liver disease)
5) Subjects with coagulopathy characterized by platelet count in the range of greater than (>) 30,000/mm3 to less than (<) 150,000/mm3 OR a greater than 30% decrease in platelets in 24 hours. |
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E.4 | Principal exclusion criteria |
Candidates for the study will be excluded if ANY of the following criteria are present:
1.Subject or Authorized Representative is unable or unwilling to provide initial or ongoing informed consent
2.Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study
3.Subject is of childbearing potential and has a positive pregnancy test
4.Subject is < 18 years of age
5.Subject has a known allergy to ART-123 or any components of the drug product
6.Subject is unwilling to allow transfusion of blood or blood products
7.Presence of an advance directive to withhold life-sustaining treatment (patients not wishing to receive CPR may qualify provided they receive all other resuscitative measures e.g. MV, vasoactive agents, cardioversion
8.Subject has had previous treatment with ART-123
9.Body weight ≥ 175 kg
10.Platelets < 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis.
11.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 the first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures
12. A history of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent
13.Cerebral Vascular Accident within 3 months prior to consent
14.Any history of Intracerebral AM, cerebral aneurysm, or mass lesions of the central nervous system
15. A history of congenital bleeding diatheses or anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia)
16.Significant gastrointestinal bleeding (e.g., melena, hematemesis) within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e., therapeutic endoscopy)
17.Subject is diagnosed with a known medical condition associated with a hypercoagulable state, including:
a.Resistance to activated protein C or known Factor V Leiden
b.Hereditary deficiency of protein C or protein S
c. Presence of anticardiolipin antibody, antiphospholipid antibody, or prothrombin gene mutation
d.Deep-vein thrombosis or pulmonary embolism within 3 months prior to consent
e. Any disorder with a requirement for full anticoagulation
18.History of cirrhosis or current Class C liver disease (Child-Pugh score of 10-15)
19.Portosystemic hypertension or known history of bleeding esophageal varices
20.History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent (uncomplicated kidney and autologous stem cell/bone marrow transplant subjects may be enrolled at any time after they have recovered from their transplant procedure)
21.Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or gram stain consistent with bacterial infection. Also, in the opinion of the treating physician the subject is at an increased risk for developing hemorrhagic pancreatitis over the duration of the study
22.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.
23.Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first dose of study drug with the exception of:
a.Heparin locks/flushes
b.DVT Prophylaxis per prophylactic dosing on the package insert as approved in your country.
c.Up to 325 mg of aspirin daily for cardiac prophylaxis only
d.Anticoagulants for RRT: Regional citrate is preferred. It is recommended that if unfractionated heparin or LMWH is used, that the systemic exposure be less than or equal to the DVT prophylaxis dose allowed.
24.Life expectancy < 90 days due to underlying conditions such as, but not limited to, the following:
a.Poorly controlled neoplasms
b.New York Heart Association class IV or pulmonary vascular disease resulting in severe exercise restriction or chronic restrictive or obstructive pulmonary disease that also results in severe exercise restriction, or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension or respiratory dependency
c.Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery, or subject with imminent death (in the next few hours)
d.End-stage neurological disorders (e.g., amyotrophic lateral sclerosis - Lou Gehrig's disease)
25.Current use of any chemotherapy agent likely to cause myeloablation
26.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
27.Confirmed or suspected endocarditis |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
Primary Efficacy Endpoint:
• 28 day all-cause mortality
Safety
Primary Safety Endpoints:
• Serious Adverse Events
• Major Bleeding Events
•Adverse Events
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Daily up to 28 days post dose, evaluation for mortality at Day 29
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E.5.2 | Secondary end point(s) |
Efficacy
Secondary Efficacy Endpoints:
Follow-up of all-cause mortality at 3 months
Resolution of organ dysfunction through Day 28 as measured by:
Shock free and alive days
Ventilator free and alive days
Dialysis free and alive days
Safety
Secondary Safety Endpoint:
• Anti-drug antibodies
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Daily for 28 days post dose and at 3 months of post dose |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
Colombia |
Croatia |
Czech Republic |
Finland |
France |
Germany |
Greece |
India |
Israel |
Korea, Republic of |
Netherlands |
New Zealand |
Peru |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |