RecruitingPhase 3ACTRN12607000460404

A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Three-Arm Study to Evaluate the Safety and Efficacy of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) Administration in Subjects with Severe Community-Acquired Pneumonia

Sponsor

Novartis Pharmaceuticals Corporation

Enrollment

2,100 participants

Start Date

Jul 1, 2004

Study Type

Interventional

Conditions

Severe Community-Acquired Pneumonia

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria38

Individuals eligible for enrollment must meet the following criteria:
Adults age 18 years old and older;
A clinical diagnosis of community-acquired pneumonia supported by the following evidence documented or obtained within 24 hours preceding hospital admission through 24 hours following hospital admission (Note: clinical signs may be present for > 24 hours preceding hospital admission, but need to be documented within the time frame specified above):
Clinical Signs (at least two of the following):
i. Fever (>= 38°C) or unexplained hypothermia (<= 36°C);
ii. Tachypnea (>= 20 breaths/min or PaCO2 < 32 mmHg [<4.2 kPa]);
iii. Leukocytosis (white blood cells [WBC] >= 12 x 10*9/L), > 10% immature
polymorphonuclear leukocytes (bands), or relative leukopenia (WBC <= 4 x 10*9/L) not due to other causes
iv. Hypoxemia (PaO2/FiO2 < 285 or SaO2 < 90%).
Radiographic Findings
New pulmonary infiltrate(s) consistent with the diagnosis of CAP
Microbiological Criteria
Appropriate specimens for microbiological documentation of CAP must be collected
as part of the screening procedures, but results are not required to determine
eligibility.
Pneumonia of sufficient severity to require ICU admission and management and meets one major or two minor severity criteria:
a. Major Criteria: one of the following:
i. Receiving mechanical ventilatory support (i.e., invasive mechanical ventilation);
ii. Receiving treatment with vasopressors at therapeutic doses (i.e.dopamine > 5 µg/kg/min. or any dose of epinephrine, norepinephrine, phenylephrine or vasopressin) for at least 2 hours to maintain or attempt to maintain systolic blood pressure (SBP) > 90 mm Hg (or mean arterial pressure (MAP) > 70 mm Hg) despite adequate fluid resuscitation.
OR
b. Minor Criteria: two of the following criteria documented within the previous 24
hours in subjects without evidence of rapid clinical improvement:
i. Systolic blood pressure < 90 mm Hg or MAP < 70 mm Hg and received >= 40 mL/kg of fluid resuscitation over a 6 hour period or vasopressors at therapeutic doses (see above) for at least 2 hours to maintain a SBP >= 90 mm Hg or a MAP >= 70 mm Hg;
ii. PaO2/FiO2 ratio < 250 or a respiratory rate >= 30/min or the need for noninvasive mechanical ventilatory support;
iii. Blood urea nitrogen (BUN) > 7.0 mM (> 19.6 mg/dL);
iv. New onset mental confusion (must be documented prior to the use of sedative or other new psychotropic medication);
v. Multi-lobar pneumonia;
vi. Platelet count < 100,000 cells/mm3 or a fall of > 25% during the previous 48 hours to a count of < 120,000 cells/mm3;
vii. Leukopenia (WBC <= 4 x 10*9/L);
viii. Hypothermia (core temperature <= 36°C).
Ability to initiate treatment as soon as all entry criteria have been met, and no later than 36 hours of ICU admission and within 72 hours of hospitalization (time of
hospitalization is the time of initial presentation to the emergency department,
hospital ward admission or admission to a transferring medical facility, whichever is
earliest).
Informed consent.
The investigator has ruled out to the best of his ability any infectious or non-infectious
condition that may mimic severe CAP (e.g., Congestive Heart Failure [CHF], Pulmonary
Embolism [PE]).

Exclusion Criteria52

Individuals who meet any of the following criteria are not eligible to be enrolled in the
study:
Pregnancy (confirmed by urine or serum test);
Weight > 150 kg;
Prior hospitalization within 14 days of current hospital admission;
Non-ambulatory resident of a long-term care facility;
Requires long-term mechanical ventilation;
Known or suspected aspiration pneumonitis;
Postobstructive pneumonia;
History of bone marrow transplantation or solid organ transplantation requiring
ongoing immunosuppressive therapy (subjects with stable renal transplantations
may be enrolled) or with evidence of acute or chronic transplant rejection;
Current diagnosis of acute leukemia, multiple myeloma, non-Hodgkin’s
lymphoma or Hodgkin's disease;
Severe neutropenia (absolute neutrophil count < 1,000 cells/mm3 due to causes other than CAP);
Significant liver disease (Child-Pugh Grade C or known esophageal varices);
Known or suspected helper/inducer T-lymphocytes (CD4+) count < 200, or a
CD4+ T-lymphocyte percentage of total lymphocytes of < 14%;
Known or suspected infective endocarditis;
Cardio-pulmonary arrest within 72 hours pre-infusion;
Platelet count < 60,000 cells/mm3 ;
International normalized ratio (INR) > 3 within 4 hours prior to the start of study
drug infusion
Major surgery <=12 hours prior to anticipated start of study drug infusion;
History of intracranial bleeding within six months or closed head trauma or stroke
within one month or other neurological condition with increased bleeding risk;
Uncontrolled hemorrhage;
Lumbar puncture or epidural catheterization within 12 hours of anticipated study drug dosing;
Treatment with drotrecogin alfa within 24 hours prior to, or anticipated need for
drotrecogin alfa within 24 hours after the start of study drug infusion;
Treatment within 24 hours prior to the anticipated start of study drug infusion
with Antithrombin III (AT-III), other systemic anticoagulants, antiplatelet drugs
(excluding aspirin up to 325 mg/day), or thrombolytics (e.g., tissue plasminogen
activator [TPA]). Thrombolytics may be used for clotted ports/lines, provided
that they are not given systemically. Citrate anticoagulation for dialysis and
hemofiltration is acceptable;
Treatment with low molecular weight heparin within 18 hours or unfractionated
heparin within 10 hours prior to the anticipated start of study drug infusion or
anticipated need (within 96 hours) for treatment with unfractionated heparin or
low molecular weight heparin. Subjects may be enrolled if heparin flushes [500
IU of unfractionated heparin or equivalent to flush intravascular catheters] were
used to maintain catheter patency prior to study entry. The use of heparin to flush
intravascular catheters is prohibited during the 96-hour infusion period. However,
arterial lines may be heparinized, with the total amount per 24 hours not expected
to be above 250 IU/24h;
For subjects requiring deep venous thrombosis prophylaxis, the inability to utilize non-pharmacological methods;
Receipt of an investigational new drug within 30 days prior to study enrollment;
Known hypersensitivity to tifacogin, other E. coli-derived proteins or any
ingredient in the final drug product;
Presence of an underlying disease/injury which is clearly irreversible and is anticipated to be rapidly fatal within 3 months or a moribund state with expected survival < 24 hours;
Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any required drug/fluid therapy at time of consent. Refusal of chest compression is
acceptable.

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Interventions

In addition to standard therapy, subjects meeting all study entry criteria will be randomized to receive low dose tifacogin (0.025 mg/kg/h), high dose tifacogin (0.075 mg/kg/h) or placebo, administered as a continuous intravenous infusion (CIV) during the 96-hour dosing period. Dose adjustments may be allowed during the infusion period.

Locations(16)

New Zealand

Argentina

Belgium

Brazil

Canada

Chile

France

Netherlands

Malaysia

Germany

Peru

Singapore

South Africa

Korea, Republic Of

Spain

United Kingdom

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ACTRN12607000460404