E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital antithrombin deficiency |
Deficit congenito di antitrombina |
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E.1.1.1 | Medical condition in easily understood language |
Inherited antithrombin deficiency |
Deficit ereditario di 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. |
L’obiettivo primario di questo studio è valutare l’incidenza del composito di eventi trombotici (TE) ed eventi tromboembolici (TEE) in pazienti con deficit congenito di antitrombina in trattamento con Atenativ nelle procedure chirurgiche o parto. |
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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 . |
Gli obiettivi secondari di questo studio sono: • Valutare la farmacocinetica (PK) a dose singola di Atenativ in pazienti con deficit congenito di antitrombina • Valutare i parametri di coagulazione in pazienti con deficit congenito di antitrombina sottoposti a procedure chirurgiche o parto • Valutare la sicurezza e la tollerabilità di Atenativ in pazienti con deficit congenito di 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 |
1. Pazienti adulti di sesso maschile o femminile di età >= 18 e <= 80 anni 2. Deficit congenito documentato di antitrombina, definito da un livello plasmatico di antitrombina minore uguale <=60% 3. Anamnesi personale o familiare di TE o TEE 4. Per la fase di trattamento: a) pazienti chirurgici non in gravidanza per i quali sono state programmate una o più procedure chirurgiche elettive, note per essere associate a un alto rischio di insorgenza di TE o TEE, o b) pazienti in gravidanza di almeno 27 settimane di età gestazionale per le quali è programmato il parto cesareo o naturale 5. Per le pazienti in età fertile che accedono alla fase PK di cui non è noto lo stato di gravidanza e per le pazienti chirurgiche in età fertile che accedono alla fase di trattamento per qualsiasi procedura diversa dal parto cesareo o naturale, test di gravidanza delle urine negativo allo screening e al basale 6. Il paziente ha fornito il consenso informato |
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E.4 | Principal exclusion criteria |
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. |
1. Necessità di intervento chirurgico o taglio cesareo di emergenza 2. Il paziente ha subito un intervento chirurgico nelle ultime 6 settimane 3. Anamnesi o sospetto di altro disturbo trombofilico ereditario diverso dal deficit di antitrombina (ad es., resistenza alla proteina C attivata [APC]/Fattore V di Leiden, deficit di proteina S o C, mutazione del gene della protrombina [G20210A] o disturbo trombofilico acquisito [lupus anticoagulante]) 4. Tumori maligni, insufficienza renale o grave malattia epatica (aspartato aminotransferasi [ASAT] >5 volte il limite superiore della norma) 5. Indice di massa corporea >40 kg/m2 6. Ipersensibilità nota o reazione allergica all’antitrombina o a uno qualsiasi degli eccipienti di Atenativ 7. Anamnesi di una o più reazioni anafilattiche a sangue o componenti ematici 8. Rifiuto di ricevere trasfusioni di prodotti derivati dal sangue 9. Somministrazione di qualsiasi concentrato di antitrombina o emoderivato contenente antitrombina diverso dal farmaco dello studio entro 14 giorni da una delle due fasi dello studio 10. Precedente diagnosi di trombocitopenia indotta da eparina 11. TE o TEE negli ultimi 6 mesi 12. Pazienti di sesso femminile che allattano al seno 13. Partecipazione a un altro studio sperimentale negli ultimi 30 giorni |
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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. |
Incidenza del composito di TE e TEE in pazienti con deficit congenito di antitrombina, in trattamento con Atenativ per procedure chirurgiche o parto a 30 giorni dopo l’inizio del trattamento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
30 days after treatment initiation |
30 giorni dopo l’inizio del trattamento |
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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(0–8)) • 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). |
Parametri PK: • Parametri PK dopo una dose singola di Atenativ in pazienti con deficit congenito di antitrombina: • Area sotto la curva (AUCnorm (0-8)) • Concentrazione plasmatica massima (Cmax) • Emivita (t1/2) •Tempo medio di permanenza (MRT) • Clearance (CL) • Recupero incrementale in vivo (IVR; picco di concentrazione di antitrombina osservato entro la prima ora dopo l’infusione) • Volume di distribuzione allo stato di equilibrio (Vss) • Tempo alla concentrazione massima nel plasma (Tmax) Parametri di Efficacia: • Attività antitrombinica • Parametri di coagulazione (tempo di tromboplastina parziale attivata [aPTT], tempo di protrombina [PT], rapporto internazionale normalizzato [INR] e fibrinogeno) Parametri di sicurezza: • Eventi avversi (EA) ed EA seri (SAE) • Durata della degenza ospedaliera • Segni vitali (inclusi pressione sanguigna sistolica e diastolica, frequenza cardiaca, temperatura corporea, frequenza respiratoria, risultati dell’esame obiettivo) • Variabili di sicurezza ematologiche e chimico-cliniche standard, nonché marcatori di trombogenicità tra cui D-dimero, frammento 1 + 2 (F1+2) della protrombina e complesso trombina-antitrombina (TAT) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
occurrence of TEs and TEEs |
occorrenza di TE e TEE |
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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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 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 | Information not present in EudraCT |
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 |
Austria |
Belgium |
Canada |
France |
Germany |
Hungary |
Italy |
Spain |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |