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

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of two different doses of Atenativ, versus placebo, in restoring heparin responsiveness in adult patients undergoing cardiopulmonary bypass (CPB) for cardiac surgery.

Official Title
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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

Conditions
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Acquired Antithrombin Deficiency

Intervention / Treatment
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* Drug: Human plasma derived antithrombin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Planned cardiac surgery with cardiopulmonary bypass, including any type of coronary artery bypass graft (CABG) Heparin-resistant patients (pre-CPB Hemochron ACT less than 480 s in the measurement taken within 5 minutes following intravenous administration of 500 U/kg UFH) Patients between 18 and 85 years of age Freely given written informed consent In female patients of childbearing potential, a pre-existing negative pregnancy test within 14 days prior to surgery Exclusion Criteria: Receiving, or have received within the timeframes specified, one or more of the following medications prior to the start of surgery: warfarin (within 3 days) direct oral anticoagulants (within 2 days) ticlopidine (within 14 days) prasugrel (within 7 days) clopidogrel (within 5 days) ticagrelor (within 5 days) glycoprotein IIb/IIIa antagonist (within 1 day) Pre-existing coagulopathy, defined as a history of bleeding problems or a laboratory history of bleeding disorder (e.g., von Willebrand disease, platelet disorder) Renal insufficiency, defined as serum creatinine level >1.5 mg/dL Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ i.e., human albumin, sodium chloride, acetyl tryptophan, caprylic acid History of anaphylactic reaction(s) to blood or blood components Refusal to receive transfusion of blood or blood-derived products Current participation in another interventional clinical trial or previous participation in the current trial Treatment with any investigational product within 30 days prior to screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose Atenativ<br> | Drug: Human plasma derived antithrombin<br>* A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma<br>|
| Experimental: High-dose Atenativ<br> | Drug: Human plasma derived antithrombin<br>* A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma<br>|
| Placebo Comparator: Placebo<br>Patients will receive a saline bolus dose | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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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 | IMP infusion and initiation of CPB | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | IMP infusion and initiation of CPB | 
| Change in 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 UFH and between 2-10 minutes after IMP infusion | 
| 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 2-10 minutes after IMP infusion | 
| Change in heparin usage | The comparison between heparin usage following the injection of each of the Atenativ doses and injection of placebo | From initiation of CBP to the end of surgery | 
| Maintaining heparin responsiveness | For subjects in whom heparin responsiveness is restored without the need for further pre-CPB therapy, the percentage of patients in each group who do not require further therapy containing antithrombin (i.e., FP or antithrombin concentrates) to maintain heparin responsiveness until the end of surgery | From initiation of CBP to the end of surgery | 
| Amounts of further therapy for maintaining heparin responsiveness | The comparison between the amounts of further therapy containing antithrombin (i.e., FP or antithrombin concentrates) needed for maintaining heparin responsiveness from the initiation of CPB until the end of surgery, for subjects in whom heparin responsiveness is restored without the need for further pre-CPB therapy | From initiation of CBP to end of surgery | 
| Adverse events | Incidence of adverse events in all three cohorts | Up to 28 days (+ 2 days) following therapy administration | 
| Survival status | Number of patients surviving in all three cohorts | 28 days (+ 2 days) following administration of IMP | 
| Red Blood Cell 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 | 
| White Blood Cell 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 | 
| Haemoglobin levels | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heparin resistance, antithrombin deficiency, cardiopulmonary bypass, cardiac surgery