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

Recruiting

• Conditions: Acquired Antithrombin Deficiency
• Interventions: Drug: Human plasma derived antithrombin; Drug: Placebo

• Registration Number: NCT06096116
• Lead Sponsor: Octapharma

Brief Summary

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)

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-10-17
• Study First Submitted QC: 2023-10-17
• Study First Posted: 2023-10-23
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-20
• Last Update Posted: 2024-11-22
• Study Start: 2024-12
• Primary Completion: 2026-09
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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

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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. warfarin (within 3 days)
   2. direct oral anticoagulants (within 2 days)
   3. ticlopidine (within 14 days)
   4. prasugrel (within 7 days)
   5. clopidogrel (within 5 days)
   6. ticagrelor (within 5 days)
   7. glycoprotein IIb/IIIa antagonist (within 1 day)

2. Pre-existing coagulopathy, a history of bleeding problems, 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 >1.5 mg/dL

4. Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ i.e., human albumin, sodium chloride, acetyl tryptophan, caprylic acid

5. History of anaphylactic reaction(s) to blood or blood components

6. Refusal to receive transfusion of blood or blood-derived products

7. Current participation in another interventional clinical trial or previous participation in the current trial

8. Treatment with any IMP within 30 days prior to screening visit

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High-dose Atenativ	Human plasma derived antithrombin	-
Placebo	Placebo	Patients will receive a saline bolus dose
Low-dose Atenativ	Human plasma derived antithrombin	-

Primary Outcome Measures

Name	Time	Method
Restoring heparin responsiveness	During surgery (from start of Investigational Medicinal Product (IMP) infusion until end of CPB)	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

Secondary Outcome Measures

Name	Time	Method
Administration of other haemostatic-relevant therapies	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	The comparison between administration of other haemostatic-relevant therapies (e.g., tranexamic acid, protamine), 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
Change in activated clotting time (ACT) values	Within 5 minutes following intravenous administration of 500 U/kg unfractionated heparin (UFH) and between 2-10 minutes after IMP infusion	The comparison between the change in ACT values following infusion of each of the Atenativ doses and placebo
Change in antithrombin plasma levels	Within 10 minutes before IMP infusion and 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	The comparison between the change in antithrombin plasma levels following infusion of each of the Atenativ doses and placebo
Change in heparin usage	From IMP infusion to the end of surgery	The comparison between heparin usage following the infusion of each of the Atenativ doses and infusion of placebo
FP unit use	From IMP infusion until 24 hours following IMP infusion, and until discharge or 7 days after surgery, whichever comes first	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
Amounts of further antithrombin concentrate for maintaining heparin responsiveness	From end of CBP until 24 hours following IMP infusion, to discharge or 7 days after surgery, whichever comes first	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)
Postoperative chest tube drainage	IMP infusion to 24 hours after infusion and until discharge or 7 days after surgery, whichever comes first	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
Haemoglobin levels	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	Standard haematological parameter
Transfusion of allogenic blood products	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	The comparison between transfusion of other allogeneic blood products (e.g., red blood cells \[RBCs\], platelets, cryoprecipitate), 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
Administration of coagulation factor concentrates	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	The comparison between administration of coagulation factor concentrates such as fibrinogen concentrate, prothrombin complex concentrate (PCC), factor XIII concentrate and recombinant activated factor VII, 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
Need for reoperation due to bleeding	24 hours after the start of IMP infusion	Comparison of the need for reoperation for bleeding, including description of the cause of bleeding (surgical vs. non-surgical)
White Blood Cell count	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	Standard haematological parameter
Amounts of further therapy for restoring heparin responsiveness	During surgery (from start of IMP infusion until end of CPB)	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
Cell saver volume	During surgery (from start of IMP infusion until end of CPB)	The comparison between cell saver volume until the end of surgery
Red Blood Cell count	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	Standard haematological parameter
Haematocrit	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	Standard haematological parameter
Platelet count	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	Standard haematological parameter
Serious adverse events	From the start of IMP infusion until 28 days after IMP administration	Incidence of serious adverse events
Survival status	At hospital discharge or 7 days after IMP administration (whichever comes first) and at 28 days (+ 4 days) after IMP administration	Number of patients surviving in all three cohorts
Adverse events	From the start of IMP infusion until hospital discharge or 7 days after IMP administration, whichever comes first	Incidence of adverse events, including all related and non-related, non-serious adverse events

Trial Locations

Locations (5)

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Atrium Health Wake Forest Baptist; 🇺🇸 Winston-Salem, North Carolina, United States

OU Health University of Oklahoma Medical Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Hospital of Lithuanian university of Health sciences Kauno Klinikos; 🇱🇹 Kaunas, Lithuania

University Medical Centre Ljubljana; 🇸🇮 Ljubljana, Slovenia