Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000460404
Ethics application status
Approved
Date submitted
28/08/2007
Date registered
11/09/2007
Date last updated
11/09/2007
Type of registration
Retrospectively registered

Titles & IDs
Public title
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
Scientific title
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
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Community-Acquired Pneumonia 2234 0
Condition category
Condition code
Respiratory 2331 2331 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 1952 0
Treatment: Drugs
Comparator / control treatment
Placebo - saline solution
Control group
Placebo

Outcomes
Primary outcome [1] 3226 0
To compare the effect of tifacogin versus placebo administration on 28-day all-cause
mortality in subjects with severe community-acquired pneumonia (CAP).

To compare the effect of tifacogin administered at a dose of 0.025 mg/kg/h and/or 0.075 mg/kg/h on 28-day all-cause mortality in subjects with severe CAP.
Timepoint [1] 3226 0
Monitored/measured daily for 28 days
Secondary outcome [1] 5385 0
To evaluate the effect of tifacogin administration on the incidence of treatment failure
defined as 28-day all-cause mortality or the administration of drotrecogin alfa within
10 days of initiating study drug infusion.
Timepoint [1] 5385 0
28-days/ 10-days

Eligibility
Key inclusion criteria
Individuals eligible for enrollment must meet the following criteria:
1. Adults age 18 years old and older;
2. 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.
3. 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).
4. 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).
5. 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]).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Individuals who meet any of the following criteria are not eligible to be enrolled in the
study:
1. Pregnancy (confirmed by urine or serum test);
2. Weight > 150 kg;
3. Prior hospitalization within 14 days of current hospital admission;
4. Non-ambulatory resident of a long-term care facility;
5. Requires long-term mechanical ventilation;
6. Known or suspected aspiration pneumonitis;
7. Postobstructive pneumonia;
8. 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;
9. Current diagnosis of acute leukemia, multiple myeloma, non-Hodgkin’s
lymphoma or Hodgkin's disease;
10. Severe neutropenia (absolute neutrophil count < 1,000 cells/mm3 due to causes other than CAP);
11. Significant liver disease (Child-Pugh Grade C or known esophageal varices);
12. Known or suspected helper/inducer T-lymphocytes (CD4+) count < 200, or a
CD4+ T-lymphocyte percentage of total lymphocytes of < 14%;
13. Known or suspected infective endocarditis;
14. Cardio-pulmonary arrest within 72 hours pre-infusion;
15. Platelet count < 60,000 cells/mm3 ;
16. International normalized ratio (INR) > 3 within 4 hours prior to the start of study
drug infusion
17. Major surgery <=12 hours prior to anticipated start of study drug infusion;
18. History of intracranial bleeding within six months or closed head trauma or stroke
within one month or other neurological condition with increased bleeding risk;
19. Uncontrolled hemorrhage;
20. Lumbar puncture or epidural catheterization within 12 hours of anticipated study drug dosing;
21. 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;
22. 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;
23. 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;
24. For subjects requiring deep venous thrombosis prophylaxis, the inability to utilize non-pharmacological methods;
25. Receipt of an investigational new drug within 30 days prior to study enrollment;
26. Known hypersensitivity to tifacogin, other E. coli-derived proteins or any
ingredient in the final drug product;
27. 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;
28. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any required drug/fluid therapy at time of consent. Refusal of chest compression is
acceptable.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
After a potential patient has been identified and appears to meet all study entry criteria, the investigator will contact the study Clinical Coordination Center. All pertinent subject information will be reviewed and, if the subject is determined to satisfy all entry criteria, the CCC will approve the accrual of the subject. This site will then access the Interactive Voice Response System (IVRS) for subject randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be randomly assigned to receive tifacogin 0.025 mg/kg/h, 0.075 mg/kg/h or placebo in an equal allocation ratio. The method of sequence generation is simple randomisation by using a randomisation table created by a computer software (i.e., computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2004
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
2100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 532 0
New Zealand
State/province [1] 532 0
Country [2] 533 0
Argentina
State/province [2] 533 0
Country [3] 534 0
Belgium
State/province [3] 534 0
Country [4] 535 0
Brazil
State/province [4] 535 0
Country [5] 536 0
Canada
State/province [5] 536 0
Country [6] 537 0
Chile
State/province [6] 537 0
Country [7] 538 0
France
State/province [7] 538 0
Country [8] 539 0
Netherlands
State/province [8] 539 0
Country [9] 540 0
Malaysia
State/province [9] 540 0
Country [10] 541 0
Germany
State/province [10] 541 0
Country [11] 542 0
Peru
State/province [11] 542 0
Country [12] 543 0
Singapore
State/province [12] 543 0
Country [13] 544 0
South Africa
State/province [13] 544 0
Country [14] 545 0
Korea, Republic Of
State/province [14] 545 0
Country [15] 546 0
Spain
State/province [15] 546 0
Country [16] 547 0
United Kingdom
State/province [16] 547 0

Funding & Sponsors
Funding source category [1] 2462 0
Commercial sector/Industry
Name [1] 2462 0
Novartis Pharmaceuticals Corporation
Country [1] 2462 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals Corporation
Address
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936-1080
Country
United States of America
Secondary sponsor category [1] 2237 0
Commercial sector/Industry
Name [1] 2237 0
PRA International
Address [1] 2237 0
Suite 1701, 323 Castlereagh Street
Sydney NSW 2000
Country [1] 2237 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4331 0
Royal Melbourne Hospital
Ethics committee address [1] 4331 0
Ethics committee country [1] 4331 0
Australia
Date submitted for ethics approval [1] 4331 0
Approval date [1] 4331 0
Ethics approval number [1] 4331 0
Ethics committee name [2] 4332 0
Western Hospital
Ethics committee address [2] 4332 0
Ethics committee country [2] 4332 0
Australia
Date submitted for ethics approval [2] 4332 0
Approval date [2] 4332 0
Ethics approval number [2] 4332 0
Ethics committee name [3] 4333 0
Box Hill Hospital
Ethics committee address [3] 4333 0
Ethics committee country [3] 4333 0
Australia
Date submitted for ethics approval [3] 4333 0
Approval date [3] 4333 0
Ethics approval number [3] 4333 0
Ethics committee name [4] 4334 0
Austin Hospital
Ethics committee address [4] 4334 0
Ethics committee country [4] 4334 0
Australia
Date submitted for ethics approval [4] 4334 0
Approval date [4] 4334 0
Ethics approval number [4] 4334 0
Ethics committee name [5] 4335 0
The Alfred Hospital
Ethics committee address [5] 4335 0
Ethics committee country [5] 4335 0
Australia
Date submitted for ethics approval [5] 4335 0
Approval date [5] 4335 0
Ethics approval number [5] 4335 0
Ethics committee name [6] 4336 0
Royal Hobart Hospital
Ethics committee address [6] 4336 0
Ethics committee country [6] 4336 0
Australia
Date submitted for ethics approval [6] 4336 0
Approval date [6] 4336 0
Ethics approval number [6] 4336 0
Ethics committee name [7] 4337 0
Launceston General Hospital
Ethics committee address [7] 4337 0
Ethics committee country [7] 4337 0
Australia
Date submitted for ethics approval [7] 4337 0
Approval date [7] 4337 0
Ethics approval number [7] 4337 0
Ethics committee name [8] 4338 0
Nepean Hospital
Ethics committee address [8] 4338 0
Ethics committee country [8] 4338 0
Australia
Date submitted for ethics approval [8] 4338 0
Approval date [8] 4338 0
Ethics approval number [8] 4338 0
Ethics committee name [9] 4339 0
Royal Prince Alfred Hospital
Ethics committee address [9] 4339 0
Ethics committee country [9] 4339 0
Australia
Date submitted for ethics approval [9] 4339 0
Approval date [9] 4339 0
Ethics approval number [9] 4339 0
Ethics committee name [10] 4340 0
Gold Coast Hospital
Ethics committee address [10] 4340 0
Ethics committee country [10] 4340 0
Australia
Date submitted for ethics approval [10] 4340 0
Approval date [10] 4340 0
Ethics approval number [10] 4340 0
Ethics committee name [11] 4341 0
Nambour General Hospital
Ethics committee address [11] 4341 0
Ethics committee country [11] 4341 0
Australia
Date submitted for ethics approval [11] 4341 0
Approval date [11] 4341 0
Ethics approval number [11] 4341 0
Ethics committee name [12] 4342 0
The Queen Elizabeth Hospital
Ethics committee address [12] 4342 0
Ethics committee country [12] 4342 0
Australia
Date submitted for ethics approval [12] 4342 0
Approval date [12] 4342 0
Ethics approval number [12] 4342 0
Ethics committee name [13] 4343 0
The Canberra Hospital
Ethics committee address [13] 4343 0
Ethics committee country [13] 4343 0
Australia
Date submitted for ethics approval [13] 4343 0
Approval date [13] 4343 0
Ethics approval number [13] 4343 0
Ethics committee name [14] 4344 0
Royal Perth Hospital
Ethics committee address [14] 4344 0
Ethics committee country [14] 4344 0
Australia
Date submitted for ethics approval [14] 4344 0
Approval date [14] 4344 0
Ethics approval number [14] 4344 0
Ethics committee name [15] 4345 0
Sir Charles Gairdner Hospital
Ethics committee address [15] 4345 0
Ethics committee country [15] 4345 0
Australia
Date submitted for ethics approval [15] 4345 0
Approval date [15] 4345 0
Ethics approval number [15] 4345 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 27733 0
Address 27733 0
Country 27733 0
Phone 27733 0
Fax 27733 0
Email 27733 0
Contact person for public queries
Name 11108 0
A/Prof David Ernest
Address 11108 0
Box Hill Hospital
Intensive Care Unit
Nelson Road
Box Hill VIC 3128
Country 11108 0
Australia
Phone 11108 0
+61(0)3 9895 3149
Fax 11108 0
+61(0)3 9895 4808
Email 11108 0
[email protected]
Contact person for scientific queries
Name 2036 0
A/Prof David Ernest
Address 2036 0
Box Hill Hospital
Intensive Care Unit
Nelson Road
Box Hill VIC 3128
Country 2036 0
Australia
Phone 2036 0
+61(0)3 9895 3149
Fax 2036 0
+61(0)3 9895 4808
Email 2036 0
[email protected]

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