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 heparin responsiveness in adult patients undergoing cardiopulmonary bypass (CPB) for cardiac surgery.

Study Overview

• Status: Not yet 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: Sigurd Knaub, PhD; Phone Number: +41554512141; Email: Sigurd.Knaub@octapharma.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Planned cardiac surgery with cardiopulmonary bypass, including any type of coronary artery bypass graft (CABG)
2. 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)
3. Patients between 18 and 85 years of age
4. Freely given written 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. 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, defined as a history of bleeding problems or a laboratory history of 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 investigational product 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
Experimental: Low-dose Atenativ	Drug: Human plasma derived antithrombin; A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma
Experimental: High-dose Atenativ	Drug: Human plasma derived antithrombin; A solvent/detergent and heat-treated antithrombin concentrate derived from human plasma
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

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	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

Collaborators and Investigators

• Sponsor: Octapharma

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

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 (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: cardiac surgery; cardiopulmonary bypass; heparin resistance; antithrombin deficiency
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Genetic Diseases, Inborn; Blood Protein Disorders; Blood Coagulation Disorders; Thrombophilia; Antithrombin III Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; 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