E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053476 |
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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 |
To evaluate the efficacy and safety of rFVIIa (NovoSeven®/NiaStase®) compared to placebo as an adjunct to standard treatment of trauma patients with active hemorrhage refractory to blood component therapy and surgical hemostatic procedures. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Informed consent (Section 17) obtained before any trial-related activities (Trial-related activities are any procedure that would not have been performed as part of the patient’s standard care). 2.Trauma injury (blunt and/or penetrating) with evidence of active torso (proximal to the inguinal creases, proximal/medial to the axillae) and/or proximal lower extremity (above knee) hemorrhage refractory to blood component therapy and surgical hemostatic procedures at the time of randomization 3.“Evidence of active hemorrhage (torso and/or proximal lower extremity) at the time of randomization” is defined as: a.Presence of hypotension due to hypovolemia (systolic blood pressure (SBP) ≤90 mmHg) documented at any point in time within 30 minutes prior to randomization or b.Presence of ongoing volume loading at a minimal rate of 1L/h (RBC or any other IV fluid/blood product) up to the point of randomization (and with continuing similar or greater need per the Investigator's judgment) or c.Presence of acidosis (lactate > 6 mmol/L (or 2 times the local upper limit of normal) or Base Deficit ≥ 5 mEq/L) documented at any point in time within 30 minutes prior to randomization 4.Receipt of a minimum of 4 units of RBC at the time of randomization and the ability to administer first dose of study drug as soon as possible upon the completion of the 4th unit and no later than the completion of the 8th unit of RBC 5.Male or female patients, between 18-70 years of age OR of legal age to consent for participation in an investigational drug trial as per local law
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E.4 | Principal exclusion criteria |
1.Moribund as defined by any one of the following (only the most recent values prior to randomization are to be considered): a.pH < 7.1* or b.Lactate > 15 mmol/l or c.Base deficit (BD) > 15 mEq/l or d.SBP ≤ 50 mmHg or use of 2 boluses or more of vasopressor treatment to support the blood pressure prior to randomization (bolus vasopressor use for reasons other than hypovolemia (i.e. spinal cord injury, anesthetic induction) does not exclude the patient) or e.Anatomical injury incompatible with life (e.g. multiple cardiac wounds, unrepairable liver or pelvic injury) or f.Cardiac arrest (cessation of spontaneous circulation) any time from injury prior to randomization. 2.Evidence of head injury and suspicion of severe brain trauma as defined by any one of the following: a.Highest GCS score ≤5 , or b.Need for immediate open intracranial operation or c.Abnormal physical examination indicative of brain injury (e.g. decorticate posturing, localizing signs such as unequal pupils due to Traumatic Brain Injury) or d.Traumatic intracranial injury of AIS > 4 demonstrated by CT scan 3.Time from injury to dosing > 12 hours 4.Estimated time of injury to trial hospital admission > 4 hours 5.Primary bleeding source localized to the upper extremities or distal lower extremities as per the Investigator's judgment 6.Treatment with aprotinin, aPCC (Activated Prothrombin Complex Concentrate) or PCC (Prothrombin Complex Concentrate) 7.Known history of thromboembolic events within 30 days 8.Presence of spinal cord injury above T6 with paralysis 9.Total body surface area burns: 2° + 3° ≥ 40% (evaluated by the Investigator according to Lund-Browder chart for estimating the extent of burns, Appendix O) 10.Known or suspected pregnancy 11.Previous randomization in this trial 12.Known participation in an investigational drug/device trial within the last 30 days 13.Estimated body weight < 43 kg 14.Known or suspected allergy to trial products or related products 15.Known presence of congenital bleeding disorder 16.Patient known or suspected of not being able to comply with this study protocol or indication of reluctance to participate in the trial (e.g. revealed by examination of an incapacitated patient's personal effects)
*In case a low pH value (less than 7.1) is predominantly or partly due to a respiratory component, it is acceptable to assess moribund criterion 1.a. based on a "corrected pH value" calculated from one of the equations: In units of mmHg: Corrected pH = actual pH + (0.008 multiplied by each mmHg pCO2 above 40 mmHg). In units of kPa:Corrected pH = actual pH + (0.06 multiplied by each kPa pCO2 above 5.33)
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint Efficacy: • A primary endpoint of all cause 30 day mortality designed to show superiority of rFVIIa compared to placebo in blunt trauma patients If mortality is not superior, then • A primary endpoint designed to demonstrate non-inferiority of rFVIIa compared to placebo on all cause 30 day mortality and superiority of rFVIIa compared to placebo on pulmonary and/or renal dysfunction requiring ongoing medical intervention at Day 30 in blunt trauma patient Safety: • Adverse events from randomization through Hour 48 in blunt and penetrating trauma patients • Serious Adverse Events (SAEs) from randomization through Day 90 in blunt and penetrating trauma patients Secondary Endpoints: Prioritized Secondary Efficacy Endpoints in blunt trauma patients 1. Days alive and free of pulmonary and/or renal dysfunction requiring ongoing medical intervention through Day 30 2. Time to death from time of first dose through Day 30 3. Number of transfused red blood cells (RBCs) from time of first dose through Hour 24 4. Number of patients receiving 10 units or more of red blood cells (RBC) from time of injury through Hour 24 5. Total number of allogeneic transfusions from time of first dose through Hour 24 Other Secondary Efficacy Endpoints in blunt trauma patients 1. Assessment of tissue bleeding, evaluated 15 minutes after administration of each dose of trial drug 2. Number of transfusion units of fresh frozen plasma (FFP) from time of first dose through Hour 24 and through Hour 48 3. Number of transfusion units of platelets from time of first dose through Hour 24 and through Hour 48 4. Number of transfusion units of cryoprecipitate/fibrinogen concentrate from time of first dose through Hour 24 and through Hour 48 5. Number of transfused red blood cells (RBCs) from time of first dose through Hour 48 6. Number of transfusion allogeneic units from time of first dose through Hour 48 7. Multi-organ failure according to Appendix G from time of first dose through Day 30 8. Single organ failure for pulmonary, renal, cardiovascular, and the hepatic systems from time of first dose through Day 30 9. ICU-free days from time of first dose through Day 30 10. Hospital-free days from time of first dose through Day 30
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |