E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paroxysmal nocturnal hemoglobinuria (PNH) |
hemoglobinuria paroxística nocturna (HPN) |
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E.1.1.1 | Medical condition in easily understood language |
Paroxysmal nocturnal hemoglobinuria (PNH) |
hemoglobinuria paroxística nocturna (HPN) |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055629 |
E.1.2 | Term | Paroxysmal nocturnal hemoglobinuria |
E.1.2 | System Organ Class | 100000004857 |
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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 the study is to describe the long-term safety, tolerability, and efficacy of pozelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria (PNH) |
El objetivo principal del estudio es describir la seguridad, tolerabilidad y eficacia a largo plazo de la terapia combinada de pozelimab y cemdisiran en pacientes con hemoglobinuria paroxística nocturna (HPN). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to describe the long-term effect of the combination of pozelimab and cemdisiran on: • Measures of intravascular hemolysis • Transfusion parameters • Hemoglobin levels • Fatigue as assessed by a Patient Reported Outcome (PRO) • Physical Function as assessed by a PRO • Change in Global Health Status (GHS) as assessed by a PRO • Complement activation • Concentrations of total pozelimab in serum and cemdisiran and total complement component 5 (C5) protein in plasma • Immunogenicity of pozelimab & cemdisiran |
El objetivo principal del estudio es definir la seguridad, tolerabilidad y eficacia a largo plazo del tratamiento combinado con pozelimab y cemdisiran: • Indicadores de hemólisis intravascular • Parámetros de transfusión • Cantidad de hemoglobina • Fatiga evaluada mediante resultados comunicados por el paciente (RCP) • Función física evaluada mediante RCP • Cambio en el estado de salud general (ESG) evaluado mediante RCP • Activación del complemento • Concentraciones totales de pozelimab en suero y cemdisiran y proteína total del componente 5 del complemento (C5) en plasma • Inmunogenicidad del pozelimab y el cemdisiran |
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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 |
Future Biomedical Research Patients who agree to participate in the future biomedical research (FBR) sub-study will be required to consent to this optional sub-study before samples are banked for FBR. The samples may be utilized for FBR that may or may not be directly related to the study, including being used as reference samples and assay development or validation. The results of these future biomedical research analyses will not be presented in the CSR.
Pharmacogenomic Analysis Patients who agree to participate in the genomics sub-study will be required to consent to this optional sub-study before collection of the samples. The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or biomarker response to pozelimab and cemdisiran, other PNH clinical outcome measures and possible AEs. In addition, associations between genomic variants and prognosis or progression of PNH as well as related complement-mediated diseases may also be studied. These data may be used or combined with data collected from other studies to identify and validate genomic markers related to the study drug, target pathway, or PNH and related diseases. |
Investigación biomédica futura Los pacientes que acepten participar en el subestudio de investigación biomédica futura (IBF) deberán dar su consentimiento para este subestudio opcional antes de que las muestras se almacenen para IBF. Las muestras se pueden utilizar para IBF que pueden o no estar directamente relacionadas con el estudio, incluido el uso como muestras de referencia y desarrollo o validación de ensayos. Los resultados de estos análisis de investigación biomédica futura no se presentarán en el CSR. Análisis farmacogenómico Los pacientes que acepten participar en el subestudio de genómica deberán dar su consentimiento para este subestudio opcional antes de la recolección de las muestras. El propósito de los análisis farmacogenómicos es identificar asociaciones genómicas con respuesta clínica o de biomarcadores a pozelimab y cemdisiran, otras medidas de resultados clínicos de HPN y posibles AA. Además, también se pueden estudiar las asociaciones entre las variantes genómicas y el pronóstico o la progresión de la HPN, así como las enfermedades relacionadas mediadas por el complemento. Estos datos pueden usarse o combinarse con datos recopilados de otros estudios para identificar y validar marcadores genómicos relacionados con el fármaco del estudio, la vía diana o la HPN y enfermedades relacionadas. |
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E.3 | Principal inclusion criteria |
1. Patients with PNH who have completed, without permanent discontinuation, study treatment in at least 1 of the parent studies (R3918-PNH-2021[NCT05133531] and/or R3918-PNH-2022 [NCT05131204]) including the transition period, if applicable.
Other protocol-defined Inclusion Criteria apply |
1. Pacientes con HPN que han completado, sin interrupción permanente, el tratamiento del estudio en al menos uno de los estudios de origen (R3918-PNH-2021 o R3918-PNH-2022), incluido el periodo de transición, si corresponde.
Se aplican otros criterios de inclusión definidos en el protocolo. |
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E.4 | Principal exclusion criteria |
1. Significant protocol deviation(s) in the parent study based on the investigator’s judgment and to the extent that these would (if continued) impact the study objectives and/or safety of the patient (eg, repetitive non-compliance with dosing by the patient). 2. Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in or completing the study.
Other protocol-defined Exclusion Criteria apply |
1. Desviaciones significativas del protocolo en el estudio de origen según la opinión del investigador y en la medida en que (si continuaran) afectarían los objetivos del estudio y/o la seguridad del paciente (por ejemplo, incumplimiento repetitivo de la administración del medicamento por parte del paciente). 2. Cualquier enfermedad nueva o empeoramiento de una enfermedad existente que, en opinión del investigador, haga que el paciente no sea adecuado para participar o pueda interferir con la capacidad del paciente para participar o finalizar el estudio.
Se aplican otros criterios de inclusión definidos en el protocolo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence and severity of treatment-emergent serious adverse events (SAEs) 2. Incidence and severity of treatment-emergent adverse events of special interest (AESIs) 3. Treatment emergent adverse events (AEs) leading to permanent treatment discontinuation 4. Maintenance of adequate control of hemolysis |
1. Incidencia y la gravedad de los acontecimientos adversos graves (AAG) surgidos durante el tratamiento 2. Incidencia y la gravedad de los acontecimientos adversos de interés especial (AAIE) 3. Incidencia y la gravedad de los AA que lleven a la suspensión permanente del tratamiento durante el periodo de extensión abierto de 108 semanas 4. Mantenimiento de un control adecuado de la hemólisis |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3: Up to week 108 4: Post-baseline to week 36 |
1-3: Hasta la semana 108 4: Post-basal hasta semana 36 |
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E.5.2 | Secondary end point(s) |
1. Maintenance of adequate control of hemolysis 2. Adequate control of hemolysis 3. Transfusion avoidance 4. Breakthrough hemolysis 5. Hemoglobin stabilization 6. Percent change in lactate dehydrogenase (LDH) 7. Change in fatigue as measured by the FACIT-Fatigue scale 8. Change in physical function (PF) scores on the EORTC QLQ-C30 9. Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 10. Normalization of LDH 11. Rate of RBC transfusion 12. Number of units of RBC transfusion 13. Percentage of days with LDH ≤1.5x upper limit of normal (ULN) 14. Change in hemoglobin levels 15. Change in CH50 16. Percent change in CH50 17. Concentrations of total pozelimab in serum 18. Concentrations of cemdisiran in plasma 19. Incidence of treatment-emergent anti-drug antibodies to pozelimab 20. Incidence of treatment-emergent anti-drug antibodies to cemdisiran 21. Concentration of total C5 in plasma 22. Percent change of concentration of total C5 in plasma |
• Mantenimiento de un control adecuado de la hemólisis • Control adecuado de la hemólisis • Evitación de transfusiones, • Hemólisis irruptiva • Estabilización de la hemoglobina • Cambio porcentual en la LDH • Variaciones en el grado de fatiga medidas a través de la escala FACIT-fatiga • Cambios en las puntuaciones de la función física (FF) en los ítems EORTC QLQ-C30 • Cambio en la escala ESG/CV (calidad de vida) en el EORTC QLQ-C30 • Normalización de la cantidad de LDH, • Porcentaje de transfusión de eritrocitos • Número de unidades de transfusión de eritrocitos • Porcentaje de días con la LDH ≤1,5 × LSN desde el momento basal • Cambio en la cantidad de hemoglobina • Cambio en CH50 • Cambio porcentual en CH50 • Concentraciones de pozelimab total en suero • Concentraciones de cemdisiran en plasma • Incidencia de anticuerpos contra el pozelimab surgidos durante el tratamiento • Incidencia de anticuerpos contra el cemdisiran surgidos durante el tratamiento • Concentración de C5 total en plasma • Cambio en el porcentaje de concentración de C5 total en plasma |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: Post-baseline through week 48, 76, 108 2, 10: Post-baseline through week 108 3-5, 11-13: Post-baseline through week 36, 48, 76, 108 6-9, 14: From baseline to week 36, 48, 76, 108 15-17, 19-22: Through week 108 18: Through week 24 |
1: Post-basal hasta el inicio de las semanas 48, 76, 108 2, 10: Post-basal hasta el inicio de la semana 108 3-5, 11-13: Post-basal hasta el inicio de las semanas 36, 48, 76, 108 6-9, 14: Desde semana basal hasta las semanas 36, 48, 76, 108 15-17, 19-22: hasta el inicio de la semana 108 18: hasta el inicio de la semana 24 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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 | 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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 19 |
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 |
Brazil |
Canada |
China |
Colombia |
India |
Japan |
Jordan |
Korea, Democratic People's Republic of |
Malaysia |
Mexico |
Peru |
Philippines |
Singapore |
South Africa |
Taiwan |
Thailand |
United States |
France |
Poland |
Romania |
Spain |
Germany |
Greece |
Italy |
Hungary |
Turkey |
United Kingdom |
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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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The end of study is defined as the date the last patient completes the last study visit, withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator) |
El fin del estudio se define como la fecha en que el último paciente completa la última visita del estudio, se retira del estudio o se pierde durante el seguimiento (es decir, el investigador ya no puede ponerse en contacto con el paciente del estudio). |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |