E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital antithrombin deficiency |
Deficiencia congénita de antitrombina |
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E.1.1.1 | Medical condition in easily understood language |
Inherited antithrombin deficiency |
Deficiencia hereditaria de antitrombina |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10083881 |
E.1.2 | Term | Antithrombin deficiency |
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 |
The primary objective of this study is to assess the incidence of the composite of thrombotic events (TEs) and thromboembolic events (TEEs) in patients with congenital antithrombin deficiency under cover of Atenativ for surgical procedures or parturition |
El objetivo principal de este estudio es evaluar la incidencia de la combinación de acontecimientos trombóticos (AT) y acontecimientos tromboembólicos (ATE) en pacientes con deficiencia congénita de antitrombina bajo la cobertura de Atenativ para procedimientos quirúrgicos o partos. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to: • Assess the single-dose PK of Atenativ in patients with congenital antithrombin deficiency • Assess coagulation parameters in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition • Assess the safety and tolerability of Atenativ in patients with congenital antithrombin deficiency |
Los objetivos secundarios de este estudio son: •Evaluar la farmacocinética (FC) de una dosis única de Atenativ en pacientes con deficiencia congénita de antitrombina •Evaluar los parámetros de coagulación en pacientes con deficiencia congénita de antitrombina sometidos a procedimientos quirúrgicos o partos •Evaluar la seguridad y tolerabilidad de Atenativ en pacientes con deficiencia congénita de antitrombina |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients who meet all of the following criteria are eligible for the study:
1. Adult male or female patients ≥18 and ≤80 years of age
2. Documented congenital antithrombin deficiency, defined by plasma level of antithrombin ≤60% [16]
3. Personal or family history of TEs or TEEs
4. For the Treatment Phase: either a) non-pregnant surgical patients scheduled for elective surgical procedure(s) known to be associated with a high risk for occurrence of TEs or TEEs, or b) pregnant patients of at least 27 weeks gestational age who are scheduled for caesarean section or delivery
5. For female patients of childbearing potential entering the PK Phase who are not known to be pregnant, and for female surgical patients of childbearing potential entering the Treatment Phase for any procedure other than caesarean section or delivery, a negative urine pregnancy test at screening and at baseline
6. Patient has provided informed consent |
Los pacientes que cumplen los siguientes criterios son elegibles para el estudio: 1. Pacientes adultos varones o mujeres de ≥18 y ≤80 años 2.Deficiencia congénita de antitrombina documentada, definida por un nivel plasmático de antitrombina ≤60 % 3.Antecedentes personales o familiares de AT o ATE 4.Para la fase de tratamiento: a) pacientes quirúrgicas no embarazadas programadas para someterse a procedimiento(s) quirúrgico(s) voluntario(s) programado(s) que se sabe que están asociados a un alto riesgo de aparición de AT o ATE, o b) pacientes embarazadas de al menos 27 semanas de edad gestacional que tengan programada una cesárea o parto 5.Para las pacientes en edad fértil que entren en la fase FC y que no se sepa que están embarazadas, y para las pacientes quirúrgicas en edad fértil que entren en la fase de tratamiento para cualquier procedimiento que no sea la cesárea o el parto, una prueba de embarazo en orina negativa en la selección y al inicio 6.El paciente ha dado su consentimiento informado |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria at the time of screening are not eligible for the study:
1. Requires emergency surgery or emergency caesarean section
2. Has undergone surgery within the last 6 weeks
3. History or suspicion of another hereditary thrombophilic disorder other than antithrombin deficiency (e.g., activated protein C [APC] resistance/Factor V Leiden, Protein S or C deficiency, prothrombin gene mutation [G20210A], or acquired [lupus anticoagulant] thrombophilic disorder)
4. Malignancies, renal failure, or severe liver disease (aspartate aminotransferase [ASAT] >5 times the upper limit of normal)
5. Body mass index >40 kg/m2
6. Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ
7. History of anaphylactic reaction(s) to blood or blood components
8. Refusal to receive transfusion of blood-derived products
9. Administration of any antithrombin concentrate or antithrombin-containing blood product other than the study medication within 14 days of either of the two phases of the study
10. Prior diagnosis with heparin-induced thrombocytopenia
11. TE or TEE within the last 6 months
12. Female patients who are nursing
13. Have participated in another investigational study within the last 30 days |
Los pacientes que cumplan cualquiera de los siguientes criterios al momento de la selección no son elegibles para el estudio: 1. Requiere cirugía de urgencia o cesárea de urgencia 2.Se ha sometido a una intervención quirúrgica en las últimas 6 semanas 3.Antecedentes o sospecha de otro trastorno trombofílico hereditario distinto de la deficiencia de antitrombina (p. ej., resistencia a la proteína C activada [PCA]/factor V Leiden, deficiencia de proteína S o C, mutación del gen de la protrombina [G20210A] o trastorno trombofílico [anticoagulante lúpico] adquirido) 4.Neoplasias malignas, insuficiencia renal o hepatopatía grave (aspartato aminotransferasa [ASAT] >5 veces el límite superior de la normalidad) 5.Índice de masa corporal >40 kg/m2 6.Hipersensibilidad conocida o reacción alérgica a la antitrombina o a cualquiera de los excipientes de Atenativ 7.Antecedentes de reacción(es) anafiláctica(s) a la sangre o a los componentes sanguíneos 8.Negativa a recibir transfusión de hemoderivados 9.Administración de cualquier concentrado de antitrombina o hemoderivado que contenga antitrombina que no sea el medicamento del estudio en los 14 días anteriores a cualquiera de las dos fases del estudio 10.Diagnóstico previo de trombocitopenia inducida por heparina 11.AT o ATE en los últimos seis meses 12.Pacientes de sexo femenino que están en periodo de lactancia 13.Haber participado en otro estudio de investigación en los últimos 30 días |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence of the composite of TEs and TEEs in patients with congenital antithrombin deficiency under cover of Atenativ for surgical procedures or parturition to 30 days after treatment initiation |
Incidencia de la combinación de AT y ATE en pacientes con deficiencia congénita de antitrombina bajo cobertura de Atenativ para procedimientos quirúrgicos o parto hasta 30 días después del inicio del tratamiento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
30 days after treatment initiation |
30 días después de la iniciación del tratamiento |
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E.5.2 | Secondary end point(s) |
Secondary endpoints include the following PK parameters following a single dose of Atenativ: • Area under the curve (AUCnorm(0–∞)) • Maximum plasma concentration (Cmax) • Half-life (t1/2) • Mean residence time (MRT) • Clearance (CL) • Incremental IVR (peak concentration of antithrombin observed within the first hour after infusion) • Volume of distribution at steady state (Vss) • Time to reach maximum plasma concentration (Tmax)
Efficacy • Antithrombin activity • Coagulation parameters (activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalised ratio [INR] and fibrinogen)
Safety • AEs and serious AEs (SAEs) • Length of hospital stay • Vital signs (including systolic and diastolic blood pressure, pulse rate, body temperature, respiration rate, results of physical examination) • Standard haematological and clinical chemical safety variables, as well as thrombogenicity markers including D-dimer, prothrombin fragment 1 + 2 (F1+2), and thrombin-antithrombin complex (TAT). |
Parámetros FC: •Parámetros FC tras una dosis única de Atenativ en pacientes con deficiencia congénita de antitrombina: oÁrea bajo la curva (ABCnorm(0–∞)) oConcentración máxima en plasma (Cmáx) oSemivida (t1/2) oTiempo medio de residencia (TMR) oAclaramiento (CL) oRecuperación incremental in vivo (RIV; concentración máxima de antitrombina observada en la primera hora después de la infusión) oVolumen de distribución en situación de equilibrio (Vse) oTiempo para lograr la máxima concentración plasmática (Tmáx)
Parámetros de eficacia: •Actividad antitrombina •Parámetros de coagulación (tiempo de tromboplastina parcial activada [TTPa], tiempo de protrombina [TP], índice internacional normalizado [INR] y fibrinógeno)
Parámetros de la seguridad: •Acontecimientos adversos (AA) y AA graves (AAG) •Duración de la hospitalización •Constantes vitales (incluidas la presión arterial sistólica y diastólica, la frecuencia cardíaca, la temperatura corporal, la frecuencia respiratoria, los resultados de la exploración física) •Variables de seguridad hematológicas y clínicas estándar, así como marcadores de trombogenicidad que incluyen dímero D, fragmento de protrombina 1 + 2 (F1+2) y complejo trombina-antitrombina (TAT) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
occurrence of TEs and TEEs |
Ocurrencia de AT o ATE |
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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 | 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) | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
United States |
Austria |
Belgium |
France |
Germany |
Hungary |
Italy |
United Kingdom |
Spain |
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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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LVLS |
Última Visita 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 | 2 |
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 |