E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hemophilia A (FVIII <1%) |
Hemofilia A severa (FVIII < 1%) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess efficacy and safety, including immunogenicity of BAX 855 administered as prophylaxis and as on-demand therapy in adult and adolescent (12-65 years) PTPs with severe hemophilia A. The primary objective is to compare the annualized rates of bleeding episodes (ABR) between subjects receiving a prophylactic dosing regimen of BAX 855 with an on-demand treatment regimen. To determine the pharmacokinetic (PK) parameters of BAX 855 |
Evaluar la eficacia y la seguridad, incluyendo la inmunogenicidad de BAX 855 administrado como profilaxis y como tratamiento a demanda en PTP adultos y adolescentes (de 12 a 65 años) con hemofilia A severa. El objetivo principal es comparar las tasas anualizadas de episodios hemorrágicos (TAH) entre pacientes que reciben una pauta posológica profiláctica de BAX 855 y los que reciben una pauta terapéutica a demanda. |
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E.2.2 | Secondary objectives of the trial |
?To characterize the success of BAX 855 for treatment of bleeding episodes through the number of BAX 855 infusions needed for the treatment of a bleeding episode and through the length of intervals between bleeding episodes ?To compare the total weight-adjusted consumption of BAX 855 for each regimen ?To determine the immunogenicity of BAX 855 ?To determine the safety of BAX 855 ?To determine the PK parameters of BAX 855 following initial and repeat administration ?To assess Health-Related Quality of Life (HRQoL) over time for subjects receiving BAX 855 |
Caracterizar el éxito de BAX 855 para el tratamiento de episodios hemorrágicos a través del número de perfusiones de BAX 855 necesarias para el tratamiento de un episodio hemorrágico y de la duración de los intervalos de tiempo entre episodios hemorrágicos. ? Comparar el consumo total de BAX 855 ajustado por peso para cada pauta posológica. Determinar la inmunogenicidad de BAX 855. Determinar la seguridad de BAX 855 ?Determinar los parámetros FC de BAX 855 tras la administración inicial y repetida. Evaluar la calidad de vida relacionada con la salud (CDVRS) conforme avance el tiempo en pacientes que reciben BAX 855. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
?Subject and/or legal representative has/have voluntarily provided signed informed consent ?Subject is 12 to 65 years old at the time of screening ?Subject is male with severe hemophilia A (FVIII clotting activity <1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity <1% ?Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ?150 documented exposure days (EDs) ?Subject is currently receiving prophylaxis or on-demand therapy with FVIII ?Subject has a Karnofsky performance score of ? 60 at screening ?Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ?200 cells/mm3, as confirmed by central laboratory at screening ?Subject is hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis ?Subject is willing and able to comply with the requirements of the protocol |
El paciente y/o su representante legal han proporcionado voluntariamente el consentimiento informado firmado. ? El paciente tiene entre 12 y 65 años en el momento de la selección. ? El paciente es un varón con hemofilia A severa (actividad coagulante del FVIII < 1%) confirmada por el laboratorio central en el momento de la selección después de un periodo de lavado adecuado o una actividad coagulante del FVIII < 1% documentada. El paciente ha recibido previamente tratamiento con concentrados de FVIII derivado de plasma o FVIII recombinante durante mayor o igual a 150 días de exposición (DE) documentada. El paciente está recibiendo actualmente profilaxis o tratamiento a demanda con FVIII. El paciente tiene una puntuación en la escala funcional de Karnofsky mayor o igual a 60 en la selección. El paciente es seronegativo para el virus de la inmunodeficiencia humana (VIH); o es VIH+ con enfermedad estable y recuento de células CD4+ mayor o igual a 200 células/mm3, confirmado por el laboratorio central en la selección. El paciente es seronegativo para el virus de la hepatitis C (VHC-) según el análisis de anticuerpos o PCR (si es positivo, el título de anticuerpos se confirmará mediante PCR), confirmado por el laboratorio central en la selección; o VHC+ con hepatitis crónica estable. El paciente está dispuesto y es capaz de cumplir los requisitos del protocolo. |
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E.4 | Principal exclusion criteria |
?Subject has detectable FVIII inhibitory antibodies (? 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening ?Subject has a history of FVIII inhibitory antibodies (? 0.4 BU using the Nijmegen modification of the Bethesda assay or ? 0.6 BU using the Bethesda assay) at any time prior to screening ?Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand?s disease) ?Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80 ?Subject has severe chronic hepatic dysfunction [eg, ?5 times upper limit of normal alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented INR > 1.5] ?Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening ?Subject has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or is scheduled to use of such drugs during study participation ?Subject has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study ?Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance ?Subject is a family member or employee of the investigator |
El paciente presenta anticuerpos inhibidores anti-FVIII detectables (mayor o igual a 0,6 UB usando la modificación de Nijmegen del análisis de Bethesda) confirmado por el laboratorio central en la selección. El paciente tiene antecedentes de anticuerpos inhibidores anti-FVIII (mayor o igual a 0,4 UB usando la modificación de Nijmegen del análisis de Bethesda o mayor o igual a 0,6 UB usando el análisis de Bethesda) en cualquier momento antes de la selección. Al paciente se le ha diagnosticado un defecto hemostático hereditario o adquirido distinto de la hemofilia A (p. ej., defecto cualitativo de las plaquetas o enfermedad de von Willebrand). ? El paciente tiene hipersensibilidad conocida a proteínas de ratón o de hámster, al PEG o al Tween 80. El paciente tiene insuficiencia hepática crónica severa (p. ej., nivel de alanina aminotransferasa [ALT] mayor o igual a 5 veces el límite superior de la normalidad, confirmado por el laboratorio central en la selección, o un INR > 1,5 documentado). El paciente tiene insuficiencia renal severa (creatinina sérica > 2 mg/dl) confirmada por el laboratorio central en la selección. El paciente usa actualmente o ha usado recientemente (< 30 días) otros fármacos PEGilados antes de su participación en el estudio o está previsto que utilice dichos fármacos durante su participación en el estudio. El paciente ha participado en otro ensayo clínico con un PEI o dispositivo en investigación en los 30 días previos a su inclusión en el estudio o está previsto que participe en otro estudio clínico con un PEI o dispositivo en investigación durante el desarrollo de este estudio. El paciente tiene una enfermedad médica, psiquiátrica o cognitiva o consume drogas/alcohol, lo que, en opinión del investigador, afectaría a su seguridad o a su cumplimiento terapéutico. El paciente es familiar o empleado del investigador. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Prophylaxis will be considered to be successful if the upper limit of the 95% CI for the ratio between treatment means (A vs B) does not exceed 0.5 (corresponding to a 50% reduction of the mean ABR compared to the on-demand treatment). |
Se considerará que el tratamiento profiláctico ha tenido éxito si el límite superior del IC del 95% para el cociente entre las medias de tratamientos (A frente a B) no excede de 0,5 (correspondiente a una reducción del 50% de la TAH media en comparación con el tratamiento a demanda). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 50 EDs or approximately 6 months (±2 weeks) for the prophylaxis arm and after 6 months (± 2 weeks) for the on-demand arm. |
Aproximadamente 50 DE o aproximadamente 6 meses [± 2 semanas] para el grupo de profilaxis y después de 6 meses [± 2 semanas] para el grupo a demanda) |
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E.5.2 | Secondary end point(s) |
Success will be defined at a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes. |
El éxito se define como una valoración de excelente o bueno usando la escala de valoración de la eficacia para el tratamiento de episodios hemorrágicos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Approximately 50 EDs or approximately 6 months (±2 weeks) for the prophylaxis arm and after 6 months (± 2 weeks) for the on-demand arm. |
Aproximadamente 50 DE o aproximadamente 6 meses [± 2 semanas] para el grupo de profilaxis y después de 6 meses [± 2 semanas] para el grupo a demanda) |
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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 | 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) | 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) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Diseño paralelo factorial |
parallel factorial design |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Australia |
Austria |
Bulgaria |
Czech Republic |
France |
Germany |
Hong Kong |
India |
Israel |
Japan |
Korea, Republic of |
Lithuania |
Malaysia |
Netherlands |
New Zealand |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Ukraine |
United Kingdom |
United States |
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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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LVLS |
Last Patient Last Visit |
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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 | 21 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 21 |