BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran 
with high affinity in a 1:1 molar ratio. We investigated the safety, 
tolerability, and efficacy of increasing doses of idarucizumab for the reversal 
of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose 
assessment and dose-finding, proof-of-concept investigation). Here we present 
the results of the proof-of-concept part of the study.
METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept 
phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a 
body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life 
Sciences Clinical Research Services, Belgium. Participants were randomly 
assigned within groups in a 3:1 ratio to idarucizumab or placebo using a 
pseudorandom number generator and a supplied seed number. Participants and care 
providers were masked to treatment assignment. All participants received oral 
dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. 
Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min 
infusions given 1 h apart) was administered about 2 h after the final dabigatran 
etexilate dose. The primary endpoint was incidence of drug-related adverse 
events, analysed in all randomly assigned participants who received at least one 
dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin 
clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin 
time (TT) were secondary endpoints assessed by measuring the area under the 
effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on 
days 3 and 4. This trial is registered with ClinicalTrials.gov, number 
NCT01688830.
FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the 
study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g 
idarucizumab groups (nine to idarucizumab and three to placebo in each group), 
and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and 
three to placebo). Drug-related adverse events were all of mild intensity and 
reported in seven participants: one in the 1 g idarucizumab group (infusion site 
erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group 
(epistaxis); one receiving placebo (infusion site haematoma), and four during 
dabigatran etexilate pretreatment (three haematuria and one epistaxis). 
Idarucizumab immediately and completely reversed dabigatran-induced 
anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to 
day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% 
reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g 
idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% 
reduction). No serious or severe adverse events were reported, no adverse event 
led to discontinuation of treatment, and no clinically relevant difference in 
incidence of adverse events was noted between treatment groups.
INTERPRETATION: These phase 1 results show that idarucizumab was associated with 
immediate, complete, and sustained reversal of dabigatran-induced 
anticoagulation in healthy men, and was well tolerated with no unexpected or 
clinically relevant safety concerns, supporting further testing. Further 
clinical studies are in progress.
FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.