Trial Outcomes & Findings for Reversal of Dabigatran Anticoagulant Effect With Idarucizumab (NCT NCT02104947)

Last Updated: 2018-01-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

503 participants

Primary outcome timeframe

from the end of the first infusion up to 4 hours after the last infusion on Day 1

Results posted on

2018-01-05

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	301	202
Overall Study COMPLETED	222	146
Overall Study NOT COMPLETED	79	56

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Withdrawal by Subject	10	3
Overall Study Lost to Follow-up	4	4
Overall Study Protocol Violation	6	8
Overall Study Adverse Event	57	38
Overall Study Other than stated above	2	3

Baseline Characteristics

Reversal of Dabigatran Anticoagulant Effect With Idarucizumab

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Idarucizumab (Group A) n=301 Participants 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.	Idarucizumab (Group B) n=202 Participants 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.	Total n=503 Participants Total of all reporting groups
Age, Continuous	77.1 Years STANDARD_DEVIATION 10.4 • n=5 Participants	75.9 Years STANDARD_DEVIATION 10.5 • n=7 Participants	76.6 Years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	129 Participants n=5 Participants	100 Participants n=7 Participants	229 Participants n=5 Participants
Sex: Female, Male Male	172 Participants n=5 Participants	102 Participants n=7 Participants	274 Participants n=5 Participants

PRIMARY outcome

Timeframe: from the end of the first infusion up to 4 hours after the last infusion on Day 1

Population: Treated Set

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=301 Participants 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.	Idarucizumab (Group B) n=202 Participants 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.
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 Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0
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 Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0

SECONDARY outcome

Timeframe: from the end of the first infusion up to 4 hours after the last infusion on Day 1

Population: Treated Set

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=301 Participants 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.	Idarucizumab (Group B) n=202 Participants 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.
Reversal of aPTT and TT From Central Laboratory aPTT (# patients evaluable for reversal=232; 141)	100.0 percentage Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0
Reversal of aPTT and TT From Central Laboratory TT (# patients evaluable for reversal=278; 188)	100.0 percentage Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0

SECONDARY outcome

Timeframe: from the first infusion up to 24 hours after the last infusion on Day 1

Population: Treated Set

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=301 Participants 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.	Idarucizumab (Group B) n=202 Participants 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.
Duration of Reversal ECT (# patients evaluable for reversal=276; 185)	13.2 hours Standard Deviation 10.0	12.8 hours Standard Deviation 9.7
Duration of Reversal dTT (# patients evaluable for reversal=244; 152)	19.8 hours Standard Deviation 6.7	18.8 hours Standard Deviation 7.6

SECONDARY outcome

Timeframe: within 24 hours of surgery

Population: Treated Set

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=202 Participants 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.	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.
Occurrence of Major/Life-threatening/Fatal Bleeding (for Group B Only) Intraoperatively	3.0 percentage of participants Interval 1.1 to 6.5	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=41 Participants 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.	Idarucizumab (Group B) n=134 Participants 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.
Time to Cessation of Bleeding (for Group A Only)	10.73 hours Interval 4.8 to 15.73	2.49 hours Interval 2.18 to 3.93

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=493 Participants 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.	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.
Cmin,1 of Unbound Sum (Free) Dabigatran	1.12 ng/mL Geometric Coefficient of Variation 61.2	—

SECONDARY outcome

Timeframe: after the first vial of idarucizumab and before the start of second vial on Day1

Population: Treated Set

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.

Outcome measures

Outcome measures
Measure	Idarucizumab (Group A) n=301 Participants 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.	Idarucizumab (Group B) n=202 Participants 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.
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 Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0
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 Interval 100.0 to 100.0	100.0 percentage Interval 100.0 to 100.0

Adverse Events

Idarucizumab (Group A)

Serious events: 160 serious events

Other events: 139 other events

Deaths: 0 deaths

Idarucizumab (Group B)

Serious events: 106 serious events

Other events: 86 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Idarucizumab (Group A) n=301 participants at risk 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.	Idarucizumab (Group B) n=202 participants at risk 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.
Blood and lymphatic system disorders Anaemia	4.3% 13/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	5.4% 11/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Gastrointestinal disorders Constipation	11.0% 33/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	9.9% 20/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Gastrointestinal disorders Diarrhoea	4.7% 14/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	8.9% 18/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Gastrointestinal disorders Nausea	7.0% 21/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	8.9% 18/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
General disorders Oedema peripheral	5.6% 17/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	6.9% 14/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
General disorders Pyrexia	7.6% 23/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	3.0% 6/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Infections and infestations Urinary tract infection	11.6% 35/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	8.4% 17/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Metabolism and nutrition disorders Hypokalaemia	7.6% 23/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	4.0% 8/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Nervous system disorders Dizziness	3.0% 9/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	5.4% 11/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Nervous system disorders Headache	9.0% 27/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	3.0% 6/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Psychiatric disorders Confusional state	2.7% 8/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	6.4% 13/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Renal and urinary disorders Haematuria	6.0% 18/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	3.0% 6/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).
Vascular disorders Hypotension	5.6% 17/301 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).	7.4% 15/202 • From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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