Hemorrhage
Conditions
Brief summary
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.
Interventions
DRUGidarucizumab
idarucizumab
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT | from the end of the first infusion up to 4 hours after the last infusion on Day 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Reversal | from the first infusion up to 24 hours after the last infusion on Day 1 | 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. |
| Occurrence of Major/Life-threatening/Fatal Bleeding (for Group B Only) Intraoperatively | within 24 hours of surgery | 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. |
| Reversal of aPTT and TT From Central Laboratory | from the end of the first infusion up to 4 hours after the last infusion on Day 1 | 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. |
| Cmin,1 of Unbound Sum (Free) Dabigatran | Since the end of first vial of idarucizumab up to 4 hours after the completion of second vial | 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. |
| 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 | after the first vial of idarucizumab and before the start of second vial on Day1 | 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. |
| Time to Cessation of Bleeding (for Group A Only) | from the first infusion up to 24 hours after the last infusion on Day 1 | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Czechia, Denmark, Finland, France, Germany, Hong Kong, India, Ireland, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Idarucizumab (Group A) Patients who were treated with dabigatran and who had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention were administered idarucizumab 5 g (two 2.5 g vials) as an intravenous (IV) infusion. A single vial contains 2.5 g of idarucizumab. Patients received a 2.5 g vial of study medication and a second 2.5-g vial within the next 15 minutes. | 301 |
| Idarucizumab (Group B) Patients who were treated with dabigatran and who may not have been bleeding, but required an emergency surgery or other invasive procedure for a condition other than bleeding where therapeutic anticoagulation might have increased the risk of intra- and post-operative bleeding were administered idarucizumab 5 g (two 2.5 g vials) as an intravenous (IV) infusion. A single vial contains 2.5 g of idarucizumab. Patients received a 2.5 g vial of study medication and a second 2.5-g vial within the next 15 minutes. | 202 |
| Total | 503 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 57 | 38 |
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Other than stated above | 2 | 3 |
| Overall Study | Protocol Violation | 6 | 8 |
| Overall Study | Withdrawal by Subject | 10 | 3 |
Baseline characteristics
| Characteristic | Idarucizumab (Group A) | Idarucizumab (Group B) | Total |
|---|---|---|---|
| Age, Continuous | 77.1 Years STANDARD_DEVIATION 10.4 | 75.9 Years STANDARD_DEVIATION 10.5 | 76.6 Years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 129 Participants | 100 Participants | 229 Participants |
| Sex: Female, Male Male | 172 Participants | 102 Participants | 274 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 139 / 301 | 86 / 202 |
| serious Total, serious adverse events | 160 / 301 | 106 / 202 |
Outcome results
Primary
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.
Time frame: from the end of the first infusion up to 4 hours after the last infusion on Day 1
Population: Treated Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idarucizumab (Group A) | Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT | dTT (# patients evaluable for reversal=244; 152) | 100.0 percentage |
| Idarucizumab (Group A) | Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT | ECT (# patients evaluable for reversal=276; 185) | 100.0 percentage |
| Idarucizumab (Group B) | Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT | dTT (# patients evaluable for reversal=244; 152) | 100.0 percentage |
| Idarucizumab (Group B) | Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT | ECT (# patients evaluable for reversal=276; 185) | 100.0 percentage |
Secondary
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.
Time frame: Since the end of first vial of idarucizumab up to 4 hours after the completion of second vial
Population: The Pharmacokinetic Set (PKS): This analysis set was used for all PK analyses and was defined as all patients in the Treated Set who provided at least one PK data point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Idarucizumab (Group A) | Cmin,1 of Unbound Sum (Free) Dabigatran | 1.12 ng/mL | Geometric Coefficient of Variation 61.2 |
Secondary
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.
Time frame: from the first infusion up to 24 hours after the last infusion on Day 1
Population: Treated Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idarucizumab (Group A) | Duration of Reversal | ECT (# patients evaluable for reversal=276; 185) | 13.2 hours | Standard Deviation 10 |
| Idarucizumab (Group A) | Duration of Reversal | dTT (# patients evaluable for reversal=244; 152) | 19.8 hours | Standard Deviation 6.7 |
| Idarucizumab (Group B) | Duration of Reversal | ECT (# patients evaluable for reversal=276; 185) | 12.8 hours | Standard Deviation 9.7 |
| Idarucizumab (Group B) | Duration of Reversal | dTT (# patients evaluable for reversal=244; 152) | 18.8 hours | Standard Deviation 7.6 |
Secondary
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.
Time frame: within 24 hours of surgery
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarucizumab (Group A) | Occurrence of Major/Life-threatening/Fatal Bleeding (for Group B Only) Intraoperatively | 3.0 percentage of participants |
Secondary
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.
Time frame: after the first vial of idarucizumab and before the start of second vial on Day1
Population: Treated Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idarucizumab (Group A) | 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 | dTT (# patients evaluable for reversal=240; 150) | 100.0 percentage |
| Idarucizumab (Group A) | 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 | ECT (# patients evaluable for reversal=271; 182) | 100.0 percentage |
| Idarucizumab (Group B) | 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 | dTT (# patients evaluable for reversal=240; 150) | 100.0 percentage |
| Idarucizumab (Group B) | 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 | ECT (# patients evaluable for reversal=271; 182) | 100.0 percentage |
Secondary
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.
Time frame: from the end of the first infusion up to 4 hours after the last infusion on Day 1
Population: Treated Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idarucizumab (Group A) | Reversal of aPTT and TT From Central Laboratory | aPTT (# patients evaluable for reversal=232; 141) | 100.0 percentage |
| Idarucizumab (Group A) | Reversal of aPTT and TT From Central Laboratory | TT (# patients evaluable for reversal=278; 188) | 100.0 percentage |
| Idarucizumab (Group B) | Reversal of aPTT and TT From Central Laboratory | aPTT (# patients evaluable for reversal=232; 141) | 100.0 percentage |
| Idarucizumab (Group B) | Reversal of aPTT and TT From Central Laboratory | TT (# patients evaluable for reversal=278; 188) | 100.0 percentage |
Secondary
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.
Time frame: from the first infusion up to 24 hours after the last infusion on Day 1
Population: Treated set with patients who stopped bleeding within 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idarucizumab (Group A) | Time to Cessation of Bleeding (for Group A Only) | 10.73 hours |
| Idarucizumab (Group B) | Time to Cessation of Bleeding (for Group A Only) | 2.49 hours |