Reversal of Dabigatran Anticoagulant Effect With Idarucizumab

Study Overview
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Brief Summary
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Evaluate the reversal of the anticoagulant effects of dabigatran by IV administration of 5.0g idarucizumab in patients treated with dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures.

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 5.0g Idarucizumab (BI 655075) in Patients Treated Wtih Dabigatran Etexilate Who Have Uncontrolled Bleeding or Require Emergency Surgery or Procedures.RE-VERSE AD (A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran) Trial

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: Group A (Bleeding patients) Overt bleeding judged by the physician to require a reversal agent Currently taking dabigatran etexilate At least 18 years of age Written informed consent Group B (Patients who are taking dabigatran who may not be bleeding, but do require an emergency surgery or procedure for a condition other than bleeding Condition requiring emergency surgery or invasive procedure where adequate hemostasis is required. Emergency is defined as within the following 8 hours. Current treatment with dabigatran At least 18 years of age Written Informed consent. Exclusion criteria: Group A (Bleeding Patients) Patients with minor bleeds (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. Group B (Patients who require emergency surgery or procedure) 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: idarucizumab<br>idarucizumab Only 1 treatment, no placebo or comparator | Drug: idarucizumab<br>* idarucizumab<br>|

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 dTT or ECT | Maximum reversal of anticoagulant effect of dabigatran based on central laboratory determination of diluted thrombin time (dTT) or ecarin clotting time (ECT), at any time point from the end of the first infusion up to 4 hours after the last infusion. Reversal is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% ULN (evaluable patients). Reversal is calculated as 100* (pre-dose value minus post dose value)/(pre-dose value minus 100% x ULN); if calculated reversal is > 100, it was set to 100. | from the end of the first infusion up to 4 hours after the last infusion on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversal of aPTT and TT From Central Laboratory | Reversal of anticoagulation as measured by Activated Partial Thromboplastin Time (aPTT) and Thrombin time (TT), at any time point since the end of first infusion up to 4 hours after the completion of the last infusion. Reversal is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% ULN (evaluable patients). Reversal is calculated as 100* (pre-dose value minus post dose value)/(pre-dose value minus 100% x ULN); if calculated reversal is > 100, it was set to 100. | from the end of the first infusion up to 4 hours after the last infusion on Day 1 | 
| Duration of Reversal | Duration of reversal, defined as the time period a patient remained completely reversed based on dTT or ECT, up to 24 hours or re-starting the treatment of dabigatran. | from the first infusion up to 24 hours after the last infusion on Day 1 | 
| Occurrence of Major/Life-threatening/Fatal Bleeding (for Group B Only) Intraoperatively | Occurrence of major/life-threatening/fatal bleeding (for group B only) intraoperatively and up to 24 hours post-surgery were classified according to major or life-threatening bleeding (ISTH [International Society for Thrombosis and Hemostasis] definition). 95% Confidence Interval (CI) is from Clopper-Pearson method. | within 24 hours of surgery | 
| Time to Cessation of Bleeding (for Group A Only) | Time to cessation of bleeding (for Group A only) since first infusion up to 24 hours after the completion of second infusion; bleeding status was to be categorized before and at several time points after treatment. | from the first infusion up to 24 hours after the last infusion on Day 1 | 
| Cmin,1 of Unbound Sum (Free) Dabigatran | Cmin,1 (Minimum concentrations at any time point since the end of first vial of idarucizumab up to 4 hours after the completion of second vial) of unbound sum (free) dabigatran, provided that two vials given not more than 15 min apart in group A and B. | Since the end of first vial of idarucizumab up to 4 hours after the completion of second vial | 
| Reversal of Anticoagulation as Measured by Diluted Thrombin Time (dTT) or Ecarin Clotting Time (ECT) After the First Vial of Idarucizumab and Before the Start of Second Vial | Reversal of anticoagulation as measured by diluted Thrombin Time (dTT) or Ecarin Clotting Time (ECT) after the first vial of idarucizumab and before the start of second vial. Reversal is defined for patients with at least one post-dose coagulation test results and pre-dose result higher than 100% ULN (evaluable patients). Reversal is calculated as 100*(pre-dose value minus post dose value)/(pre-dose value minus 100% x ULN); if calculated reversal is > 100, it was set to 100. | after the first vial of idarucizumab and before the start of second vial on Day1 |