| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hemophilia A. |
| Hemofilia A |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hemophilia A is a rare but serious bleeding disorder which affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. |
| Hemofilia A es un trastorno hemorrágico poco frecuente pero grave que afecta a los hombres y se caracteriza por una deficiencia de la proteína plasmática conocida como factor VIII de la coagulación. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060612 |
| E.1.2 | Term | Hemophilia A |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 characterize the PK profile of CSL627
To demonstrate efficacy in the prevention and treatment of bleeding events
To demonstrate the efficacy of CSL627 in surgical prophylaxis
Characterize the rate of inhibitor formation. |
Caracterizar el perfil FC de CSL627
Demostrar su eficacia en la prevención y el tratamiento de los episodios hemorrágicos
Demostrar la eficacia de CSL627 en la profilaxis quirúrgica.
Caracterizar la frecuencia de formación de inhibidores. |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the safety profile of CSL627.
To establish the PK comparison of CSL627 to octocog alfa. |
Caracterizar el perfil de seguridad de CSL627.
Establecer la comparación FC entre CSL627 y octocog alfa. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An evaluation of the safety and efficacy of CSL627 in the prevention and treatment of bleeding during surgical procedures.
Main objective of substudy: to demonstrate the efficacy of CSL627 in surgical procedures. |
Una evaluación de la seguridad y la eficacia de CSL627 en la prevenciaón y tratamiento de hemorragias durante procesos quirúrgicos.
Objetivo principal del subestudio: demostrar la eficacia de CSL627 en procesos quirúrgicos. |
|
| E.3 | Principal inclusion criteria |
- Diagnosis of severe hemophilia A defined as <1% FVIII:C documented in medical records.
- Males between >= 18 and 65 years of age (Parts 1 and 2).
- Males between >= 12 and 65 years of age (Part 3).
- Subjects who have received or are currently receiving FVIII products (plasma-derived and/or recombinant FVIII) and have had >150 exposure days (EDs) with a FVIII product
- Written informed consent for study participation obtained before undergoing any study specific procedures. |
? Diagnóstico de hemofilia A grave definida como C:FVIII <1% documentada en la historia clínica.
? Hombres de entre >=18 y 65 años de edad (Partes 1 y 2).
? Hombres de entre >=12 y 65 años de edad (Parte 3).
? Sujetos que hayan recibido o están recibiendo actualmente productos de FVIII (FVIII derivado de plasma y/o recombinante) y que hayan tenido >150 días de exposición (DE) con un producto de factor VIII.
? Obtención del consentimiento informado por escrito a participar en el estudio antes de la realización de cualquier procedimiento específico del estudio. |
|
| E.4 | Principal exclusion criteria |
- Any history of or current FVIII inhibitors
- Any first order family history of FVIII inhibitors
- Use of an Investigational Medicinal Product within 30 days prior to the first rFVIII administration
- Not capable of receiving treatment at home
- Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rFVIII or reference product.
- Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein.
- Any known congenital or acquired coagulation disorder other than congenital FVIII deficiency.
- Platelet count < 100,000/µl at screening.
- HIV positive subjects with a CD4 count < 200/mm3, in their medical history or at screening if available results are older than one year. (HIV positive subjects may participate in the study and antiviral therapy are permitted, at the discretion of the Investigator).
- Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment.
- Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values > 5 times (x) the upper limit of normal (ULN) at Screening.
- Subjects with serum creatinine values > 2 x ULN at Screening.
- Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1.
- Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months prior to Day 1.
- Demonstrated inability (e.g., language problem or mental condition) or unwillingness to comply with study procedures or history of noncompliance.
- Employee at the study site, or spouse/partner or relative of the investigator or subinvestigators.
- Re-entry of subjects previously enrolled or participating in the current study.
- Suspected inability (eg, language problems) or unwillingness to comply with study procedures.
- Mental condition rendering the subject (or the subject's legally acceptable representative[s]) unable to understand the nature, scope and possible consequences of the study).
- Any condition that is likely to interfere with evaluation of the IMP or satisfactory conduct of the study. |
? Cualquier antecedente de inhibidores de FVIII, o presencia actual de dichos inhibidores
? Antecedente de inhibidores del FVIII en cualquier familiar de primer grado
? Uso de un medicamento en investigación en los 30 días previos a la primera dosis de rFVIII.
? No capaces de recibir tratamiento en su domicilio
? Administración de cualquier crioprecipitado, sangre entera o plasma en los 30 días previos a la administración de rFVIII o del producto de referencia.
? Hipersensibilidad conocida (reacción alérgica o anafilaxia) a cualquier producto de FVIII o a las proteínas del hámster.
? Cualquier trastorno de la coagulación conocido, congénito o adquirido, aparte de la deficiencia congénita de FVIII.
? Recuento plaquetario < 100.000/µl en la selección.
? Pacientes infectados por el VIH con un recuento de CD4 < 200/mm3, en la historia clínica o en la selección, si los resultados disponibles tienen una antigüedad mayor de un año. (Los sujetos infectados por el VIH pueden participar en el estudio y se permite el tratamiento antivírico, a discreción del investigador).
? El sujeto está recibiendo actualmente inmunomoduladores i.v., como inmunoglobulina o tratamiento crónico con corticoesteroides sistémicos.
? El sujeto tiene concentraciones plasmáticas de aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) >5 veces (×) el límite superior de la normalidad (LSN) en la selección.
? Sujetos con concentraciones plasmáticas de creatinina > 2× LSN en la selección.
? Presencia de trombosis, como trombosis venosa profunda, accidente cerebrovascular, embolia pulmonar, infarto de miocardio y embolia arterial, en los 3 meses previos al día 1.
? Ha tenido un episodio hemorrágico potencialmente mortal o se le ha realizado cirugía mayor o una intervención quirúrgica ortopédica en los 3 meses previos al día 1.
? Ha demostrado su incapacidad (p. ej., problemas de lenguaje o enfermedad mental) o su falta de voluntad de cumplir los procedimientos del estudio, o antecedente de incumplimiento.
? Empleado en el centro de estudio, o cónyuge/pareja o familiar del investigador o de los subinvestigadores.
? Repetición de la inclusión de los sujetos incluidos previamente o que hayan participado en el estudio actual.
? Sospecha de incapacidad (p. ej., problemas de lenguaje) o falta de voluntad de cumplir los procedimientos del estudio.
? Enfermedad mental que hace que el sujeto (o el representante legalmente aceptable del sujeto) sea incapaz de comprender la naturaleza, el alcance y las posibles consecuencias del estudio.
? Cualquier enfermedad que pueda interferir con la evaluación del MI o con la realización satisfactoria del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The rate of treatment success for bleeding episodes defined as a rating of "excellent" or "good" on the investigator´s overall clinical assessment of hemostatic efficacy four-point scale.
The rate of inhibitor formation to FVIII evaluated from the time of first dose through the End of Study visit.
For surgical sub-study the primary efficacy endpoint:
-the rate of treatment success during the peri-operative surgical sub-study defined as an investigator rating of "excellent" or "good" on the four-point efficacy evaluation of surgical treatment scale. |
La tasa de éxito del tratamiento de los episodios hemorrágicos, definida como una calificación de ?excelente? o ?buena? en la evaluación clínica general por el investigador en una escala de eficacia hemostática de cuatro puntos.
La frecuencia de formación de inhibidores de FVIII evaluada desde el momento de la primera dosis hasta la visita del final del estudio.
El criterio principal de valoración de eficacia del subestudio quirúrgico es:
La tasa de éxito del tratamiento durante el subestudio quirúrgico preoperatorio, definida como una calificación por el investigador de ?excelente? o ?buena? en la evaluación de la eficacia en la escala de tratamiento quirúrgico de cuatro puntos. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
study duration up to 12 months
Assessment on monthly visits. Months 1 to 6, 9 and 12. |
La duración del estudio es de hasta 12 meses
Evaluaciones en las visitas mensuales. Meses 1 a 6, 9 y 12. |
|
| E.5.2 | Secondary end point(s) |
PK parameters for CSL627 and octocog alfa collected during Part 1 of the study including incremental recovery, AUC0-t, AUC0-t, percent of area extrapolated, Cmax, Tmax, elimination constant, half-life (t1/2), AUMC0??, mean residence time (MRT), clearance (Cl), and volume of distribution at steady-state (Vss).
The proportion of bleeding episodes requiring one, 2, 3 or > 3 infusions of CSL627 to achieve hemostasis.
The safety assessment of CSL627 including AEs, SAEs, laboratory safety parameters (serum chemistry and hematology), antibodies to CSL627, pre- and post-infusion vital signs, and physical examination. |
| Parámetros FC de CSL627 y octocog alfa obtenidos durante la Parte 1 del estudio, como recuperación incremental, ABC0?t, ABC0?t, porcentaje del área extrapolada, Cmáx, Tmáx, constante de eliminación, semivida (t1/2), ABCM0?t, tiempo medio de permanencia (TMP), aclaramiento (Cl) y volumen de distribución en estado de equilibrio (Vss). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood draws for the full PK analysis will be at pre-dose (immendiately prior to the initial dose), then at intervals after infusion over 72 hours (0,5, 1, 4, 8, 10, 24, 32, 48 and 72 hours) measured by the CS and OC assays.
Blood draws for the PK analysis -PART 3 will be at pre-dose (immediately prior to the initial dose), then at intervals after infusion over 96 hours (10-15 min., 0.5, 1, 3, 6, 9, 24, 28, 32, 48, 72 and 96 hours). |
Se extraerán muestras de sangre para el análisis FC completo antes de la dosis (inmediatamente antes de la dosis inicial), y después a intervalos después de la infusión durante 72 horas (0.5, 1, 4, 8, 10, 24, 32, 48 y 72 horas), con medición mediante los métodos de EC y UF.
Las muestras de sangre para el análisis FC - Parte 3 se extraerán antes de la dosis (inmediatamente antes de la dosis inicial) y a continuación, a intervalos después de la infusión durante 96 horas (10-15 min, 0,5, 1, 3, 6, 9, 24, 28, 32, 48, 72 y 96 horas). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| 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 | 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Australia |
| Canada |
| Korea, Republic of |
| Malaysia |
| Russian Federation |
| Ukraine |
| United States |
|
| 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
|
| The end of the trial is defined as the last-patient-last-visit. |
| El final del estudio se define como la última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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