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

Official title

A Multicenter, 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

Overview

The goal 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 when they receive Atenativ for surgical procedures or parturition.

Interventions

• Drug Atenativ
  Antithrombin concentrate

Primary outcome measures

• Thrombotic event incidence [Time frame: Up to day 30 post treatment initiation]

Secondary outcome measures (12)

• Single dose Pharmacokinetics of Atenativ: Area under the curve (AUCnorm(0-∞)) [Time frame: Up to day 14 post PK infusion]
• Single dose Pharmacokinetics of Atenativ: Maximum plasma concentration (Cmax) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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] [Time frame: Up to day 7 post treatment initiation]
• Coagulation parameters: Prothrombin time [PT] [Time frame: Up to day 7 post treatment initiation]
• Coagulation parameters: International normalised ratio [INR] [Time frame: Up to day 7 post treatment initiation]
• Coagulation parameters: Fibrinogen level [Time frame: Up to day 7 post treatment initiation]

Eligibility criteria

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 subsequently in the treatment phase, if applicable
• Documented congenital antithrombin deficiency, defined by plasma activity level of antithrombin ≤60% from medical history
• Personal or family history of TEs or TEEs (except for PK patients)
• 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 (patients on renal replacement therapy), 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 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 at the time of screening\*
• Have participated in another investigational study within the last 30 days
• Persons dependent on the sponsor, the investigator or the centre of investigation
• Persons placed in an institution by administrative or judicial order

• criterion does not include female patients who plan to breastfeed after giving birth

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 5 centers

• Georgetown University — Washington D.C.
• University of Miami — Miami
• Bleeding and Clotting Disorders Institute — Peoria
• Weill Cornell Medicine — New York
• Duke University — Durham

Italy · 4 centers

• Unita Strutturale Complessa di Immunoematologia e Medicina Trasfusionale -Dipartimento Int — Bergamo
• Universita degli Studi di Milano - IRCCS Ospedale Maggiore Policlinico - Centro Emofilia e — Milan
• University of Padua Medical School — Padua
• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Roma

Spain · 4 centers

• Central University Hospital of Asturias — Oviedo
• Hospital Universitario La Paz — Madrid
• Hospital Universitario Morales Meseguer — Murcia
• Ourense University Hospital — Ourense

France · 3 centers

• Centre de Référence de l'Hémophilie Unité d'Hémostase Clinique Hôpital Cardiologique Louis — Bron
• University Hospital of Reims — Reims
• Centre Hospitalier Universitaire de Rouen (CHU de Rouen) - Centre de Traitement des Maladi — Rouen

Germany · 3 centers

• Klinik fur Angiologie Hamostaseologie Haus 12 A Gerinnungssprechstunde — Berlin
• UKB Bonn Institut für Experimentelle Hämatologie und Transfusionsmedizin — Bonn
• Gerinnungszentrum Rhein-Ruhr — Duisburg

Israel · 2 centers

• Rabin Medical Centre, Institute of Haematology — Petah Tikva
• Sheba Medical Centre — Ramat Gan

United Kingdom · 2 centers

• Royal-free Hospital-Katherine Dormandy Haemophilia and Thrombosis Centre — London
• St. Thomas Hospital — London

Armenia · 1 center

• Yeolyan Hematology and Oncology Centre — Yerevan

Austria · 1 center

• Universitätsklinik für Innere Medizin Klinische Abteilung für Hämatologie und Hämostaseolo — Vienna

Czechia · 1 center

• Centre for Thrombosis and Haemaostasis — Nymburk

Georgia · 1 center

• Aversi Clinic — Tbilisi

Hungary · 1 center

• University of Debrecen, Medical and Health Science Centre — Debrecen

Romania · 1 center

• Emergency County Hospital Craiova — Craiova

Serbia · 1 center

• Clinical Center of Serbia — Belgrade

Identifiers

NCT: NCT04918173 · ATN-106

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗