E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Emphysema due to Alpha-1-Antitrypsin Deficiency |
Enfisema pulmonar por deficiencia de alfa1-antitripsina |
|
E.1.1.1 | Medical condition in easily understood language |
Severe deficiency of alpha-1 antitrypsin, complicated by emphysema of the lungs |
Deficiencia grave de alfa 1- antitripsina, complicada por enfisema pulmonar |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
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 | 10014563 |
E.1.2 | Term | Emphysema pulmonary |
E.1.2 | System Organ Class | 100000004855 |
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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 |
The primary objective of this study is to demonstrate, using whole lung computed tomography (CT) densitometry (15th percentile point [PD15]), a slower progression of lung tissue loss in subjects with alpha1-antitrypsin deficiency (AATD) on Alpha-1 MP (alpha1-proteinase inhibitor [human], modified process) treatment (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo. |
El objetivo principal de este estudio es demostrar, mediante densitometría por tomografía computarizada (TC) pulmonar (punto percentil 15 [PD15]), una progresión más lenta de la pérdida de tejido pulmonar en sujetos con deficiencia de alfa1-antitripsina (DAAT) en tratamiento con Alpha-1 MP (inhibidor de la proteinasa alfa1 [humano], proceso modificado) (ya sea 60 mg/kg/semana o 120 mg/kg/semana) en comparación con el placebo. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to demonstrate the efficacy of each IV dose of Alpha-1 MP (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo in subjects with AATD by:
- Reducing the incidence of severe COPD exacerbations as defined by an American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force criteria, and
- Slowing the progression of lung tissue loss as measured by basal lung CT densitometry (PD15).
The safety objective of this study is to evaluate the safety and tolerability of two separate IV dose regimens (60 mg/kg/week and 120 mg/kg/week) of Alpha-1 MP. |
Los objetivos secundarios de este estudio son demostrar la eficacia de cada una de las dosis i.v. de Alpha-1 MP (60 mg/kg/semana o 120 mg/kg/semana) en comparación con el placebo en sujetos con DAAT en función de: ? La reducción de la incidencia de exacerbaciones severas de la EPOC, según la definición de los criterios del Grupo de Trabajo de la American Thoracic Society (ATS)/European Respiratory Society (ERS) y ? La ralentización de la progresión de la pérdida de tejido pulmonar determinada mediante densitometría por TC (PD15) pulmonar basal
El objetivo de seguridad de este estudio es evaluar la seguridad y la tolerabilidad de dos pautas posológicas de administración i.v. diferentes (60 mg/kg/semana y 120 mg/kg/semana) de Alpha-1 MP. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have a documented total alpha1-PI serum level < 11 ?M.
2. Have a diagnosis of congenital AATD with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or ?at-risk? alleles. If the genotype has yet to be documented, genotyping (i.e., allelic discrimination) and phenotyping will be performed at the Screening (Week -3) Visit.
3. At the Screening (Week -3) Visit, have a post-bronchodilator FEV1 ? 30% and < 80% of predicted and FEV1/forced vital capacity (FVC) < 70% (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II or III).
4. Have a carbon monoxide diffusing capacity (DLCO) ? 60% of predicted (corrected for HgB) within the past 2 years OR evidence of pulmonary emphysema on CT scan within the past 2 years per the Investigator?s judgment.
5. Have clinical evidence of pulmonary emphysema per the Investigator?s judgment. |
1. Tener una concentración sérica total confirmada de inhibidor de la proteinasa alfa1 (IP-alfa1) < 11 µM. 2. Tener un diagnóstico de DAAT congénita con una combinación alélica de ZZ, SZ, Z(nulo), (nulo)(nulo), S(nulo) o alelos «en riesgo». Si el genotipo está pendiente de confirmar, el genotipado (es decir, la discriminación alélica) y el fenotipado se realizarán en la visita de selección (semana -3). 3. En la visita de selección (semana -3), tener un VEF1 posterior al uso de un broncodilatador ? 30% y < 80% del valor previsto y VEF1/capacidad vital forzada (CVF) < 70% (estadio II o III según la Iniciativa Mundial para la Enfermedad Pulmonar Obstructiva Crónica [GOLD]). 4. Tener una capacidad de difusión de monóxido de carbono (DLCO) ? 60% del valor previsto (corregida para la Hb) en los 2 años anteriores O signos de enfisema pulmonar en una TC realizada en los 2 años anteriores, a criterio del investigador. 5. Tener signos clínicos de enfisema pulmonar a criterio del investigador. |
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E.4 | Principal exclusion criteria |
1. Has received alpha1-PI augmentation therapy for more than 1 month within the six months prior to the Screening (Week -3) Visit. 2. Has received alpha1-PI augmentation therapy within one month of the Screening (Week -3) Visit. 3. Has had a COPD exacerbation within the 5 weeks prior to the Screening (Week -3) Visit or during the Screening Phase. Investigator discretion should be used to determine if a subject is appropriate for study participation if the subject has had a COPD exacerbation which occurred more than 5 weeks prior to the Screening (Week -3) Visit. 4. Unable to physically (e.g., unable to fit inside the CT scanner) or mentally (e.g., claustrophobic) undergo a CT scan. 5. History of lung or liver transplant. 6. Any lung surgery during the past 2 years (excluding lung biopsy). 7. On the waiting list for lung surgery, including lung transplant. 8. Smoking during the past 12 months or a positive urine cotinine test at screening that is due to smoking. 9. History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s). 10. Use of systemic steroids above a stable dose equivalent to 5 mg/day prednisone (i.e., 10 mg every 2 days) within the 5 weeks prior to the Screening (Week -3) Visit (inhaled steroids are not considered systemic steroids) or during the Screening Phase. It is recommended to maintain the same dose throughout the study. 11. Use of systemic or aerosolized antibiotics for a COPD exacerbation within the 5 weeks prior to the Screening (Week -3) Visit or during the Screening Phase. 12. Known selective or severe Immunoglobulin A (IgA) deficiency. |
1. Haber recibido tratamiento de aumento con IP-alfa1 durante más de un mes en los 6 meses previos a la visita de selección (semana -3). 2. Haber recibido tratamiento de aumento con IP-alfa1 en el mes previo a la visita de selección (semana -3). 3. Haber experimentado una exacerbación de la EPOC en las 5 semanas previas a la visita de selección (semana -3) o durante la fase de selección. Se utilizará el criterio del investigador para determinar la idoneidad de un sujeto para participar en el estudio si el sujeto ha experimentado una exacerbación de la EPOC más de 5 semanas antes de la visita de selección (semana -3). 4. Incapacidad física (p. ej., si no cabe dentro del escáner de TC) o mental (p. ej., claustrofobia) para someterse a una TC. 5. Antecedentes de trasplante de pulmón o hígado. 6. Cualquier intervención quirúrgica pulmonar en los 2 años anteriores (excepto biopsia pulmonar). 7. En lista de espera para una intervención de pulmón, incluido un trasplante de pulmón. 8. Consumo de tabaco durante los 12 meses anteriores o prueba de cotinina en orina positiva en la selección que se deba al consumo de tabaco. 9. Antecedentes de anafilaxia o respuesta sistémica severa a cualquier preparado de IP-alfa1 derivado del plasma u otros hemoderivados. 10. Uso de esteroides sistémicos en una dosis superior a una dosis fija equivalente a 5 mg/día de prednisona (es decir, 10 mg cada 2 días) en las 5 semanas previas a la visita de selección (semana -3) (los esteroides inhalados no se consideran esteroides sistémicos) o durante la fase de selección. Se recomienda mantener la misma dosis a lo largo de todo el estudio. 11. Uso de antibióticos sistémicos o aerosolizados para una exacerbación de la EPOC en las 5 semanas previas a la visita de selección (semana -3) o durante la fase de selección. 12. Deficiencia de inmunoglobulina A (IgA) conocida selectiva o grave. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to demonstrate, using whole lung computed tomography (CT) densitometry (15th percentile point [PD15]), a slower progression of lung tissue loss in subjects with alpha1-antitrypsin deficiency (AATD) on Alpha-1 MP (alpha1-proteinase inhibitor [human], modified process) treatment (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo. |
El objetivo principal de este estudio es demostrar, mediante densitometría por tomografía computarizada (TC) pulmonar (punto percentil 15 [PD15]), una progresión más lenta de la pérdida de tejido pulmonar en sujetos con deficiencia de alfa1-antitripsina (DAAT) en tratamiento con Alpha-1 MP (inhibidor de la proteinasa alfa1 [humano], proceso modificado) (ya sea 60 mg/kg/semana o 120 mg/kg/semana) en comparación con el placebo. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
weeks 52, 104,130 & 156 |
semanas 52, 104,130 y 156 |
|
E.5.2 | Secondary end point(s) |
The secondary objectives of this study are to demonstrate the efficacy of each IV dose of Alpha-1 MP (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo in subjects with AATD by:
- Reducing the incidence of severe COPD exacerbations as defined by an American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force criteria, and
- Slowing the progression of lung tissue loss as measured by basal lung CT densitometry (PD15).
The exploratory objectives for this study are to evaluate the effects of each IV dose of Alpha-1 MP (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo in subjects with AATD on: - The incidence and severity of COPD exacerbations as defined by ATS/ERS criteria, - Change from baseline in forced expiratory volume in 1 second (FEV1), and - Health-related quality of life as measured by the Saint George?s Respiratory Questionnaire (SGRQ).
CT scan parameters other than basal and whole lung PD15 may also be evaluated.
An additional exploratory objective is to compare the efficacy of 120 mg/kg/week Alpha-1 MP to 60 mg/kg/week Alpha-1 MP as evidenced by the change from baseline in whole lung PD15 using CT densitometry.
The safety objective of this study is to evaluate the safety and tolerability of two separate IV dose regimens (60 mg/kg/week and 120 mg/kg/week) of Alpha-1 MP. |
Los objetivos secundarios de este estudio son demostrar la eficacia de cada una de las dosis i.v. de Alpha-1 MP (60 mg/kg/semana o 120 mg/kg/semana) en comparación con el placebo en sujetos con DAAT en función de: ? La reducción de la incidencia de exacerbaciones severas de la EPOC, según la definición de los criterios del Grupo de Trabajo de la American Thoracic Society (ATS)/European Respiratory Society (ERS) y ? La ralentización de la progresión de la pérdida de tejido pulmonar determinada mediante densitometría por TC (PD15) pulmonar basal.
Los objetivos exploratorios de este estudio son evaluar los efectos de cada una de las dosis i.v. de Alpha-1 MP (60 mg/kg/semana o 120 mg/kg/semana) en comparación con el placebo en sujetos con DAAT sobre: ? La incidencia y la intensidad de las exacerbaciones de la EPOC según la definición de los criterios de ATS/ERS, ? El cambio respecto al valor basal en el volumen espiratorio forzado en 1 segundo (VEF1), y ? La calidad de vida relacionada con la salud determinada mediante el Cuestionario respiratorio de Saint George (SGRQ).
Es posible que también se evalúen parámetros de TC distintos del PD15 pulmonar basal y total. Otro objetivo exploratorio es comparar la eficacia de 120 mg/kg/semana de Alpha-1 MP con la de 60 mg/kg/semana de Alpha-1 MP según el cambio respecto al valor basal en la PD15 pulmonar total determinada mediante densitometría por TC. El objetivo de seguridad de este estudio es evaluar la seguridad y la tolerabilidad de dos pautas posológicas de administración i.v. diferentes (60 mg/kg/semana y 120 mg/kg/semana) de Alpha-1 MP. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study (please ref. ATS/ERS COPD Exacerbation Assessment row in Appendix1: study flow chart - page 64) |
A lo largo del estudio (por favor vea la línea de Evaluación de las exacerbaciones de la EPOC según ATS/ERS en el Apéndice 1:Calendario de procedimientos del estudio, página 64) |
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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 | 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 | Yes |
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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Serbia |
Argentina |
Australia |
Brazil |
Canada |
Czech Republic |
Denmark |
Estonia |
France |
Hungary |
Ireland |
Latvia |
Lithuania |
Netherlands |
New Zealand |
Norway |
Spain |
Sweden |
Poland |
Slovakia |
United Kingdom |
United States |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 4 |