E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary infection prophylaxis in patients with chronic lymphocytic leukemia (CLL) and secondary hypogammaglobulinemia |
Profilaxis primaria de la infección en pacientes con leucemia linfocítica crónica (LLC) e hipogammaglobulinemia secundaria. |
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E.1.1.1 | Medical condition in easily understood language |
Prophylaxis to prevent infection in patients with a type of cancer that starts in bone marrow and then go into the blood |
Profilaxis para prevenir infecciones en pacientes con un tipo de cáncer que comienza en la médula ósea y continua hasta la sangre. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 primary objective of this study is to demonstrate the benefit of Panzyga administration compared with placebo as primary infection prophylaxis in CLL patients with secondary immunodeficiency (SID) undergoing CLL antineoplastic therapy. |
El objetivo principal de este estudio es demostrar el beneficio de la administración de Panzyga, en comparación con placebo, como profilaxis primaria de la infección en pacientes con LLC e inmunodeficiencia secundaria (IDS) que reciben tratamiento antineoplásico para la LLC. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to compare the following aspects in CLL patients with SID treated with and without primary Panzyga prophylaxis: • Overall infection rate • Frequency of prophylaxis with anti-infectives (antibacterials and antivirals) • Duration of prophylaxis with anti-infectives (antibacterials and antivirals) |
Los objetivos secundarios de este estudio son comparar los siguientes aspectos en pacientes con LLC e IDS tratados con y sin profilaxis primaria con Panzyga: • Tasa global de infecciones. • Frecuencia de la profilaxis con antiinfecciosos (antibacterianos y antivirales). • Duración de la profilaxis con antiinfecciosos (antibacterianos y antivirales). |
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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 |
Pharmacokinetic (PK) Sub-study: Pharmacokinetic parameters will be determined in a subgroup of patients. Blood samples for the PK profiles of total IgG will be taken. The following parameters will be assessed for patients treated with Panzyga. • Half-life (T1/2) • Area under the curve (AUC0-t; AUC0-infinity) • Volume of distribution (Vd) • Concentration maximum (Cmax; Tmax) • Clearance (Cl) For patients treated with Placebo, no PK parameters will be estimated, as the underlying assumptions for exponential modelling are not fulfilled. |
Sub-estudio farmacocinético: Los parámetros farmacocinéticos se determinarán en un subgrupo de los pacientes. Las muestra |
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E.3 | Principal inclusion criteria |
1. Treatment-naïve or relapsed/refractory CLL patients undergoing CLL antineoplastic treatment. Diagnosis of B-cell CLL established according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and documented within medical records. 2. Hypogammaglobulinemia (IgG levels <5 g/L) as confirmed by the Central Laboratory. 3. ≥18 years of age. 4. Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted. |
1. Pacientes con LLC no tratada previamente o recidivante/resistente que reciben tratamiento antineoplásico para la LLC. Diagnóstico de LLC de linfocitos B establecido conforme a los criterios del International Workshop on Chronic Lymphocytic Leukemia (iwCLL) y documentado en la historia clínica. 2. Hipogammaglobulinemia (concentración de IgG <5 g/l) confirmada por el laboratorio central. 3. Edad ≥18 años. 4. Consentimiento informado por escrito y firmado, otorgado voluntariamente antes de realizar ningún procedimiento relacionado con el estudio. |
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E.4 | Principal exclusion criteria |
1. IgG treatment within 3 months prior to Screening. 2. Antibiotic prophylaxis and/or treatment within 7 days prior to Baseline (with the exception of trimethoprim-sulfamethoxazole [TMP/SMX], diaminodiphenyl sulfone [dapsone] and pentamidine inhalation). 3. Current major infection or >1 major infection in the previous 6 months before Baseline. 4. History of anaphylaxis or severe systemic response to immunoglobulin, blood or plasma-derived products or any Panzyga component. 5. History of a non-CLL malignancy or other medical condition with life-expectancy of less than two years. 6. Severe liver disease, with signs of ascites and/or hepatic encephalopathy. 7. Severe kidney disease (as defined by estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2). 8. Body weight >140 kg. 9. Eastern Cooperative Oncology Group (ECOG) performance score of >2 (Appendix 1). 10. Female patients of childbearing potential unwilling to use a protocol-required method of contraception from the Screening Visit throughout the study treatment period and for 30 days following the last dose of study drug. 11. Human immunodeficiency virus (HIV) infection at Screening (defined for the study as positive HIV antibody test). 12. Patients found to be chronic carriers of hepatitis B virus (HBV), defined by positive surface antigen (HBsAg), positive Hepatitis B core antibodies (HBcAb) and/or low HBV titers, who will not receive targeted antiviral therapy while undergoing CLL therapy, and patients with active HBV, defined as high HBV titers. 13. Uncontrolled hepatitis C infection at Screening (defined for the study as positive hepatitis virus C [HCV] polymerase chain reaction [PCR]). 14. Pregnant and lactating women. 15. Subjects with a history of thromboembolic events (TEE) such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease (Fontaine IV) within 6 months before Baseline. 16. Planned or ongoing immunosuppressive treatment (other than for CLL or corticosteroids) or other forbidden medication during the entire study duration after study enrollment. 17. Participation in another interventional clinical trial that is either blinded or involves an investigational (not approved) product within 3 months before Baseline or during the course of the clinical study. Participation in observational clinical trials or open-label trials involving an approved product may be permitted after consultation with the medical monitor. 18. Known IgA deficiency with antibodies to IgA (as part of the patient´s medical history). 19. Known blood hyperviscosity, or other hypercoagulable states. 20. Patients unable or unwilling to understand or comply with the study protocol. |
1. Tratamiento con IgG en los 3 meses previos a la selección. 2. Profilaxis y/o tratamiento con antibióticos en los 7 días previos al momento basal (con la excepción de trimetoprima-sulfametoxazol [TMP/SMX], diaminodifenil sulfona [dapsona] y pentamidina inhalada). 3. Infección importante actual o >1 infección importante en los 6 meses previos al momento basal. 4. Antecedentes de anafilaxia o respuesta sistémica grave a inmunoglobulinas, a productos derivados de la sangre o el plasma o a cualquier componente de Panzyga. 5. Antecedentes de neoplasia maligna distinta de la LLC u otra enfermedad con una esperanza de vida inferior a dos años. 6. Enfermedad hepática grave, con signos de ascitis y/o encefalopatía hepática. 7. Enfermedad renal grave (definida por una filtración glomerular estimada [FGe]<30 ml/min/1,73 m2). 8. Peso corporal >140 kg. 9. Estado funcional del Eastern Cooperative Oncology Group (ECOG) >2 (apéndice 1). 10. Mujeres en edad fértil que no estén dispuestas a utilizar un método anticonceptivo exigido por el protocolo (según la sección 7.3.9 b del protocolo) desde la visita de selección, durante todo el período de tratamiento del estudio y hasta 30 días después de la última dosis del fármaco del estudio. 11. Infección por el virus de la inmunodeficiencia humana (VIH) en la selección (definida en este estudio como un resultado positivo en un análisis de anticuerpos anti-VIH). 12. Pacientes que resulten ser portadores crónicos del virus de la hepatitis B (VHB), definidos por positividad para el antígeno de superficie del virus de la hepatitis B (HBsAg), positividad para anticuerpos contra el antígeno central del virus de la hepatitis B (HBcAb) y/o títulos bajos de VHB que no recibirán tratamiento antiviral dirigido durante el tratamiento de la LLC y pacientes con VHB activo, definido como títulos altos de VHB. 13. Infección por el virus de la hepatitis C no controlada en la selección (definida en este estudio como un resultado positivo en la reacción en cadena de la polimerasa [PCR] para el virus de la hepatitis C [VHC]). 14. Mujeres embarazadas o en período de lactancia. 15. Sujetos con antecedentes de episodios tromboembólicos (ETE) como trombosis venosa profunda, embolia pulmonar, infarto de miocardio, ictus isquémico, accidente isquémico transitorio o arteriopatía periférica (Fontaine IV) en los 6 meses previos al momento basal. 16. Tratamiento inmunodepresor previsto o en curso (que no sea para la LLC o corticosteroides) u otra medicación prohibida durante todo el estudio tras el reclutamiento en el estudio. 17. Participación en otro ensayo clínico intervencionista con enmascaramiento o que incluya un producto en investigación (no aprobado) en los 3 meses previos al momento basal o durante el transcurso del estudio clínico. Podrá permitirse la participación en ensayos clínicos observacionales o ensayos abiertos de un producto aprobado previa consulta con el monitor médico. 18. Déficit conocido de IgA con anticuerpos anti-IgA (como parte de los antecedentes médicos del paciente). 19. Hiperviscosidad sanguínea conocida u otros estados de hipercoagulabilidad. 20. Pacientes incapaces o no dispuestos a comprender o cumplir el protocolo del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Since the study objective is to show the benefit of Panzyga administration as primary infection prophylaxis, the primary endpoint is not the major infection rate but occurrence of at least one major infection in CLL patients with or without primary infection prophylaxis with Panzyga. Therefore, although patients will stay in the study regardless of the number of major infections, each patient will be counted only once for the primary endpoint calculation. Major infection for this trial is defined as: • Bacterial and/or viral infections resulting in death. Confirmed cases of COVID-19 are excluded. • Bacterial and/or viral infections, which are microbiologically documented (MDI) or clinically documented (CDI) requiring treatment with anti-infectives; upper respiratory tract infections, bronchitis, lower urinary tract infections, localized skin infections and stomatitis (MDI or CDI) are considered major only if they require treatment with anti-infectives AND hospitalization or hospitalization prolongation. Confirmed cases of COVID-19 are excluded. • FUO requiring hospitalization or hospitalization prolongation |
Dado que el objetivo del estudio es demostrar el beneficio de la administración de Panzyga como profilaxis de infecciones primarias, el criterio de valoración primario no es la tasa de infecciones importantes, sino la aparición de al menos una infección importante en pacientes con LLC con o sin profilaxis de infecciones primarias con Panzyga. Por lo tanto, aunque los pacientes permanecerán en el estudio independientemente del número de infecciones graves, cada paciente se contará una sola vez para el cálculo del criterio de valoración principal.
En este ensayo, una infección importante se define como:
• Infecciones bacterianas o virales con resultado de muerte. Quedan excluidos los casos confirmados de COVID-19. • Infecciones bacterianas o virales, documentadas microbiológicamente (IDM) o documentadas clínicamente (IDC) que requieren tratamiento con antiinfecciosos; las infecciones de las vías respiratorias superiores, bronquitis, infecciones de las vías urinarias inferiores, infecciones cutáneas localizadas y estomatitis (IDM o IDC) se consideran importantes solo si requieren tratamiento con antiinfecciosos Y hospitalización o prolongación de una hospitalización. Quedan excluidos los casos confirmados de COVID-19. • Fiebre de origen desconocido (FOD) que requiere hospitalización o prolongación de una hospitalización. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint of major infection. |
Punto temporal de infección importante. |
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E.5.2 | Secondary end point(s) |
• Overall infection rate: infection rate for all infections. • Frequency of prophylaxis with anti-infectives (antibacterials and antivirals). • Duration of prophylaxis with anti-infectives (antibacterials and antivirals). |
• Tasa global de infecciones: tasa de infecciones de cualquier tipo. • Frecuencia de la profilaxis con antiinfecciosos (antibacterianos y antivirales). • Duración de la profilaxis con antiinfecciosos (antibacterianos y antivirales). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Infections throughout the study • anti-infectives frequency throughout the study • duration of prophylaxis throughout the study |
• Infecciones durante el estudio • Frecuencia de antiinfecciosos durante el estudio • Duración de la profilaxis durante el estudio |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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 | 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 | 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 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
United States |
Poland |
Spain |
Czechia |
Greece |
Italy |
Denmark |
Hungary |
Russian Federation |
Turkey |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |