NCT02104947

Reversal of Dabigatran Anticoagulant Effect With Idarucizumab

Completed Phase 3 Results posted Last updated 5 January 2018

What this trial tests

Phase 3 trial testing idarucizumab in Hemorrhage in 503 participants. Completed in 20 October 2016.

Timeline

6 May 2014

Primary endpoint
25 July 2016

20 October 2016

Quick facts

Lead sponsor	Boehringer Ingelheim
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	503
Start date	6 May 2014
Primary completion	25 July 2016
Estimated completion	20 October 2016
Sites	176 locations across Hong Kong, Colombia, Finland, Italy, Japan, Taiwan, Ireland, Poland

Drugs / interventions tested

• idarucizumab (IDARUCIZUMAB) — full drug profile →

Conditions studied

• Hemorrhage — all drugs for Hemorrhage →

Sponsor

Boehringer Ingelheim — full company profile →

Who can join

18 and older, any sex, with Hemorrhage. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Reversal of Anticoagulant Effect of Dabigatran Based on Central Laboratory Determination of dTT or ECT Primary · 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.

dTT (# patients evaluable for reversal=244; 152)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

ECT (# patients evaluable for reversal=276; 185)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

Reversal of aPTT and TT From Central Laboratory Secondary · 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.

aPTT (# patients evaluable for reversal=232; 141)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

TT (# patients evaluable for reversal=278; 188)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

Duration of Reversal Secondary · 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.

ECT (# patients evaluable for reversal=276; 185)

Group	Value	95% CI
Idarucizumab (Group A)	13.2	± 10.0
Idarucizumab (Group B)	12.8	± 9.7

dTT (# patients evaluable for reversal=244; 152)

Group	Value	95% CI
Idarucizumab (Group A)	19.8	± 6.7
Idarucizumab (Group B)	18.8	± 7.6

Occurrence of Major/Life-threatening/Fatal Bleeding (for Group B Only) Intraoperatively Secondary · 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.

Group	Value	95% CI
Idarucizumab (Group B)	3.0	1.1 – 6.5

Time to Cessation of Bleeding (for Group A Only) Secondary · 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.

Group	Value	95% CI
ICH (Group A)	10.73	4.80 – 15.73
Non-ICH (Group A)	2.49	2.18 – 3.93

Cmin,1 of Unbound Sum (Free) Dabigatran Secondary · 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.

Group	Value	95% CI
Idarucizumab (Group A & B)	1.12	± 61.2

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 Secondary · 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.

dTT (# patients evaluable for reversal=240; 150)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

ECT (# patients evaluable for reversal=271; 182)

Group	Value	95% CI
Idarucizumab (Group A)	100.0	100.0 – 100.0
Idarucizumab (Group B)	100.0	100.0 – 100.0

Adverse events — posted to ClinicalTrials.gov

Time frame: From the first vial of idarucizumab until end of study (90 ± 7 days after the second vial).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Idarucizumab (Group A)

Serious: 160/301 (53%)

Deaths: —

Idarucizumab (Group B)

Serious: 106/202 (52%)

Deaths: —

Serious adverse events (221 terms)

Reaction	System	Idarucizumab (Group A)	Idarucizumab (Group B)
Pneumonia	Infections and infestations	—	—
Delirium	Psychiatric disorders	—	—
Cardiac failure	Cardiac disorders	—	—
Septic shock	Infections and infestations	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Subdural haematoma	Injury, poisoning and procedural complications	—	—
Sepsis	Infections and infestations	—	—
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Deep vein thrombosis	Vascular disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Ischaemic stroke	Nervous system disorders	—	—
Renal failure	Renal and urinary disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—
Multiple organ dysfunction syndrome	General disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Cardiac failure chronic	Cardiac disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Anuria	Renal and urinary disorders	—	—
Hydronephrosis	Renal and urinary disorders	—	—

Other adverse events (13 terms — click to expand)

Reaction	System	Idarucizumab (Group A)	Idarucizumab (Group B)
Urinary tract infection	Infections and infestations	—	—
Constipation	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Pyrexia	General disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Haematuria	Renal and urinary disorders	—	—
Oedema peripheral	General disorders	—	—
Hypotension	Vascular disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Confusional state	Psychiatric disorders	—	—
Dizziness	Nervous system disorders	—	—

Most-reported serious reactions: Pneumonia, Delirium, Cardiac failure, Septic shock, Cardiac failure congestive, Cardiac arrest, Subdural haematoma, Sepsis.

Data from ClinicalTrials.gov NCT02104947 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Idarucizumab for Dabigatran Reversal.
   Pollack CV, Reilly PA, Eikelboom J, Glund S, et al · · 2015 · cited 961× · PMID 26095746 · DOI 10.1056/nejmoa1502000
2. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.
   Pollack CV, Reilly PA, van Ryn J, Eikelboom JW, et al · · 2017 · cited 643× · PMID 28693366 · DOI 10.1056/nejmoa1707278
3. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran.
   Pollack CV, Reilly PA, Bernstein R, Dubiel R, et al · · 2015 · cited 101× · PMID 26020620 · DOI 10.1160/th15-03-0192
4. Measurement and reversal of the direct oral anticoagulants.
   Samuelson BT, Cuker A. · · 2017 · cited 72× · PMID 27625113 · DOI 10.1016/j.blre.2016.08.006
5. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab.
   Hu TY, Vaidya VR, Asirvatham SJ. · · 2016 · cited 58× · PMID 26937198 · DOI 10.2147/vhrm.s89130
6. Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding.
   Van der Wall SJ, Lopes RD, Aisenberg J, Reilly P, et al · · 2019 · cited 33× · PMID 30586692 · DOI 10.1161/circulationaha.118.036710
7. An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants.
   Mujer MTP, Rai MP, Atti V, Dimaandal IL, et al · · 2020 · cited 29× · PMID 32231703 · DOI 10.1155/2020/7636104
8. Reversal of direct oral anticoagulants: a practical approach.
   Shih AW, Crowther MA. · · 2016 · cited 23× · PMID 27913536 · DOI 10.1182/asheducation-2016.1.612