Reversal of Dabigatran Anticoagulant Effect With Idarucizumab

Hemorrhage Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02104947
• Other study ID #: 1321.3
• Secondary ID: 2013-004813-41
• Status: Completed
• Phase: Phase 3
• First received: April 2, 2014
• Last updated: January 3, 2018
• Start date: May 6, 2014
• Est. completion date: October 20, 2016

Study information

• Verified date: January 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 503
• Est. completion date: October 20, 2016
• Est. primary completion date: July 25, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Hemorrhage

Intervention

Drug:
• idarucizumab
idarucizumab

Locations

Country	Name	City	State
Argentina	Centro Privado de Cardiología	Tucumán
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	St. Vincents Hospital (MEL)	Fitzroy	Victoria
Australia	St George Hospital	Kogarah	New South Wales
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Westmead Hospital-Clinical Haematology Dept	Westmead	New South Wales
Austria	Kepler Univ. Klinikum Linz	Linz
Austria	KH der Barmherzigen Schwestern Linz	Linz
Austria	AKH - Medical University of Vienna	Wien
Austria	Wilhelminenspital	Wien
Belgium	Aalst - HOSP Onze-Lieve-Vrouw	Aalst
Belgium	Brussels - UNIV UZ Brussel	Brussel
Belgium	Brussels - UNIV St-Pierre	Brussels
Belgium	Brussels - UNIV St-Luc	Bruxelles
Belgium	Genk - HOSP ZOL (St-Jan)	Genk
Belgium	UZ Leuven	Leuven
Brazil	Hospital Nossa Senhora de Pompéia	Caxias do Sul
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	Juravinski Hospital	Hamilton	Ontario
Canada	Jewish General Hospital	Montreal	Migration Data
Canada	St. Paul's Hospital	Vancouver	British Columbia
Colombia	Centro Médico Imbanaco de Cali S.A.	Cali
Colombia	Fundación Valle del Lili	Cali
Colombia	Fundación Cardiovascular de Colombia	Floridablanca
Colombia	Hospital Pablo Tobón Uribe	Medellin
Czechia	University Hospital Brno	Brno
Czechia	Hospital,Neurology Dept,Ceske Budejovice	Ceske Budejovice
Czechia	Hospital Hradec Kralove	Hradec Kralove
Czechia	Regional Hospital Liberec	Liberec
Czechia	Univ. Hospital Kralovske Vinohrady	Praha
Czechia	University Hospital Motol	Praha 5
Denmark	Aarhus Universitetshospital	Aarhus C
Finland	HUS, Kirurginen päivystysosasto P1P, Meilahti, Helsinki	Helsinki
Finland	Keski-Suomen keskussairaala	Jyväskylä
Finland	Oulun yliopistollinen keskussairaala	Oulu
Finland	TAYS, Acuta, Tampere	Tampere
Finland	TYKS, Akuutti sisätautihoito ASIS, Turku	Turku
France	HOP Trousseau	Chambray les tours
France	HOP Bocage	Dijon
France	HOP André Mignot	Le Chesnay
France	HOP Lille, SAMU 59, Lille	Lille cedex
France	HOP Dupuytren	Limoges
France	HOP Herriot	Lyon
France	HOP Lapeyronie	Montpellier cedex
France	HOP Haut-Lévêque	Pessac
France	HOP Lyon Sud	Pierre Benite
France	HOP Nord	Saint-Priest-en-Jarez
France	HOP Sainte Anne, Urgence, Toulon	Toulon
Germany	Vivantes Netzwerk für Gesundheit GmbH	Berlin
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Hong Kong	Pamela Youde Nethersole Eastern Hospital	Hong Kong
Hong Kong	Prince of Wales Hosp, Dept of Med & Therapeutics	Hong Kong
Hong Kong	Prince of Wales Hospital	Hong Kong
India	B.M. Birla Heart research Centre	Kolkatta
India	Fortis Escorts Heart Institute	New Delhi
Ireland	St James's Hospital	Dublin
Ireland	Cork University Hospital	Wilton
Israel	Rambam Medical Center	Haifa
Israel	Meir Medical Center	Kfar Saba
Israel	The Chaim Sheba Medical Center Tel Hashomer	Ramat Gan
Israel	Sourasky Medical Center	Tel Aviv
Italy	Azienda Ospedaliera Careggi	Firenze
Italy	Ospedale S.Maria della Misericordia, AO di Perugia	Perugia
Italy	Azienda Unità Sanitaria Locale di Reggio Emilia	Reggio Emilia
Italy	Az. Osp. S.Giovanni-Addolorata	Roma
Italy	Policlinico Gemelli	Roma
Japan	Japanese Red Cross Nagoya Daini Hospital	Aichi, Nagoya
Japan	Ehime Prefectural Central Hospital	Ehime, Matsuyama
Japan	Fukuoka Tokushukai Medical Center	Fukuoka, Kasuga
Japan	Ogaki Municipal Hospital	Gifu, Ogaki
Japan	National Hospital Organization Takasaki General Medical Center	Gunma, Takasaki
Japan	Hyogo College of Medicine Hospital	Hyogo, Nishinomiya
Japan	National Hospital Organization Kagoshima Medical Center	Kagoshima, Kagoshima
Japan	Shonan Kamakura General Hospital	Kanagawa, Kamakura
Japan	National Cerebral and Cardiovascular Center	Osaka, Suita
Japan	Nippon Medical School Hospital	Tokyo, Bunkyo-Ku
Japan	National Hospital Organization Disaster Medical Center	Tokyo, Tachikawa
Japan	Yamagata City Hospital SAISEIKAN	Yamagata, Yamagata
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	The Catholic University of Korea, Seoul St.Mary's Hospital	Seoul
Mexico	Hospital Cardiologica Aguascalientes	Aguascalientes
Netherlands	Academisch Medisch Centrum (AMC)	Amsterdam
Netherlands	OLVG, locatie Oosterpark	Amsterdam
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Maastricht Universitair Medisch Centrum	Maastricht
Netherlands	Radboud Universitair Medisch Centrum	Nijmegen
Netherlands	Erasmus Medisch Centrum	Rotterdam
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Auckland City Hospital	Grafton / Auckland
New Zealand	Waikato Hospital	Hamilton
New Zealand	Middlemore Hospital	Otahuhu South Auckland
New Zealand	North Shore Hospital, Takapuna	Takapuna Auckland
Norway	Haukeland Universitetssykehus	Bergen
Norway	Vestre Viken HF, Drammen Sykehus	Drammen
Norway	Sykehuset Østfold Kalnes	Grålum
Norway	Oslo Universitetssykehus HF, Ullevål sykehus	Oslo
Norway	Universitetssykehuset Nord-Norge, Tromsø	Tromsø
Poland	Univ. Clinic Hosp, Bialystok	Bialystok
Poland	University Clinical Center, Gdansk	Gdansk
Poland	Saint Wincenty a Paulo Hosp., Cardiology Dept., Gdynia	Gdynia
Poland	Reg.Hosp Kielce,Swietokrzyskie,1.Clinic of Cardiology,Kielce	Kielce
Poland	The John Paul II Hosp.,Dept.of Coronary Heart Disease,Krakow	Krakow
Poland	Stefan Kardynal Wyszynski Reg.Hosp,Cardiol&IntensUnit,Lublin	Lublin
Poland	Independent Public Healthcare, Dept. of Cardiology, Pulawy	Pulawy
Poland	Central Hosp.Minis.Interior,Dep.Noninvasive Cardiol,Warszawa	Warszawa
Portugal	Centro Hospitalar da Cova da Beira Hospital Pêro da Covilhã	Covilhã
Portugal	CHLO, EPE - Hospital S. Francisco Xavier	Lisboa
Portugal	Centro Hospitalar do Porto, EPE	Porto
Portugal	Centro Hospitalar São João,EPE	Porto
Russian Federation	City Pokrovskiy Hospital, Cardiology Dept., Saint Petersburg	Saint Petersburg
Russian Federation	Military Medical Academy n.a. S. M. Kirov, St. Petersburg	St. Petersburg
Singapore	Changi General Hospital	Singapore
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
South Africa	Dr. D. Adler	Sandton
South Africa	Dr. Engelbrecht	Somerset West
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital de Bellvitge	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital La Paz	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Regional Universitario de Málaga	Malaga
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Clínico de Valencia	Valencia
Spain	Hospital Politècnic La Fe	Valencia
Spain	Hospital Álvaro Cunqueiro	Vigo (Pontevedra)
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
Sweden	Sahlgrenska US, Göteborg	Göteborg
Sweden	Skånes universitetssjukhus	Lund
Sweden	Akademiska sjukhuset	Uppsala
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Far Eastern Memorial Hospital	New Taipei City
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipe Veterans General Hospital	Taipei
United Kingdom	North Hampshire Hospital	Basingstoke
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Royal London Hospital	London
United Kingdom	St George's Hospital	London
United Kingdom	Emergency Department, John Radcliffe Hospital, Oxford	Oxford
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Musgrove Park Hospital	Taunton
United States	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Health Research and Education Institute	Fort Worth	Texas
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Genesys Regional Medical Center	Grand Blanc	Michigan
United States	Sentara RMH Medical Center	Harrisonburg	Virginia
United States	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	Henry Ford Allegiance Health	Jackson	Michigan
United States	Baptist Medical Center	Jacksonville	Florida
United States	Mayo Clinic Cancer Center	Jacksonville	Florida
United States	St. Mary Medical Center	Langhorne	Pennsylvania
United States	Baptist Health Center for Clinical Research	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Community Hospital	Munster	Indiana
United States	Newton-Wellesley Hospital	Newton	Massachusetts
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mercy Hospital St. Louis	Saint Louis	Missouri
United States	St. Joseph's Hospital	Tampa	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	St. John Health System Inc	Tulsa	Oklahoma
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	St. Elizabeth Youngstown Hospital	Youngstown	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Colombia,  Czechia,  Denmark,  Finland,  France,  Germany,  Hong Kong,  India,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Norway,  Poland,  Portugal,  Russian Federation,  Singapore,  South Africa,  Spain,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	from the end of the first infusion up to 4 hours after the last infusion on Day 1
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.	from the end of the first infusion up to 4 hours after the last infusion on Day 1
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.	from the first infusion up to 24 hours after the last infusion on Day 1
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.	within 24 hours of surgery
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.	from the first infusion up to 24 hours after the last infusion on Day 1
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.	Since the end of first vial of idarucizumab up to 4 hours after the completion of second vial
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.	after the first vial of idarucizumab and before the start of second vial on Day1

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