E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A or B |
Hemofilia A o B |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A or B |
Hemofilia A o B |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066439 |
E.1.2 | Term | Hemophilia |
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 confirm appropriate dose levels of fitusiran when administered to male pediatric participants (ages 1 to <12 years of age) with severe hemophilia A or B |
Confirmar los niveles de dosis adecuados de fitusiran cuando se administra a participantes pediátricos varones (de 1 a menos de 12 años de edad) que padecen hemofilia A o B grave. |
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E.2.2 | Secondary objectives of the trial |
- To characterize the safety and tolerability - To characterize the pharmacokinetics (PK) |
- Caracterizar la seguridad y tolerabilidad - Caracterizar la farmacocinética (FC) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male, aged 1 to <12 years at the time of enrollment. - Severe hemophilia A or B (Factor VIII (FVIII) <1% or Factor IX (FIX) ≤2%) - Participants must have inhibitory antibodies to FVIII or FIX and must meet one of the following Nijmegen-modified Bethesda assay results criteria: - Inhibitor titer of ≥0.6 BU/mL at screening, OR - Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, OR - Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of anamnestic response. - Adequate peripheral venous access, as determined by the Investigator, to allow the blood draws required by the study protocol. - Weight requirements at the time of enrollment: 8 to <45 kg - Willing and able to comply with the study requirements and to provide signed written informed consent obtained from parent(s)/legal guardian (hereinafter the “parent”) and written or oral assent obtained from participant, per local and national requirements. |
- Hombres, de 1 a menos de 12 años en el momento de la selección - Hemofilia severa A o B (Factor VIII (FVIII) inferior a 1% o Factor IX (FIX) inferior o igual a 2%) - Los participantes deben tener anticuerpos inhibidores contra FVIII o FIX y deben cumplir uno de los siguientes criterios de resultados del ensayo Nijmegen-modified Bethesda: - Título de inhibidor de mayor o igual a 0.6 BU / mL en la selección, O - Título de inhibidor de menos de 0,6 BU / mL en la selección con evidencia de registro médico de 2 títulos consecutivos mayor o igual a 0,6 BU / mL, O - Título de inhibidor de menos de 0,6 BU / mL en el cribado con evidencia de registro clínico de respuesta anamnésica. - Acceso venoso periférico adecuado, según lo determine el investigador, para permitir las extracciones de sangre requeridas por el protocolo del estudio. - Requisitos de peso en el momento de la inscripción: 8 a menos de 45 kg. - Estar dispuesto y ser capaz de cumplir con los requisitos del estudio y proporcionar el consentimiento informado por escrito y firmado obtenido de los padres / tutor legal (en adelante, el "padre") y el consentimiento escrito u oral obtenido del participante, según los requisitos locales y nacionales. |
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E.4 | Principal exclusion criteria |
- Known co-existing bleeding disorders other than hemophilia A or B - Antithrombin (AT) activity <60% at Screening - Co-existing thrombophilic disorder - Clinically significant liver disease - Active Hepatitis C virus infection - Acute or chronic Hepatitis B virus infection - Acute Hepatitis A or hepatitis E infection - HIV positive with a CD4 count of <400 cells/μL - History of arterial or venous thromboembolism, unrelated to an indwelling venous access - Inadequate renal function - History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc) - Subjects with central or peripheral indwelling catheters, with history of venous access complications leading to hospitalization and/or systemic anticoagulation therapy. - History of intolerance to subcutaneous (SC) injection(s) - Any other conditions or comorbidities that would make the patient unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment |
- Trastornos hemorrágicos coexistentes conocidos distintos de la hemofilia A o B - Actividad de antitrombina (AT) inferior a 60% en la selección - Trastorno trombofílico coexistente - Enfermedad hepática clínicamente significativa. - Infección activa por el virus de la hepatitis C - Infección aguda o crónica por el virus de la hepatitis B - Infección aguda por hepatitis A o hepatitis E - VIH positivo con un recuento de CD4 de menos de 400 células / μL - Antecedentes de tromboembolismo arterial o venoso, no relacionado con un acceso venoso permanente. - Función renal inadecuada. - Historial de alergias a múltiples medicamentos o historial de reacción alérgica a un oligonucleótido o N-acetilgalactosamina (GalNAc) - Sujetos con catéteres permanentes centrales o periféricos, con antecedentes de complicaciones de acceso venoso que llevan a hospitalización y / o terapia de anticoagulación sistémica. - Historial de intolerancia a la inyección (s) subcutánea (SC) - Cualquier otra condición o comorbilidad que haga que el paciente no sea adecuado para la selección o que pueda interferir con la participación o la finalización del estudio, según el criterio del investigador. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Lowering of plasma antithrombin (AT) activity level; Lowering of plasma antithrombin (AT) activity level from Day 1 pre-fitusiran dose to Day 85 |
Reducción del nivel de actividad de antitrombina (AT) plasmática desde el día 1 antes de la dosis de fitusiran hasta el día 85. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1 to Day 85 |
Desde el día 1 hasta el día 85. |
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E.5.2 | Secondary end point(s) |
1 - Number of participants reported with adverse events; Number of participants reported with treatment-emergent adverse events (TEAEs) 2 - Pharmacokinetics (PK): Maximum plasma concentration (Cmax); Plasma samples will be collected for measurement of plasma concentrations of fitusiran such as Cmax. 3 - Pharmacokinetics (PK): Time to reach maximum plasma concentration (Tmax); To evaluate time to reach Cmax 4 - Pharmacokinetics (PK): Ctrough; To evaluate concentration observed just before investigational medicinal product (IMP) administration during repeated dosing (Ctrough) |
1 - Número de participantes que informan acontecimientos adversos (AA); Número de participantes que informan de acontecimientos adversos emergentes del tratamiento (AAET) 2 - Farmacocinética (FC): concentración plasmática máxima (Cmax); Se recogerán muestras de plasma para medir las concentraciones plasmáticas de fitusiran, como la Cmax. 3 - Farmacocinética (FC): tiempo para alcanzar la concentración plasmática máxima (Tmax); Evaluar el tiempo para alcanzar la Cmax. 4 - Farmacocinética (FC): Ctrough; Para evaluar la concentración observada justo antes de la administración del medicamento en investigación (IMP) durante la dosificación repetida (Ctrough) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 : 160 weeks 2, 3, 4 : Day 1, Day 29, Day 57 |
1: 160 semanas 2, 3, 4: Día 1, Día 29, Día 57 |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 |
Canada |
Italy |
Spain |
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 |
Última visita del último paciente |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |