The primary objectives of this study are:• To determine whether ART-123, when administered to subjects with infection complicated by at least one organ dysfunction and coagulopathy, can reduce mortality.• To determine the safety of ART-123 in this…
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Brief title
Condition
- Ancillary infectious topics
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Twenty-eight (28) day all-cause mortality is the generally accepted primary
efficacy outcome for sepsis treatments. Because ART-123 acts on the coagulation
pathway, major bleeding events will be considered as a safety endpoint,
together with adverse events and other serious adverse events.
Primary Efficacy Endpoint:
• 28 day all-cause mortality
Secondary outcome
Secondary Efficacy Endpoints:
• Follow-up of all-cause mortality at 3 months
• Resolution of Organ Dysfunction through Day 28 as measured by
o Shock free and alive days
o Ventilator free and alive days
o Dialysis free and alive days
Tertiary Efficacy Endpoints:
• Follow-up of all-cause mortality at 6 and 12 months
• Organ Dysfunction (Hepatic, Renal, Respiratory and Cardiac (Septic Shock) at
Baseline, Day 3, Day 7, Day 14 and Day 28
• ICU free and alive days through Day 28
• Hospitalization free and alive days through Day 28
• INR at Baseline, Day 3, Day 7, Day 14 and Day 28
Safety
Primary Safety Endpoints:
• Serious Adverse Events
• Major Bleeding Events
• Adverse Events
Secondary Safety Endpoint:
• Anti-drug antibodies
Background summary
ART-123 treated subjects with infection and coagulopathy have shown reduced
mortality in a Phase III clinical trial conducted in Japan and a positive trend
of reduced mortality in a Phase IIb clinical trial conducted globally. These
earlier studies used various criteria for DIC to identify coagulopathic
subjects. This DIC based approach was not fully successful in selecting
subjects most likely to respond to ART-123, perhaps because of changes in the
methods of identifying subjects with DIC. These studies did not require organ
dysfunction other than DIC. Analysis of data from the global Phase IIb trial
showed that subjects with cardiac or respiratory organ dysfunctions and
coagulopathy at study entry had better response to treatment than subjects
without these conditions and it was not always feasible to identify the cause
of renal or hepatic dysfunction as sepsis or *other*.
The population for the present study will be limited to subjects with
cardiovascular and/or respiratory dysfunction, plus coagulopathy in addition to
infection characterized by a known site of the infection, fever/hypothermia and
the typical WBC response to infection (leukocytosis, leukopenia, or left
shifted differential count).
Study objective
The primary objectives of this study are:
• To determine whether ART-123, when administered to subjects with infection
complicated by at least one organ dysfunction and coagulopathy, can reduce
mortality.
• To determine the safety of ART-123 in this patient population.
Secondary objectives include:
• Assessment of the efficacy of ART-123 in resolution of organ dysfunction in
this population.
• Assessment of antidrug antibody development in subjects with coagulopathy due
to infection treated with ART-123.
Study design
This is a randomized, double-blind, placebo-controlled, multi-center,
parallel-group study of ART-123 in subjects with coagulopathy due to severe
sepsis and a concurrent diagnosis of shock and/or respiratory dysfunction that
requires mechanical ventilation for hypoxemia. At randomization, subjects who
meet all inclusion criteria and no exclusion criteria will be randomly
assigned, in a 1:1 ratio, to receive ART-123 in a dose of 0.06 mg/kg/day up to
a maximum dose of 6 mg/day or a matching placebo for 6 consecutive days. These
doses will be administered as an intravenous bolus injection or diluted in 50
mL of Normal Saline and infused over the period of 15 minutes. Blood samples
for assessing coagulation and inflammation parameters, ART-123 concentration,
organ dysfunction and safety laboratory tests will be obtained between baseline
assessments and the end of the study procedures. Safety-related assessments
will include reports of adverse events, ECGs and clinical laboratory test
results.
Intervention
At randomization, subjects who meet all inclusion criteria and no exclusion
criteria will be randomly assigned, in a 1:1 ratio, to receive ART-123 in a
dose of 0.06 mg/kg/day up to a maximum dose of 6 mg/day or a matching placebo
for 6 consecutive days. These doses will be administered as an intravenous
bolus injection or diluted in 50 mL of Normal Saline and infused over the
period of 15 minutes.
Study burden and risks
Based on the experience gathered from previous clinical studies, there are two
types of side effects you may experience that are possibly caused by ART-123:
• Bleeding Events:
Because ART-123 changes how your blood clots, bleeding events may occur. Your
doctor will carefully monitor your medical condition with particular attention
to any signs of bleeding, and in case of serious bleeding study drug may be
stopped.
Because bleeding is often caused by your illness (serious blood infection)
even without ART-123, severe bleeding has been observed in approximately 5% of
the patients in a previous clinical trial (5.1% in patients dosed with ART-123
vs 4.6% in patients dosed with dummy medication). You may experience bleeding
from various locations in your body, not only from the skin but also from
organs inside your body and it could be observed in your urine or feces. You
may also experience events caused by the bleeding, such as anemia or bruising.
• Skin symptoms and allergic reactions:
ART-123 is a protein. Drugs made of protein always have a potential risk of
allergic reactions (fever, swelling, sweating and itching) or skin symptoms
(rash and eruption). Such symptoms could be potentially life-threatening or
fatal, and if they occur your doctor will stop study drug and will start
appropriate therapies.
Additionally, the following side effects were reported as possibly caused by
ART-123 in recent studies with illness similar to yours:
Common adverse events below were reported in 1% to 10% of treated subjects:
Anemia, liver lab test abnormal, decrease of platelets in the blood, fever,
irregular heartbeat, low blood electrolytes potassium.
Additionally, side effects seen in less than 1% of subjects in previous studies
include: central nervous problems, problems of the stomach and intestines,
liver problems, problems with food digestion, cardiac (heart) problems,
vascular problems, problems with breathing, urinary system problems and body as
a whole-general problems.
Fifth Avenue 200
Waltham MA 02451 USA
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Waltham MA 02451 USA
NL
Listed location countries
Age
Inclusion criteria
1) Subjects must be receiving treatment in an ICU, or in an acute care
setting (e.g., ER, RR)
2) Subjects with
- clinical objective evidence of bacterial infection and a known site of infection
- currently receiving treatment with antibiotics.
- white Blood Cell WBC count greater than (>) 12,000/mm3 or less than (<) 4,000/mm3 or Bandemia greater than (>) 10%.
- temperature of <36ºC or fever >38ºC.
- core or axillary temperature of temperature of <36ºC or fever >38ºC. For hypothermia a core reading is preferred. ;Note 1: If a subject has a 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 # 2b or 2d 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.
Exclusion criteria
- Presence of an advance directive to withhold life-sustaining treatment (patients not
wishing to receive Cardiopulmonary Resuscitation (CPR) may qualify provided they
receive all other resuscitative measures e.g. mechanical ventilation, vasoactive agents,
cardioversion)
- Body weight >= 175 kg
- 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) within 12 hours prior to the first dose of study drug, 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 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
- A history of congenital bleeding diatheses (e.g. hemophilia)
- Significant gastrointestinal bleeding (e.g., melena, hematemesis) within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e. endoscopy)
- 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 (if evaluation is in progress, this should be completed before consideration for this trial)
e. Any disorder with a requirement for full anticoagulation
- History of cirrhosis or current Class C liver desease (Child-Pugh score of 10-15
- 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.
- Subjects with renal dysfunction defined as:
a. Chronic renal failure requiring renal replacement therapy (RRT), or
b. Subjects with sepsis induced renal dysfunction (average urine output < 0.3 ml/kg/hr) for greater than 36 hours prior to first qualifying INR whether receiving RRT or not.
- Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to consent 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 325mg 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.
- 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 subjects or pulmonary vascular disease resulting in severe exercise restriction (i.e., unable to climb stairs or perform household duties), or chronic restrictive or obstructive pulmonary disease that also results in severe exercise restriction, or documented chronic hypoxia (needs continuous home oxygen treatment), hypercapnia, secondary polycythemia, severe pulmonary hypertension (Mean Arterial Pulmonary pressure level of >40 mmHg) or respiratory dependency
c.Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery, or subject with imminent death
d. End-stage neurological disorders (e.g., amyotrophic lateral sclerosis - Lou Gehrig's disease)
- Current use of any chemotherapy agent likely to cause myeloablation
- Confirmed or suspected endocartis
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002251-42-NL |
| ClinicalTrials.gov | NCT01598831 |
| CCMO | NL41432.099.12 |