E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Elective spine surgery with expected major blood loss |
operacion de columna vertebral con importante pérdida de sangre esperada |
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E.1.1.1 | Medical condition in easily understood language |
Acquired Fibrinogen deficiency |
Deficiencia de fibrinógeno adquirida |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051125 |
E.1.2 | Term | Hypofibrinogenaemia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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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 |
The main purpose of this phase III study is to demonstrate the efficacy of BT524 as a complementary therapy to management of uncontrolled severe hemorrhage in subjects undergoing elective major spine surgery. The primary objective of this study is to demonstrate that BT524 is therapeutically equivalent that means not worse than fresh frozen plasma (FFP) with a non-inferiority margin of 150 mL in reducing intra-operative blood loss by intravenous (IV) administration in subjects with acquired hypofibrinogenaemia undergoing elective major spine surgery. If therapeutical equivalence has been demonstrated, therapeutical superiority of BT524 compared with FFP will also be assessed. |
El objetivo principal de este estudio de fase III consiste en demostrar la eficacia de BT524 como terapia complementaria para el tratamiento de las hemorragias graves incontroladas en sujetos sometidos a operaciones de cirugía mayor programada de columna vertebral. El objetivo principal de este estudio consiste en demostrar que BT524 es terapéuticamente equivalente, lo que significa que no es peor que el plasma congelado en fresco (PCF) con un margen de no inferioridad de 150 ml en la reducción de la pérdida de sangre intraoperatoria mediante administración intravenosa (i.v.) en sujetos con hipofibrinogenemia adquirida sometidos a operaciones de cirugía mayor programada de columna vertebral. Si se ha demostrado la equivalencia terapéutica, también se evaluará la superioridad terapéutica de BT524 con respecto al PCF. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to demonstrate the efficacy of BT524 by assessing the correction of the fibrinogen level intra-operatively, the transfusion requirements, 24 hours post-operative blood loss, the number of subjects with rebleeds, the hospital length of stay and the in-hospital mortality. Secondary objectives also comprise the safety of BT524 by documenting the number of adverse events (AE) including changes in laboratory parameters, the virus status, and the frequency and severity of thrombosis and of thromboembolic events (TEEs). |
Los objetivos secundarios consisten en demostrar la eficacia de BT524 evaluando la corrección intraoperatoria del nivel de fibrinógeno, las necesidades de transfusiones, la pérdida de sangre en las 24 horas siguientes a la operación, el número de sujetos con hemorragias recidivantes, la duración de la estancia hospitalaria y la mortalidad intrahospitalaria. Los objetivos secundarios también comprenden la seguridad de BT524 mediante la documentación del número de acontecimientos adversos (AA), lo que incluye los cambios en los parámetros analíticos, el estado vírico y la frecuencia y gravedad de las trombosis y de los episodios tromboembólicos (ETE). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
At screening: 1.Written informed consent 2.Subjects scheduled for elective major spine surgery with expected major blood loss 3.Male or female, aged ≥ 18 years 4.No increased bleeding risk as assessed by standard coagulation tests and medical history
Intra-operative: 5.Intra-operative bleeding > 1,000 mL (total blood loss), resulting in a high risk for the need of FFP transfusion during surgery. |
En la selección: 1.Consentimiento informado por escrito. 2.Sujetos que tengan programadas operaciones de cirugía mayor de columna vertebral en las que se prevea una pérdida de sangre importante. 3.Hombre o mujer de Eedad ≥18 años. 4.Ausencia de aumento del riesgo de hemorragia, evaluada mediante las pruebas de coagulación estándar y el historial medico.
Intraoperatorios: 5.Hemorragia intraoperatoria >1000 ml (pérdida total de sangre) que conlleve un riesgo elevado de necesidad de transfusión de PCF durante la intervención. |
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E.4 | Principal exclusion criteria |
1.Pregnancy or unreliable contraceptive measures or lactation period (women only) 2.Hypersensitivity to proteins of human origin or known hypersensitivity reactions to components of the Investigational Medicinal Products (IMP) 3.Participation in another clinical study within 30 days before entering the study or during the study and/or previous participation in this study 4.Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 30 days prior to infusion of BT524 5.Employee or direct relative of an employee of the Contract Research Organization (CRO), the study site, or Biotest 6.Inability or lacking motivation to participate in the study 7.Medical condition, laboratory finding (e.g. clinically relevant biochemical or hematological findings outside the normal range), or physical exam finding that in the opinion of the investigator precludes participation 8.Presence or history of venous/arterial thrombosis or TEE in the preceding 6 months |
1.Embarazo, métodos anticonceptivos poco fiables o periodo de lactancia (solo mujeres). 2.Hipersensibilidad a las proteínas de origen humano o reacciones de hipersensibilidad conocidas a algún componente de los productos en investigación (PEI). 3.Participación en otro estudio clínico dentro de los 30 días anteriores al ingreso en el estudio o durante el estudio y/o participación previa en este studio. 4.Tratamiento con algún concentrado de fibrinógeno y/o producto con fibrinógeno dentro de los 30 días anteriores a la infusión de BT524. 5.Empleado o familiar directo de un empleado de la organización de investigación por contrato (CRO), del centro del estudio o de Biotest. 6.Incapacidad o falta de motivación para participar en el studio. 7.Afección médica, resultado analítico (p. ej., resultados de bioquímica o hematología clínicamente relevantes fuera del intervalo normal) o hallazgo de la exploración física que, en opinión del investigador, impida la participación. 8.Presencia o antecedentes de trombosis venosa/arterial o de ETE en los 6 meses anteriores. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery as measured by amount of blood from blood suction unit and amount of blood from surgical cloths and compresses. |
Eficacia: perdida de sangre intraoperatoria despues de tomar la decision de tartar al sujeto con el PEI hasta el final de la operacion, medida a traves de la cantidad de sangre de los paños y compresas quirurgicos. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery |
perdida de sangre intraoperatoria después detomar la decision de tartar al paciente con el PEI hasta el final de la operacion. |
|
E.5.2 | Secondary end point(s) |
Efficacy: Proportion (%) of subjects with successful correction of fibrinogen level 15 minutes after start of IMP administration •First time of successful correction of fibrinogen level •Total amount of transfusion products (allogenic blood products) or autologous blood transfusion infused after IMP administration until end of surgery •Amount of red blood cells (allogenic and autologous RBCs) infused after IMP administration until end of surgery •24 hours post-operative blood loss •Proportion (%) of subjects with rebleeds after the end of surgery until Day 8 •Hospital length of stay after surgery •In-hospital mortality Safety |
Eficacia: •Proporción (%) de sujetos con una corrección satisfactoria del nivel de fibrinógeno 15 minutos después del inicio de la administración del PEI. •Primer momento de corrección satisfactoria del nivel de fibrinógeno. •Cantidad total de productos de transfusión (hemoderivados alógenos) o de transfusión de sangre autóloga infundida después de la administración del PEI hasta el final de la operación. •Cantidad de eritrocitos (alógenos y autólogos) infundida después de la administración del PEI hasta el final de la operación. •Pérdida de sangre en las 24 horas siguientes a la operación. •Proporción (%) de sujetos con hemorragias recidivantes después del final de la operación hasta el día 8. •Duración de la estancia hospitalaria después de la operación. •Mortalidad durante la hospitalización. Seguridad |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Until closing visit (up to 70 days) |
Hasta la visita de cierre (hasta 70 dias) |
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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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Parcialmente ciego |
Partially blinded |
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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 |
Plasma Fresco Congelado |
fresh frozen plasma (FFP) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | No |
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 |
European Union |
Switzerland |
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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
|
LVLS |
Ultima visita ultimo paciente |
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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 | 26 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 26 |