Efficacy of Atenativ in Patients With Congenital Antithrombin Deficiency Undergoing Surgery or Delivery

Study Overview
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Brief Summary
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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.

Official Title
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A Multicentre, Prospective, Open-label, Uncontrolled Phase 3 Study to Assess the Efficacy, Safety and Pharmacokinetics of Atenativ in Patients With Congenital Antithrombin Deficiency Undergoing Surgery or Delivery

Conditions
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Congenital Antithrombin Deficiency

Intervention / Treatment
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* Drug: Atenativ


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female patients ≥18 and ≤80 years of age. Solely in the US, 4 male or female patients between ≥12 and <17 years of age will be enrolled into the PK phase, and the treatment phase, if needed Level of antithrombin ≤60% Personal or family history of TEs or TEEs 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 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 Patient has provided informed consent Exclusion Criteria: Requires emergency surgery or emergency caesarean section Has undergone surgery within the last 6 weeks 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) Malignancies, renal failure, or severe liver disease (aspartate aminotransferase [ASAT] >5 times the upper limit of normal) Body mass index >40 kg/m2 (for non-pregnant patients, only) Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ History of anaphylactic reaction(s) to blood or blood components Refusal to receive transfusion of blood-derived products 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 Prior diagnosis of heparin-induced thrombocytopenia TE or TEE within the last 6 months Female patients who are nursing Have participated in another investigational study within the last 30 days

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atenativ treatment<br>Patients will receive a single intravenous infusion of Atenativ for PK analysis. Patients will receive a single intravenous dose followed by maintenance doses administered every 24 hours for approximately 2-7 days for surgical patients and approximately 5 days for parturients | Drug: Atenativ<br>* Antithrombin concentrate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombotic event incidence | The primary objective of this study is to assess the incidence of the composite of TEs and TEEs in patients with congenital antithrombin deficiency under cover of Atenativ for surgical procedures or parturition | Up to day 30 post treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single dose Pharmacokinetics of Atenativ: Area under the curve (AUCnorm(0-∞)) | Assess the area under the curve (AUCnorm(0-∞)) of Atenativ in patients with congenital antithrombin deficiency | Up to day 14 post PK infusion | 
| Single dose Pharmacokinetics of Atenativ: Maximum plasma concentration (Cmax) | Assess the maximum plasma concentration (Cmax) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Half-life (t1/2) | Assess the half-life (t1/2) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Mean residence time (MRT) | Assess the mean residence time (MRT) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Clearance (CL) | Assess the clearance (CL) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Incremental in vivo recovery (IVR) | Assess the Incremental in vivo recovery after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Volume of distribution at steady state (Vss) | Assess the volume of distribution at steady state (Vss) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| Single dose Pharmacokinetics of Atenativ: Maximum Plasma Concentration (Tmax) | Assess the time to reach Maximum Plasma Concentration (Tmax) after a single dose of Atenativ in patients with congenital antithrombin deficiency | Before first infusion, 20 minutes, 1 hour, 3 hours, 8 hrs, 1 day, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days and 14 days post-infusion | 
| 10. Coagulation parameters: Activated partial thromboplastin time [aPTT] | Assess activated partial thromboplastin time [aPTT] in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition | Up to day 7 post treatment initiation | 
| Coagulation parameters: Prothrombin time [PT] | Assess prothrombin time [PT] in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition | Up to day 7 post treatment initiation | 
| Coagulation parameters: International normalised ratio [INR] | Assess international normalised ratio [INR] in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition | Up to day 7 post treatment initiation | 
| Coagulation parameters: Fibrinogen level | Assess fibrinogen in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition | Up to day 7 post treatment initiation | 
| Safety and tolerability: Number of adverse events (AEs) | Number of adverse events (AEs) following treatment with Atenativ in patients with congenital antithrombin deficiency | Up to day 30 post treatment initiation |