This Study Looks at the Effects of Idarucizumab in Patients Who Take Dabigatran and Need Emergency Surgery or Are Bleeding

Study Overview
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Brief Summary
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The primary objective is to demonstrate reversal of the anticoagulant effect of dabigatran in patients treated with dabigatran etexilate who have uncontrolled or life-threatening bleeding requiring urgent intervention, and in patients treated with dabigatran etexilate who require emergency surgery or other invasive procedure. The secondary objectives are to assess the reduction or cessation of bleeding, evaluate the clinical outcomes, safety and the pharmacokinetics of dabigatran in the presence of idarucizumab.

Official Title
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A Phase III, Case Series Clinical Study of the Reversal of the Anticoagulant Effects of Dabigatran by Intravenous Administration of Idarucizumab (BI 655075) in Patients Treated With Dabigatran Etexilate Who Have Uncontrolled Bleeding or Require Emergency Surgery or Procedures.

Conditions
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Hemorrhage

Intervention / Treatment
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* Drug: Idarucizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: ≥ 18 years at screening. Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial Currently taking dabigatran etexilate They meet the following criteria: Group A: Overt bleeding judged by the physician to require a reversal agent. OR Group B: A condition requiring emergency surgery or invasive procedure where adequate hemostasis is required. Emergency is defined as within the following 8 hours. Exclusion criteria: Group A: Patients with minor bleeding (e.g. epistaxis, hematuria) who can be managed with standard supportive care. Patients with no clinical signs of bleeding. Contraindications to study medication including known hypersensitivity to the drug or its excipients (subjects with hereditary fructose intolerance may react to sorbitol). Group B: A surgery or procedure which is elective or where the risk of uncontrolled or unmanageable bleeding is low. Contraindications to study medication including known hypersensitivity to the drug or its excipients (subjects with hereditary fructose intolerance may react to sorbitol).

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - patients with uncontrolled or life-threatening bleeding<br> | Drug: Idarucizumab<br>* Intravenous<br>* Other names: PRAXBIND, Praxbind, Prizbind;|
| Experimental: Group B - patients not bleeding but requiring emergency surgery or invasive procedure<br> | Drug: Idarucizumab<br>* Intravenous<br>* Other names: PRAXBIND, Praxbind, Prizbind;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of Ecarin Clotting Time | Maximum reversal of anticoagulant effect of dabigatran based on central laboratory determination of ecarin clotting time is reported. The maximum reversal of anticoagulant effect of dabigatran is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% Upper limit of normal (ULN). Maximum reversal is calculated as 100% x (pre-dose value - post-dose value)/(pre-dose value - 100% ULN). If the calculated reversal is > 100, it was set to 100. 100% ULN is 41.26 seconds. | From the end of first infusion up to 4 hours after the completion of the second infusion on Day 1 of the treatment period. | 
| Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of Diluted Thrombin Time | Maximum reversal of anticoagulant effect of dabigatran based on central laboratory determination of diluted thrombin time is reported. The maximum reversal of anticoagulant effect of dabigatran is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% Upper limit of normal (ULN). Maximum reversal is calculated as 100% x (pre-dose value - post-dose value)/(pre-dose value - 100% ULN). If the calculated reversal is > 100, it was set to 100. 100% ULN is 35.54 seconds. | From the end of first infusion up to 4 hours after the completion of the second infusion on Day 1 of the treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Cessation of Bleeding Within 24 Hours After Completion of Second Infusion (for Group A Only) | Percentage of participants achieving cessation of bleeding within 24 hours after completion of second infusion for Group A is reported. | Up to 24 hours after the completion of the second infusion on Day 1 of the treatment period. | 
| Number of Participants With Major Bleeding (for Group B Only) Intra-operatively and up to 24 Hours Post-surgery | Number of participants with major bleeding (for Group B only) intra-operatively and up to 24 hours post-surgery per International Society for Thrombosis and Hemostasis (ISTH) classification is reported. | Up to 24 hours post-surgery. | 
| Minimum Unbound Sum Dabigatran Concentrations Since the End of First Infusion up to 4 Hours After the Completion of the Last Infusion (Cmin,1) | Minimum unbound sum dabigatran concentrations since the end of first infusion up to 4 hours after the completion of the last infusion (Cmin,1) is reported. | Just prior to the second infusion (last infusion) and 10 minutes (min), 30 min, 1 hour (h), 2 h, and 4 h after the end of the second infusion. | 
| Maximum Reversal of Anticoagulation as Measured by Activated Partial Thromboplastin Time (aPTT) | Maximum reversal of anticoagulation as measured by activated partial thromboplastin time (aPTT) is reported. The reversal of anticoagulant effect of dabigatran is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% Upper limit of normal (ULN). Maximum reversal is calculated as 100% x (pre-dose value - post-dose value)/(pre-dose value - 100% ULN). If the calculated reversal is > 100, it was set to 100. 100% ULN is 39.80 seconds. | From the end of first infusion up to 4 hours after the completion of the second infusion on Day 1 of the treatment period. | 
| Maximum Reversal of Anticoagulation as Measured by Thrombin Time (TT) | Maximum reversal of anticoagulation as measured by thrombin time (TT) is reported. The reversal of anticoagulant effect of dabigatran is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% Upper limit of normal (ULN). Maximum reversal is calculated as 100% x (pre-dose value - post-dose value)/(pre-dose value - 100% ULN). If calculated reversal is > 100, it was set to 100. 100% ULN is 14.22 seconds. | From the end of first infusion up to 4 hours after the completion of the second infusion on Day 1 of the treatment period. | 
| Numbers of Participants With Any Adverse Events - on Treatment | Numbers of participants with any adverse events during on treatment period is reported. | Since the first infusion up until 5 days after the completion of the second infusion. | 
| Numbers of Participants With Any Adverse Events - Including Post Treatment Period | Numbers of participants with any adverse events until end of study is reported. | Since informed consent up to 30 days (± 7 days) after the completion of the second infusion, up to 37 days. | 
| Number of Participants With Serious Adverse Events - on Treatment | Number of participants with Serious adverse events during on treatment period is reported. | Since the first infusion up until 5 days after the completion of the second infusion. | 
| Number of Participants With Serious Adverse Events - Including Post Treatment Period | Number of participants with Serious adverse events until the end of study is reported. | Since informed consent up to 30 days (± 7 days) after the completion of the second infusion, up to 37 days. | 
| Number of Participants With Drug-related Adverse Events - on Treatment | Numbers of patients with drug-related adverse events during on treatment period is reported. | Since the first infusion up until 5 days after the completion of the second infusion. | 
| Number of Participants With Drug-related Adverse Events - Including Post Treatment Period | Numbers of patients with drug-related adverse events until end of study is reported. | Since informed consent up to 30 days (± 7 days) after the completion of the second infusion, up to 37 days. | 
| Number of Participants With Immune Reaction Adverse Event - on Treatment | Number of participants with immune reaction adverse event during on treatment period is reported. | Since the first infusion up until 5 days after the completion of the second infusion. | 
| Number of Participants With Immune Reaction Adverse Event - Including Post Treatment Period | Number of participants with immune reaction adverse event until end of study is reported. | Since informed consent up to 30 days (± 7 days) after the completion of the second infusion, up to 37 days. | 
| Number of Participants With Thrombotic Events - on Treatment | Number of participants with thrombotic events (ischemic stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, systemic embolism) during on treatment period is reported. | Since the first infusion up until 5 days after the completion of the second infusion. | 
| Number of Participants With Thrombotic Events - Including Post Treatment Period | Number of participants with thrombotic events (ischemic stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, systemic embolism) until end of study is reported. | Since informed consent up to 30 days (± 7 days) after the completion of the second infusion, up to 37 days. |