Acquired Bleeding Disorder, Trauma
Conditions
Brief summary
This trial is conducted globally. The purpose of the trial is to evaluate that activated recombinant human factor VII (eptacog alfa (activated)) is safe and effective in severely injured trauma patients by assessing mortality and morbidity. Please note that this trial and trial F7TRAUMA-1648 (NCT00323570) have been merged.
Detailed description
The decision to discontinue the F7TRAUMA-1711 trial is not due to any safety concerns. The result of the pre-planned futility analysis performed in June 2008 predicted a very low likelihood of reaching a successful outcome on the primary efficacy endpoint at the end of the trial and as a consequence, the company has decided to close the trial as this juncture.
Interventions
DRUGeptacog alfa (activated)
Sterile, freeze-dried powder in single-use vials to be reconstituted with sterile water for injection. Three doses of 200, 100 and 100 mcg/kg to be administered bolus i.v. (intravenous) over approx. three hours.
DRUGplacebo
placebo
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Trauma injury (blunt and/or penetrating) with evidence of active hemorrhage (torso and/or proximal lower extremity) refractory to blood component therapy and surgical haemostatic procedures at the time of randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | from day 0 to 30 | Number of participants to die from day 0 to day 30 from all causes. |
| Morbidity | from day 0 to day 30 | Morbidity reflects the number of patients who had pulmonary and/or renal dysfunction requiring ongoing medical intervention on day 30. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Units of Transfused Red Blood Cells From Time of First Dose | from hour 0 to 24 | The number of units of transfused red blood cells in the first 24 hours from the time of the first dose of rFVIIa or placebo. |
| Number of Days Alive and Free of Pulmonary and/or Renal Dysfunction Requiring Medical Intervention | from day 0 to day 30 | The number of days alive and free of pulmonary and/or renal dysfunction requiring medical intervention from day 0 to day 30. |
| Number of Units of All Allogeneic Transfusions From Time of First Dose | from hour 0 to 24 | The number of units of all allogeneic transfusions in the first 24 hours from the time of the first dose of rFVIIa or placebo. |
| Number of Patients Receiving 10 Units or More (Massive Transfusion) of Red Blood Cells From Time of Injury | from hour 0 to 24 | The number of patients receiving 10 units or more of red blood cells in the first 24 hours from the time of injury. |
| Time to Death From Time of First Dose | from day 0 to day 30 | The time of first dose refers to the time of the first dose of rFVIIa or placebo. |
Countries
Brazil, Czechia, France, Germany, Greece, Hong Kong, Hungary, Italy, Netherlands, South Africa, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
150 trial sites globally.
Pre-assignment details
Eligible subjects were those with either blunt and/or penetrating trauma injuries and confirmed clinical indicators for active haemorrhage refractory to standard treatment (including blood component therapy and surgical haemostatic procedures).
Participants by arm
| Arm | Count |
|---|---|
| rFVIIa, Blunt Trauma | 221 |
| Placebo, Blunt Trauma | 247 |
| rFVIIa, Penetrating Trauma | 46 |
| Placebo, Penetrating Trauma | 40 |
| Total | 554 |
Baseline characteristics
| Characteristic | rFVIIa, Blunt Trauma | Placebo, Blunt Trauma | rFVIIa, Penetrating Trauma | Placebo, Penetrating Trauma | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 14.4 | 39.9 years STANDARD_DEVIATION 14.2 | 33.8 years STANDARD_DEVIATION 11.9 | 29.4 years STANDARD_DEVIATION 10.3 | 38.4 years STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 59 Participants | 65 Participants | 3 Participants | 3 Participants | 130 Participants |
| Sex: Female, Male Male | 162 Participants | 182 Participants | 43 Participants | 37 Participants | 424 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 108 / 224 | 125 / 250 | 26 / 46 | 24 / 40 |
| serious Total, serious adverse events | 147 / 224 | 177 / 250 | 18 / 46 | 20 / 40 |
Outcome results
Primary
Morbidity
Morbidity reflects the number of patients who had pulmonary and/or renal dysfunction requiring ongoing medical intervention on day 30.
Time frame: from day 0 to day 30
Population: Blunt trauma patient population: According to protocol, morbidity is not part of the primary endpoint since non-inferiority test of mortality was not passed. Penetrating Trauma patient population: No analysis done due to low statistical power.
Primary
Mortality
Number of participants to die from day 0 to day 30 from all causes.
Time frame: from day 0 to 30
Population: Blunt trauma patient population: Intention-to-treat (ITT) analysis set. Patients who discontinued (withdrawn or lost to follow up) before day 30 were excluded from analyses. Penetrating Trauma patient population: No analysis done due to low statistical power.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIIa, Blunt Trauma | Mortality | 24 Participants |
| Placebo, Blunt Trauma | Mortality | 26 Participants |
Comparison: Test for Odds ratio=1, corresponding to a null hypothesis of no difference in mortality for patients who died between groups for Blunt Trauma. Odds-ratio is adjusted for baseline covariates: Age, Injury Severity Score (ISS), Glasgow Coma -Scale Score (GCS), International Normalized Ratio (INR) and acute lung injury (P/F \> 200). Missing covariates are imputed by the mean value.p-value: 0.934Regression, Logistic
Comparison: Treatment groups are compared using a Cox Proportional Hazards model with treatment as factor and adjusting for age, Injury Severity Score (ISS), Glasgow Coma -Scale Score(GCS), International Normalized Ratio (INR) and acute lung injury.p-value: 0.58995% CI: [0.64, 2.17]Cox Proportional Hazards Model
Secondary
Number of Days Alive and Free of Pulmonary and/or Renal Dysfunction Requiring Medical Intervention
The number of days alive and free of pulmonary and/or renal dysfunction requiring medical intervention from day 0 to day 30.
Time frame: from day 0 to day 30
Population: Blunt trauma patient population: Intention-to-treat (ITT) analysis set. Penetrating Trauma patient population: No analysis done due to low statistical power.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIIa, Blunt Trauma | Number of Days Alive and Free of Pulmonary and/or Renal Dysfunction Requiring Medical Intervention | 17.2 Days | Standard Deviation 10.3 |
| Placebo, Blunt Trauma | Number of Days Alive and Free of Pulmonary and/or Renal Dysfunction Requiring Medical Intervention | 16.4 Days | Standard Deviation 10.3 |
Comparison: Baseline covariates: Age, Injury Severity Score (ISS), Glasgow Coma -Scale Score (GCS), International Normalized Ratio (INR) and acute lung injury.p-value: 0.30895% CI: [-0.83, 2.63]ANCOVA
Secondary
Number of Patients Receiving 10 Units or More (Massive Transfusion) of Red Blood Cells From Time of Injury
The number of patients receiving 10 units or more of red blood cells in the first 24 hours from the time of injury.
Time frame: from hour 0 to 24
Population: Blunt trauma patient population: Intention-to-treat (ITT) analysis set including patients who discontinued before day 30. Penetrating Trauma patient population: No analysis done due to low statistical power.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIIa, Blunt Trauma | Number of Patients Receiving 10 Units or More (Massive Transfusion) of Red Blood Cells From Time of Injury | 111 Participants |
| Placebo, Blunt Trauma | Number of Patients Receiving 10 Units or More (Massive Transfusion) of Red Blood Cells From Time of Injury | 134 Participants |
p-value: 0.38495% CI: [0.817, 1.69]Regression, Logistic
Secondary
Number of Units of All Allogeneic Transfusions From Time of First Dose
The number of units of all allogeneic transfusions in the first 24 hours from the time of the first dose of rFVIIa or placebo.
Time frame: from hour 0 to 24
Population: Blunt trauma patient population: Intention-to-treat (ITT) analysis set, including patients who discontinued before day 30. Penetrating Trauma patient population: No analysis done due to low statistical power.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIIa, Blunt Trauma | Number of Units of All Allogeneic Transfusions From Time of First Dose | 17.1 Units of allogeneic transfusions | Standard Deviation 26.8 |
| Placebo, Blunt Trauma | Number of Units of All Allogeneic Transfusions From Time of First Dose | 20.7 Units of allogeneic transfusions | Standard Deviation 25.7 |
p-value: 0.0395% CI: [0, 4]Wilcoxon (Mann-Whitney)
Secondary
Number of Units of Transfused Red Blood Cells From Time of First Dose
The number of units of transfused red blood cells in the first 24 hours from the time of the first dose of rFVIIa or placebo.
Time frame: from hour 0 to 24
Population: Blunt trauma patient population: Intention-to-treat (ITT) analysis set including patients who discontinued before day 30. Penetrating Trauma patient population: No analysis done due to low statistical power.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIIa, Blunt Trauma | Number of Units of Transfused Red Blood Cells From Time of First Dose | 6.9 Units of transfused red blood cells | Standard Deviation 10.4 |
| Placebo, Blunt Trauma | Number of Units of Transfused Red Blood Cells From Time of First Dose | 8.1 Units of transfused red blood cells | Standard Deviation 10.9 |
p-value: 0.03895% CI: [0, 2]Wilcoxon (Mann-Whitney)
Secondary
Time to Death From Time of First Dose
The time of first dose refers to the time of the first dose of rFVIIa or placebo.
Time frame: from day 0 to day 30
Population: There is no measure summary for time to event type of endpoint as this would be a Kaplan-Meier graph.