E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Therapy of major bleeding resulting from an acquired deficiency of vitamin K-dependent coagulation factors and proteins C and S due to use of oral anticoagulation therapy |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009789 |
E.1.2 | Term | Coagulation factors decreased |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10005103 |
E.1.2 | Term | Bleeding |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
PRIMARY OBJECTIVE: To compare the hemostatic efficacy of Beriplex® P/N and plasma in ceasing spontaneous or traumatically-induced major bleeding in subjects who have a deficiency of vitamin K-dependent coagulation factors II, VII, IX, and X, as well as the proteins C and S, acquired from oral anticoagulation therapy. CO-PRIMARY OBJECTIVE: To compare the efficacy of Beriplex® P/N and plasma in rapidly reducing the international normalized ratio (INR, i.e. INR ≤ 3) values between the 2 treatment groups at 30 minutes after end of infusion. |
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E.2.2 | Secondary objectives of the trial |
· To compare the plasma levels of coagulation factors II, VII, IX, and X, protein C and S between the 2 treatment groups, · To document the time from start of infusion until INR correction for both treatment groups, · To document the time from randomization until INR correction for both treatment groups, · To compare INR values between the 2 treatment groups at 30 minutes from the start of infusion · To compare the use of non-study-prescribed blood products and/or hemostatic agents in both treatment groups, · All-cause mortality at 45 days after treatment, · To determine the safety and tolerability of Beriplex® P/N compared to that of plasma. · To evaluate the neurological outcome as assessed by mRS for ICH subjects at day 45. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female subjects ≥ 18 years, • Subjects who have received anticoagulation therapy (warfarin, acenocoumarol or phenprocoumon) , • Subjects who have acute major bleeding, defined as one of the following: o Life-threatening or potentially life-threatening, o Acute bleeding associated with a fall in Hb level ≥ 2g/dL, o Bleeding requiring blood product transfusion (blood products include plasma, red blood cells and other coagulation factor products), • INR ≥ 2 within 3 hours before start of study treatment, • Informed consent has been obtained. |
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E.4 | Principal 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, • For patients with ICH: o Glasgow coma score < 9, o Intracerebral hematoma volume > 30cc as assessed by ABC/21, o For subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm, o For subarachnoid hemorrhage: any evidence of hydrocephalus, o Infratentorial ICH location, o Epidural hematomas, o Intraventricular extension of hemorrhage, o Modified Rankin score 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 o Note: Administration of packed red blood cells is not an exclusion criterion, • 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 heparininduced, 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. ٭Subjects with acute major bleeding requiring minimal invasive procedures (e.g. endoscopy, bronchoscopy, central lines) that are indicated for diagnostic or therapeutic reasons are not excluded per protocol, as long as plasma is intended to be given for treatment of major bleeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint: Hemostatic efficacy The primary efficacy variable will be the hemostatic efficacy over the period from start of infusion until 24 hours after the start of infusion with respect to the adequacy of stopping an ongoing bleed. For hemostatic efficacy, the adequacy of cessation of a bleed will be rated by the DSMB (primary assessment) and the physician (secondary assessment) as excellent, good, or poor/none, based onpre-specified definitions. The hemostatic efficacy (DSMB and investigator’s classification of clinical efficacy) will be described in frequency tables. The primary analysis will be performed on the DSMB assessment in the ITT population. A secondary analysis will be performed for the PP population. Additional subgroup analyses by type of oral coagulation will be provided (ITT and PP). The primary efficacy analysis in this study will be a test for the non-inferiority of the effect of Beriplex® P/N compared to that of plasma on the binary hemostatic efficacy variable (a score of “excellent” or “good” versus a score of “poor/none” as specified in Table 4 – Rating of hemostatic efficacy). If the above null hypothesis of inferiority can be rejected, Beriplex® P/N will also be tested for superiority compared to plasma.
Co-primary endpoint: INR decrease The co-primary endpoint will be the proportion of subjects who have a rapid decrease of INR, defined as an INR value of 1.3 or less at 30 minutes after end of infusion. The non-inferiority of the effect of Beriplex® P/N compared to that of plasma on the proportion of subjects who have a rapid decrease of INR will be tested, if non-inferiority with regard to the primary endpoint (hemostatic efficacy) is shown. The method to test for non-inferiority will be the same as for hemostatic efficacy, including hypothesis, test procedure, maximum type I error, and non-inferiority margin. The course of INR will be shown graphically and descriptively by treatment group (mean, standard deviation (SD), median, quartiles, minimum, and maximum). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Fresh-frozen or 24-hour or thawed plasma that has been donor tested |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last visit (end of viral safety follow-up) of the last subject undergoing the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | 45 |
E.8.9.2 | In all countries concerned by the trial months | 30 |
E.8.9.2 | In all countries concerned by the trial days | 45 |