Phase 3 Study on the Efficacy and Safety of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass

Phase 3, Double-blind, Placebo-controlled, Multicentre Study on the Efficacy and Safety of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass

The primary objective of this study is to evaluate the efficacy of two different doses of Atenativ, versus placebo, in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB)

Study Overview

• Status: Recruiting
• Conditions: Acquired Antithrombin Deficiency
• Intervention / Treatment: Drug: Human plasma derived antithrombin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Cristina Solomon, MD; Phone Number: +41 79 585 90 42; Email: Cristina.Solomon@octapharma.com

Study Locations

• Austria
  • Innsbruck, Austria
    • Recruiting
    • University Hospital Innsbruck
  • Vienna, Austria
    • Recruiting
    • Vienna General Hospital AKH, Medical University of Vienna
• Canada
  • British Columbia
    • New Westminster, British Columbia, Canada, V3L0A4
      • Recruiting
      • Royal Columbian Hospital
  • Ontario
    • Kingston, Ontario, Canada, K7L2V7
      • Recruiting
      • Kingston Health Sciences Centre
    • Toronto, Ontario, Canada, M5G2C4
      • Recruiting
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T1C8
      • Recruiting
      • Montreal Heart Institute
• Czechia
  • Brno, Czechia
    • Recruiting
    • Center of Cardiovascular and Transplant Surgery
  • Prague, Czechia
    • Recruiting
    • Institute for Clinical and Experimental Medicine
• France
  • Reims, France
    • Terminated
    • CHU de Reims, Hôpital Robert Debré
  • Rennes, France
    • Withdrawn
    • CHU de Rennes
• Lithuania
  • Kaunas, Lithuania
    • Recruiting
    • Hospital of Lithuanian University of Health Sciences Kauno klinikos
  • Vilnius, Lithuania
    • Recruiting
    • Vilnius University hospital Santaros klinikos
• Romania
  • Bucharest, Romania
    • Recruiting
    • Institute for Cardiovascular Diseases C.C. Iliescu
• Serbia
  • Kamenitz, Serbia
    • Not yet recruiting
    • Institute of Cardiovascular Diseases Vojvodina
• Slovenia
  • Ljubljana, Slovenia
    • Recruiting
    • University Medical Centre Ljubljana
• United Kingdom
  • Cambridge, United Kingdom
    • Recruiting
    • Royal Papworth Hospital
  • Coventry, United Kingdom
    • Recruiting
    • University Hospital Coventry and Warwickshire
  • Middlesbrough, United Kingdom
    • Recruiting
    • The James Cook University Hospital
• United States
  • California
    • Stanford, California, United States, 94305-5101
      • Recruiting
      • Stanford University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710-1000
      • Recruiting
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Atrium Health Wake Forest Baptist
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Not yet recruiting
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43214
      • Recruiting
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • OU Health University of Oklahoma Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Planned cardiac surgery with CPB
2. Heparin-resistant patients (pre-CPB Hemochron ACT less than 480 s in the measurement taken between 2-5 minutes following intravenous administration of 500 U/kg UFH)
3. Patients between 18 and 85 years of age, inclusive
4. Freely given written or electronic informed consent
5. In female patients of childbearing potential, a pre-existing negative pregnancy test within 14 days prior to surgery

Exclusion Criteria:

1. Receiving, or have received within the timeframes specified, one or more of the following medications prior to the start of surgery:

   1. vitamin K antagonists (within 3 days)
   2. direct oral anticoagulants (within 2 days)
   3. thienopyridines (ticlopidine within 14 days, prasugrel within 7 days, or clopidogrel within 5 days), unless platelet function is satisfactory according to local standard of care assessment
   4. ticagrelor (within 5 days), unless platelet function is satisfactory according to local standard of care assessment
   5. glycoprotein IIb/IIIa antagonist (within 24 hours)
2. Pre-existing coagulopathy, a history of bleeding problems, or a laboratory-diagnosed bleeding disorder (e.g., von Willebrand disease, platelet disorder)
3. Renal insufficiency, defined as serum creatinine level >2.0 mg/dL
4. Thrombocytosis, defined as platelet count >400,000 per μL
5. Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ, i.e., human albumin, sodium chloride, acetyl tryptophan, caprylic acid
6. History of anaphylactic reaction(s) to blood or blood components
7. Refusal to receive transfusion of blood or blood-derived products
8. Current participation in another interventional clinical trial or previous participation in the current trial
9. Treatment with any IMP within 30 days prior to screening visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients will receive a saline bolus dose	Drug: Placebo; Half of the patients in the placebo group will be randomised to receive a volume of placebo corresponding to the low dose of Atenativ and the other half to receive a volume of placebo corresponding to a high dose of Atenativ
Experimental: Low-dose Atenativ; Patients will receive a single bolus of 30 international units (IU)/kg body weight (BW) Atenativ.	Drug: Human plasma derived antithrombin; A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma
Experimental: High-dose Atenativ; Patients will receive a single bolus of 60 international units (IU)/kg body weight (BW) Atenativ.	Drug: Human plasma derived antithrombin; A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Restoring heparin responsiveness	The percentage of patients in each group in whom no further therapy containing antithrombin (i.e. frozen plasma or other antithrombin concentrates) is needed for restoring pre-CPB heparin responsiveness after administration of Atenativ or placebo, and for maintaining it during CPB	During surgery (from the time of the first surgical incision to the time at which the final suture or staple is placed)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Haematocrit	Standard haematological parameter	Within 10 minutes before IMP infusion, between 2-10 minutes after IMP infusion, within 10 minutes after weaning from CPB, at the end of surgery, and at 24 hours after infusion
Platelet count	Standard haematological parameter	Within 10 minutes before IMP infusion, between 2-10 minutes after IMP infusion, within 10 minutes after weaning from CPB, at the end of surgery, and at 24 hours after infusion
Change in activated clotting time (ACT) values	The comparison between the change in ACT values following infusion of each of the Atenativ doses and placebo	Within 5 minutes following intravenous administration of 500 U/kg unfractionated heparin (UFH) and between 2-10 minutes after IMP infusion
Need for reoperation due to bleeding	Comparison of the need for reoperation for bleeding, including description of the cause of bleeding (surgical vs. non-surgical)	24 hours after the start of IMP infusion
Adverse events	Incidence of adverse events, including all related and non-related, non-serious adverse events	From the start of IMP infusion until hospital discharge or 7 days after IMP administration, whichever comes first
Serious adverse events	Incidence of serious adverse events	From the start of IMP infusion until 28 days after IMP administration
Survival status	Number of patients surviving in all three cohorts	At hospital discharge or 7 days after IMP administration (whichever comes first) and at 28 days (+ 4 days) after IMP administration
Red Blood Cell count	Standard haematological parameter	Within 10 minutes before IMP infusion, between 2-10 minutes after IMP infusion, within 10 minutes after the end of CPB, at the end of surgery, and at 24 hours after infusion
White Blood Cell count	Standard haematological parameter	Within 10 minutes before IMP infusion, between 2-10 minutes after IMP infusion, within 10 minutes after the end of CPB, at the end of surgery, and at 24 hours after infusion
Haemoglobin levels	Standard haematological parameter	Within 10 minutes before IMP infusion, between 2-10 minutes after IMP infusion, within 10 minutes after the end of CPB, at the end of surgery, and at 24 hours after infusion
Amounts of further therapy for restoring heparin responsiveness	The comparison between the amounts of further therapy containing antithrombin (i.e., FP or antithrombin concentrates) needed for restoring pre-CPB heparin responsiveness, after administration of Atenativ or placebo, and for maintaining it during CPB	During surgery (from the time of the first surgical incision to the time at which the final suture or staple is placed)
Change in antithrombin plasma levels	The comparison between the change in antithrombin plasma levels following infusion of each of the Atenativ doses and placebo	Within 10 minutes before IMP infusion and between 2 and 10 minutes after IMP infusion, within 10 minutes after the end of CPB, at the end of surgery, and at 24 hours after the start of IMP infusion
Change in heparin usage	The comparison between heparin usage following the infusion of each of the Atenativ doses and infusion of placebo	From end of IMP infusion to the end of surgery
FP unit use	The comparison between the number of units of FP transfused for reasons other than restoring or maintaining heparin responsiveness, both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively	From the start of IMP infusion until 24 hours following IMP infusion, and until discharge or 7 days after surgery, whichever comes first
Amounts of further antithrombin concentrate for maintaining heparin responsiveness	The comparison between postoperative use of antithrombin concentrates for reasons other than restoring heparin responsiveness (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first)	From placement of the final suture or staple until 24 hours following IMP infusion, to discharge or 7 days after surgery, whichever comes first
Transfusion of allogenic blood products	The comparison between transfusion of other allogeneic blood products (e.g., red blood cells [RBCs], platelets, cryoprecipitate, whole blood, albumin, other transfusion), both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively	From the start of IMP infusion until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first
Administration of coagulation factor concentrates	The comparison between administration of coagulation factor concentrates (fibrinogen concentrate, factor XIII concentrate, recombinant activated factor VII, other therapy)", both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively	From the start of IMP infusion until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first
Administration of other haemostatic-relevant therapies	The comparison between administration of other haemostatic-relevant therapies (i.e., tranexamic acid, aminocaproic acid, protamine, other therapies), both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively	From the start of IMP infusion until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first
Postoperative chest tube drainage	The comparison between postoperative chest tube drainage volume at 24 hours after the start of Atenativ or placebo infusion, and the comparison between total chest tube drainage volume until discharge or 7 days after surgery, whichever comes first	From the start of IMP infusion to 24 hours after infusion and until discharge or 7 days after surgery, whichever comes first
Cell saver volume	The comparison between cell saver volume until the end of surgery	During surgery (from the time of the first surgical incision to the time at which the final suture or staple is placed)

Collaborators and Investigators

• Sponsor: Octapharma

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: October 17, 2023
• First Submitted That Met QC Criteria: October 17, 2023
• First Posted (Actual): October 23, 2023

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: cardiac surgery; cardiopulmonary bypass; heparin resistance; antithrombin deficiency
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Blood Protein Disorders; Blood Coagulation Disorders, Inherited; Thrombophilia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Antithrombin III Deficiency; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anticoagulants; Serine Proteinase Inhibitors; Antithrombins; Antithrombin III
• Other Study ID Numbers: ATN-108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No