Acute Major Bleeding, Blood Coagulation Disorders
Conditions
Keywords
Anticoagulant reversal, Prothrombin, Complex, Concentrate, Coagulopathy, induced by, coumarin, derivatives, Kcentra
Brief summary
The purpose of this study is to evaluate efficacy, safety and tolerance of BERIPLEX® P/N (Kcentra) compared with plasma in regard to rapid reversal of coagulopathy induced by coumarin derivatives in subjects who require immediate correction of INR (International Normalized Ratio)and to stop an acute major bleeding.
Interventions
BIOLOGICALBeriplex® P/N (Kcentra)
Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body weight
BIOLOGICALFresh frozen plasma
Intravenous Infusion, dosage depending on baseline INR and body weight
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female subjects ≥ 18 years * Subjects who have received oral vitamin K-antagonist therapy * Subjects who have acute major bleeding, defined as one of the following: life-threatening or potentially life-threatening, acute bleeding associated with a fall in hemoglobin (Hb) level ≥ 2g/dL, bleeding requiring blood product transfusion * INR ≥ 2 within 3 hours before start of study treatment * Informed consent has been obtained
Exclusion criteria
* Expected survival of less than 3 days, or expected surgery in less than 1 day * Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control the acute bleeding event * Use of unfractionated or low molecular weight heparin use from 24 hours prior to enrollment or expected need within 24 hours after start of infusion * For patients with ICH: Glasgow coma score (GCS) \< 7; intracerebral hematoma volume \> 30cc as assessed by ABC/21; for subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm; for subarachnoid hemorrhage: any evidence of hydrocephalus; infratentorial ICH location; epidural hematomas; intraventricular extension of hemorrhage; modified Rankin score (mRS) of \>3 prior to ICH * History of thrombotic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within 3 months of enrollment * Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies * Suspected or confirmed sepsis at time of enrollment * Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study * Large blood vessel rupture (e.g. in advanced cancer patient) * Pre-existing progressive fatal disease with a life expectancy of less than 2 months * Known inhibitors to coagulation factors II, VII, IX, or X; or hereditary protein C or protein S deficiency; or heparin-induced, type II thrombocytopenia * Treatment with any other investigational medicinal product within 30 days prior to inclusion into the study * Presence or history of hypersensitivity to components of the study medication * Pregnant or breast-feeding women * Prior inclusion in this study or any other CSL Behring-sponsored Beriplex study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed | At 1 and 4 hours after the end of infusion | Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 1 and 4 hours after the end of infusion. Hemostatic efficacy was the binary endpoint of effective or non-effective hemostasis, where 'effective' was a hemostatic efficacy rating of excellent or good, and 'non-effective' was a hemostatic efficacy rating of poor/none. |
| Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR) | 30 minutes after end of infusion | A rapid decrease of the international normalized ratio (INR) was defined as an INR ≤ 1.3 at 30 minutes after the end of the infusion. The INR is a standard way to describe the time it takes for blood to clot; an INR range of 0.8 to 1.2 is considered normal for a healthy person who is not using oral anticoagulant therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | From preinfusion until 24 h after the start of infusion | Plasma levels are presented as the percentage of normal at pre-infusion and 30 min and 24 h after the start of infusion. The plasma level assay results are reported as a potency relative to a standard, where 100% is considered to be normal. |
| Percentage of Participants With INR Correction at Various Times After the Start of Infusion | From the start of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion. | The time taken from the start of infusion to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion. |
| Percentage of Participants With INR Correction at Various Times After Randomization | From randomization until INR correction; calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization. | The time taken from randomization to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization. |
| Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding | At 3 and 6 hours after the start of infusion | Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 3 and 6 hours after the start of infusion. Hemostatic efficacy was the binary endpoint of effective or non-effective hemostasis, where 'effective' was a hemostatic efficacy rating of excellent or good, and 'non-effective' was a hemostatic efficacy rating of poor/none. |
| Use of Other Blood Products and Hemostatic Agents | From the start of infusion until 24 h after the start of infusion | Other blood products and hemostatic agents containing coagulation factors (such as whole blood, plasma, albumin, platelets) not including PRBCs. |
| 45-Day All-cause Mortality | Until Day 45 | — |
| Overall Treatment-emergent Adverse Events (TEAEs) | From the start of infusion up to the allowed time window of the Day 10 visit for non-serious AEs and from the start of infusion up to the allowed time window of the Day 45 visit for SAEs. | Number of participants with TEAEs. Treatment-related AEs were defined as events whose relationship to study treatment was definitely related, probably related, or possibly related in the opinion of the investigator. AEs with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent SAEs. Deaths reported up to and including Day 45; one additional Beriplex death occurred after Day 45. |
| Transfusion of Red Blood Cells | From the start of infusion until 24 h after the start of infusion | Red blood cells were packed red blood cells (PRBCs). |
| Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Before infusion and up to 3 h after the start of infusion | The incremental IVR \[(IU/dL)/(IU/kg)\] was calculated as follows: (IU/dL activity rise in plasma)/(IU/kg body weight infused) = \[maximum increase in component plasma level within 3 hours compared to pre-infusion (IU/dL)\]/{\[exact dose of component in drug administered (IU)\]/\[body weight (kg)\]}. |
Countries
Belarus, Bulgaria, Romania, Russia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Beriplex® P/N Beriplex® P/N : Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body weight | 107 |
| Fresh Frozen Plasma Fresh frozen plasma : Intravenous Infusion, dosage depending on baseline INR and body weight | 109 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death / Serious Adverse Event | 10 | 5 |
| Overall Study | Intervention by primary care physician | 1 | 0 |
| Overall Study | Lost to Follow-up | 9 | 4 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Refused hospitalization | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Beriplex® P/N | Fresh Frozen Plasma | Total |
|---|---|---|---|
| Age, Customized ≥ 65 to < 75 years | 28 Participants | 29 Participants | 57 Participants |
| Age, Customized < 65 years | 36 Participants | 32 Participants | 68 Participants |
| Age, Customized ≥ 75 years | 43 Participants | 48 Participants | 91 Participants |
| Sex: Female, Male Female | 52 Participants | 55 Participants | 107 Participants |
| Sex: Female, Male Male | 55 Participants | 54 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 103 | 40 / 109 |
| serious Total, serious adverse events | 32 / 103 | 26 / 109 |
Outcome results
Primary
Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed
Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 1 and 4 hours after the end of infusion. Hemostatic efficacy was the binary endpoint of effective or non-effective hemostasis, where 'effective' was a hemostatic efficacy rating of excellent or good, and 'non-effective' was a hemostatic efficacy rating of poor/none.
Time frame: At 1 and 4 hours after the end of infusion
Population: The Intention-to-Treat Efficacy (ITT-E) population included all randomized participants who had received any study product, presented with acute major bleeding, and had an international normalized ratio (INR) \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Beriplex® P/N | Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed | 72.4 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed | 65.4 percentage of participants |
Comparison: The analysis of hemostatic efficacy was via calculation of the 95% confidence interval (CI) for the difference (Beriplex minus plasma) in the percentage of participants with effective hemostasis.95% CI: [-5.8, 19.9]95% confidence interval
Primary
Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR)
A rapid decrease of the international normalized ratio (INR) was defined as an INR ≤ 1.3 at 30 minutes after the end of the infusion. The INR is a standard way to describe the time it takes for blood to clot; an INR range of 0.8 to 1.2 is considered normal for a healthy person who is not using oral anticoagulant therapy.
Time frame: 30 minutes after end of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Beriplex® P/N | Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR) | 62.2 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR) | 9.6 percentage of participants |
Comparison: The analysis of the percentage of participants who had a rapid decrease of the INR was via calculation of the 95% confidence interval (CI) for the difference (Beriplex minus plasma) in the percentage of participants with a rapid decrease of the INR.95% CI: [39.4, 65.9]95% confidence interval
Secondary
45-Day All-cause Mortality
Time frame: Until Day 45
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Beriplex® P/N | 45-Day All-cause Mortality | 9 participants |
| Fresh Frozen Plasma | 45-Day All-cause Mortality | 5 participants |
Secondary
Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex
The incremental IVR \[(IU/dL)/(IU/kg)\] was calculated as follows: (IU/dL activity rise in plasma)/(IU/kg body weight infused) = \[maximum increase in component plasma level within 3 hours compared to pre-infusion (IU/dL)\]/{\[exact dose of component in drug administered (IU)\]/\[body weight (kg)\]}.
Time frame: Before infusion and up to 3 h after the start of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Factor II | 2.00 (IU/dL)/(IU/kg body weight) | Standard Deviation 0.879 |
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Factor VII | 2.15 (IU/dL)/(IU/kg body weight) | Standard Deviation 2.958 |
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Factor IX | 1.29 (IU/dL)/(IU/kg body weight) | Standard Deviation 0.711 |
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Factor X | 1.96 (IU/dL)/(IU/kg body weight) | Standard Deviation 0.871 |
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Protein C | 2.04 (IU/dL)/(IU/kg body weight) | Standard Deviation 0.958 |
| Beriplex® P/N | Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | Protein S | 2.17 (IU/dL)/(IU/kg body weight) | Standard Deviation 1.661 |
Secondary
Overall Treatment-emergent Adverse Events (TEAEs)
Number of participants with TEAEs. Treatment-related AEs were defined as events whose relationship to study treatment was definitely related, probably related, or possibly related in the opinion of the investigator. AEs with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent SAEs. Deaths reported up to and including Day 45; one additional Beriplex death occurred after Day 45.
Time frame: From the start of infusion up to the allowed time window of the Day 10 visit for non-serious AEs and from the start of infusion up to the allowed time window of the Day 45 visit for SAEs.
Population: The ITT-S population included all participants who were randomized and who had received any portion of study product. Participants in the ITT-S population were analyzed 'as treated'.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Beriplex® P/N | Overall Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 66 participants |
| Beriplex® P/N | Overall Treatment-emergent Adverse Events (TEAEs) | At least possibly treatment-related TEAE | 10 participants |
| Beriplex® P/N | Overall Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 32 participants |
| Beriplex® P/N | Overall Treatment-emergent Adverse Events (TEAEs) | Death | 10 participants |
| Fresh Frozen Plasma | Overall Treatment-emergent Adverse Events (TEAEs) | Death | 5 participants |
| Fresh Frozen Plasma | Overall Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 71 participants |
| Fresh Frozen Plasma | Overall Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 26 participants |
| Fresh Frozen Plasma | Overall Treatment-emergent Adverse Events (TEAEs) | At least possibly treatment-related TEAE | 23 participants |
Secondary
Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding
Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 3 and 6 hours after the start of infusion. Hemostatic efficacy was the binary endpoint of effective or non-effective hemostasis, where 'effective' was a hemostatic efficacy rating of excellent or good, and 'non-effective' was a hemostatic efficacy rating of poor/none.
Time frame: At 3 and 6 hours after the start of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Beriplex® P/N | Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding | 73.5 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding | 67.3 percentage of participants |
Secondary
Percentage of Participants With INR Correction at Various Times After Randomization
The time taken from randomization to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization.
Time frame: From randomization until INR correction; calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization.
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 2.5 h | 59 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 3 h | 67 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 5 h | 76 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 8 h | 79 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 14 h | 84 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After Randomization | 26 h | 90 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 14 h | 38 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 2.5 h | 2 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 8 h | 22 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 3 h | 2 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 26 h | 70 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After Randomization | 5 h | 10 percentage of participants |
Secondary
Percentage of Participants With INR Correction at Various Times After the Start of Infusion
The time taken from the start of infusion to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion.
Time frame: From the start of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion.
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 0.5 h | 4 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 1 h | 69 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 3 h | 71 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 6 h | 78 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 12 h | 80 percentage of participants |
| Beriplex® P/N | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 24 h | 88 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 12 h | 36 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 0.5 h | 0 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 6 h | 16 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 1 h | 0 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 24 h | 58 percentage of participants |
| Fresh Frozen Plasma | Percentage of Participants With INR Correction at Various Times After the Start of Infusion | 3 h | 9 percentage of participants |
Secondary
Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S
Plasma levels are presented as the percentage of normal at pre-infusion and 30 min and 24 h after the start of infusion. The plasma level assay results are reported as a potency relative to a standard, where 100% is considered to be normal.
Time frame: From preinfusion until 24 h after the start of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, pre-infusion (n = 98; 103) | 20.1 percentage of normal | Standard Deviation 14.56 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, 0.5 h after infusion start (n = 88; 90) | 87.5 percentage of normal | Standard Deviation 44.48 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, 24 h after infusion start (n = 92; 99) | 77.1 percentage of normal | Standard Deviation 22.06 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, pre-infusion (n = 98; 103) | 25.9 percentage of normal | Standard Deviation 35.01 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, 0.5h after infusion start (n = 88; 90) | 60.5 percentage of normal | Standard Deviation 45.23 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, 24 h after infusion start (n = 92; 99) | 114.8 percentage of normal | Standard Deviation 165.28 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, pre-infusion (n = 98; 103) | 36.1 percentage of normal | Standard Deviation 22.56 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, 0.5 h after infusion start (n = 88; 90) | 76.8 percentage of normal | Standard Deviation 35.47 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, 24 h after infusion start (n = 92; 99) | 88.5 percentage of normal | Standard Deviation 35.65 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, pre-infusion (n = 98; 102) | 13.0 percentage of normal | Standard Deviation 11.25 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, 0.5 h after infusion start (n = 88; 90) | 99.8 percentage of normal | Standard Deviation 56.07 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, 24 h after infusion start (n = 92; 99) | 83.7 percentage of normal | Standard Deviation 27.05 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, pre-infusion (n = 98; 103) | 39.3 percentage of normal | Standard Deviation 17.15 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, 0.5 h after infusion start (n = 88; 90) | 110.3 percentage of normal | Standard Deviation 47.37 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, 24h after infusion start (n = 92; 98) | 90.3 percentage of normal | Standard Deviation 27.19 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, pre-infusion (n = 97; 102) | 27.8 percentage of normal | Standard Deviation 11.34 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, 0.5 h after infusion start (n = 88; 89) | 59.4 percentage of normal | Standard Deviation 28.56 |
| Beriplex® P/N | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, 24 h after infusion start (n = 91; 97) | 47.8 percentage of normal | Standard Deviation 16.54 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, 0.5 h after infusion start (n = 88; 90) | 50.9 percentage of normal | Standard Deviation 24.78 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, pre-infusion (n = 98; 103) | 22.3 percentage of normal | Standard Deviation 22.39 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, pre-infusion (n = 98; 102) | 14.7 percentage of normal | Standard Deviation 18.83 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, 0.5 h after infusion start (n = 88; 90) | 31.9 percentage of normal | Standard Deviation 22.55 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, 24 h after infusion start (n = 91; 97) | 45.4 percentage of normal | Standard Deviation 16 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor II, 24 h after infusion start (n = 92; 99) | 58.1 percentage of normal | Standard Deviation 19.55 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, 0.5 h after infusion start (n = 88; 90) | 23.9 percentage of normal | Standard Deviation 20.4 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, pre-infusion (n = 98; 103) | 23.5 percentage of normal | Standard Deviation 23.45 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, 24h after infusion start (n = 92; 98) | 82.8 percentage of normal | Standard Deviation 24.34 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, 0.5h after infusion start (n = 88; 90) | 34.6 percentage of normal | Standard Deviation 26.18 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor X, 24 h after infusion start (n = 92; 99) | 58.2 percentage of normal | Standard Deviation 21.78 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor VII, 24 h after infusion start (n = 92; 99) | 101.3 percentage of normal | Standard Deviation 79.01 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, 0.5 h after infusion start (n = 88; 89) | 38.6 percentage of normal | Standard Deviation 20.45 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, pre-infusion (n = 98; 103) | 39.0 percentage of normal | Standard Deviation 27.56 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein C, pre-infusion (n = 98; 103) | 41.1 percentage of normal | Standard Deviation 18.84 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, 0.5 h after infusion start (n = 88; 90) | 47.7 percentage of normal | Standard Deviation 26.78 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Protein S, pre-infusion (n = 97; 102) | 29.6 percentage of normal | Standard Deviation 12.97 |
| Fresh Frozen Plasma | Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Factor IX, 24 h after infusion start (n = 92; 99) | 93.0 percentage of normal | Standard Deviation 29.95 |
Secondary
Transfusion of Red Blood Cells
Red blood cells were packed red blood cells (PRBCs).
Time frame: From the start of infusion until 24 h after the start of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Beriplex® P/N | Transfusion of Red Blood Cells | 1.4 Units of PRBCs | Standard Deviation 1.77 |
| Fresh Frozen Plasma | Transfusion of Red Blood Cells | 1.2 Units of PRBCs | Standard Deviation 1.57 |
Secondary
Use of Other Blood Products and Hemostatic Agents
Other blood products and hemostatic agents containing coagulation factors (such as whole blood, plasma, albumin, platelets) not including PRBCs.
Time frame: From the start of infusion until 24 h after the start of infusion
Population: The ITT-E population included all randomized participants who had received any study product, presented with acute major bleeding, and had an INR \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Beriplex® P/N | Use of Other Blood Products and Hemostatic Agents | 0.3 Units of blood products | Standard Deviation 1.36 |
| Fresh Frozen Plasma | Use of Other Blood Products and Hemostatic Agents | 0.3 Units of blood products | Standard Deviation 0.87 |