Clinical trial NCT02072434: Edoxaban vs. Warfarin in Subjects Undergoing Cardioversion of Nonvalvular Atrial Fibrillation (NVAF)
Official title: A Prospective, Randomized, Open-Label Blinded Endpoint Evaluation (PROBE) Parallel Group Study Comparing Edoxaban (DU-176b) With Enoxaparin/Warfarin Followed by Warfarin Alone in Subjects Undergoing Planned Electrical Cardioversion of Nonvalvular Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrial Fibrillation
Keywords: Nonvalvular atrial fibrillation (NVAF)
anti-coagulant
warfarin
edoxaban
electrical cardioversion
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2014-02-26
Enrollment: 2199
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare edoxaban to warfarin (with enoxaparin, if needed). It will see if edoxaban prevents stroke and other blood clotting problems as well and as safely as warfarin. People with atrial fibrillation (irregular heartbeat) might be able to join. Their doctors must plan to use shock to make their hearts beat normally. About 2200 people from different countries will join. They will have an equal chance of receiving either treatment. They are anticipated to be in the study for around 82 days. Tests will include physicals and finger-pricks. Participants will provide blood and urine samples.

Detailed description: The purpose of this study is to compare edoxaban (investigational drug) with warfarin and enoxaparin, to see if it is safe and effective in preventing stroke and other blood clot complications in subjects with atrial fibrillation whose doctors plan to treat them with an electrical cardioversion. It is expected that 284 sites will recruit 2200 subjects from North America, EU, Russia, Ukraine and Israel. Participants will be randomly allocated to receive either treatment with edoxaban, or treatment with warfarin, plus enoxaparin if required. Participants will have an equal chance of receiving either treatment. Participants will be in the study for a maximum of 82 days. Study procedures will include physical examinations, vital signs (pulse and sitting blood pressure), ECG (electrocardiogram), finger prick blood clotting tests, blood samples and urine samples.

The study is expected to show that edoxaban will provide comparable incidence rates to warfarin plus enoxaparin, the current standard treatment for both efficacy and bleeding.

Eligibility criteria: Inclusion Criteria:

* Has signed informed consent
* Is older than minimum legal adult age (country specific)
* Has had ongoing AF lasting at least 48 hrs but \<= 12 months (with or without valvular heart disease)
* Has treatment plan that includes for electrical cardioversion
* Has NVAF or other specific valvular heart diseases (eg, mitral valve prolapse, mitral valve regurgitation, and aortic valve disease)

Exclusion Criteria:

* Has AF that is transient or reversible
* Has contraindicated condition, ie, conditions considered to be formal indication for conventional anticoagulation
* Has a history of left atrial appendage (LAA) closure
* Has a known thrombus in LAA, the left atrial, left ventricle or aorta - or an intracardial mass
* Has had myocardial infarction (MI), stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI) within the past 30 days
* Has any contraindication to anticoagulant agents
* Has had protocol-defined signs of bleeding or conditions associated with high risk of bleeding that would preclude participation
* Is receiving, or plans to receive during the study period, dual antiplatelet therapy (DAPT) or invasive procedures (other than routine endoscopy) in which bleeding would be anticipated
* Has received prohibited concomitant medication or therapy
* Has had protocol-defined signs of bleeding or high
* Has inadequate liver, kidney, and blood test results
* Received any investigational drug or device within the past 30 days or plans to during the study period
* Has reproductive potential and does not agree to take proper contraceptive measures
* Has active cancer requiring chemotherapy/radiation/major surgery within the next 3 months
* Has significant active concurrent medical illness or infection or life expectancy less than 6 months
* In the opinion of the investigator, is unlikely to comply with the protocol or complete the study, has had drug or alcohol dependence within the past year, or has any other condition that might place the participant at increased risk of harm
* Is a participant in the United States after January 2015 with creatinine clearance (CrCL) greater than 95 mL/minute

Primary outcomes:
measure: Percentage of Participants With Composite Endpoint of Stroke, Systemic Embolic Stroke (SEE), Myocardial Infarction (MI) and Cardiovascular (CV) Mortality From Randomization to End of Follow up
timeFrame: Randomization to end of follow-up (within 2 years)
measure: Percentage of Participants With Composite Endpoints of Major and Clinically-relevant Non-major (CRNM) Bleeding
timeFrame: During treatment period (within 2 years)
Secondary outcomes:
measure: Percentage of Participants With Composite Endpoints of Stroke, SEE, MI, CV Mortality, and Major Bleeding
timeFrame: From randomization to the end of follow-up (within 2 years)
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Escondido
country: United States
state: California
city: Newport Beach
country: United States
state: California
city: Riverside
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Santa Rosa
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Stamford
country: United States
state: Connecticut
city: Newark
country: United States
state: Delaware
city: Clearwater
country: United States
state: Florida
city: Daytona Beach
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Rockledge
country: United States
state: Florida
city: Sarasota
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Boise
country: United States
state: Idaho
city: Auburn
country: United States
state: Maine
city: Rochester
country: United States
state: Minnesota
city: Allentown
country: United States
state: Pennsylvania
city: Butler
country: United States
state: Pennsylvania
city: Camp Hill
country: United States
state: Pennsylvania
city: Hershey
country: United States
state: Pennsylvania
city: Jackson
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Plano
country: United States
state: Texas
city: Tyler
country: United States
state: Texas
city: Richmond
country: United States
state: Virginia
city: Graz
country: Austria
city: Innsbruck
country: Austria
city: Linz
country: Austria
city: Modling
country: Austria
city: Wien
country: Austria
city: Brussels
country: Belgium
city: Genk
country: Belgium
city: Gent
country: Belgium
city: Hasselt
country: Belgium
city: Huy
country: Belgium
city: Leuven
country: Belgium
city: Liege
country: Belgium
city: Mechelen
country: Belgium
city: Tienen
country: Belgium
city: Turnhout
country: Belgium
city: Burgas
country: Bulgaria
city: Gabrovo
country: Bulgaria
city: Pazardzhik
country: Bulgaria
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Stara Zagora
country: Bulgaria
city: Varna
country: Bulgaria
city: Veliko Tarnovo
country: Bulgaria
city: Brno
country: Czechia
city: Cesky Krumlov
country: Czechia
city: Havlickuv Brod
country: Czechia
city: Hodonin
country: Czechia
city: Kolin
country: Czechia
city: Kromeriz
country: Czechia
city: Nachod
country: Czechia
city: Praha 4
country: Czechia
city: Praha 6
country: Czechia
city: Pribram
country: Czechia
city: Slany
country: Czechia
city: Aalborg
country: Denmark
city: Copenhagen
country: Denmark
facility: First site in
city: Copenhagen
country: Denmark
facility: Second site in
city: Frederiksberg
country: Denmark
city: Hellerup
country: Denmark
city: Herning
country: Denmark
city: Holbaek
country: Denmark
city: Køge
country: Denmark
city: Silkeborg
country: Denmark
city: Slagelse
country: Denmark
city: Svendborg
country: Denmark
city: Vejle
country: Denmark
city: Viborg
country: Denmark
city: Angers cedex 9
country: France
city: Bordeaux
country: France
city: Bron cedex
country: France
city: Corbeil Essonnes
country: France
city: Dijon cedex
country: France
city: Grenoble cedex 09
country: France
city: Lyon
country: France
city: Marseille cedex 20
country: France
city: Marseille cedex 5
country: France
city: Montfermeil
country: France
city: Montpellier Cedex 5
country: France
city: Nice
country: France
city: Paris
country: France
city: Saint-Denis cedex
country: France
city: Toulouse cedex 9
country: France
city: Vandoeuvre les Nancy cedex
country: France
city: Bad Berka
country: Germany
city: Berlin
country: Germany
city: Bielefeld
country: Germany
city: Coburg
country: Germany
city: Dortmund
country: Germany
city: Dresden
country: Germany
city: Freiburg
country: Germany
city: Giessen
country: Germany
city: Hamburg
country: Germany
city: Heidelberg
country: Germany
city: Heilbronn
country: Germany
facility: Bad Friedrichshall
city: Langen
country: Germany
city: Leipzig
country: Germany
city: Ludwigsburg
country: Germany
city: Mainz
country: Germany
city: Marburg
country: Germany
city: Monchengladbach
country: Germany
city: Munchen
country: Germany
city: Paderborn
country: Germany
city: Regensburg
country: Germany
city: Balatonfured
country: Hungary
city: Budapest
country: Hungary
facility: First site in
city: Budapest
country: Hungary
facility: Second site in
city: Cegled
country: Hungary
city: Debrecen
country: Hungary
city: Gyula
country: Hungary
city: Győr
country: Hungary
city: Hodmezovasarhely
country: Hungary
city: Kecskemet
country: Hungary
city: Nagykanizsa
country: Hungary
city: Pécs
country: Hungary
city: Szeged
country: Hungary
city: Szekesfehervar
country: Hungary
city: Szolnok
country: Hungary
city: Szombathely
country: Hungary
city: Zalaegerszeg
country: Hungary
city: Afula
country: Israel
city: Ashkelon
country: Israel
city: Hadera
country: Israel
city: Haifa
country: Israel
city: Holon
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Acquaviva delle Fonti
country: Italy
state: BA
city: Santa Maria Capua Vetere
country: Italy
state: CE
city: Mestre
country: Italy
state: VE
city: Bologna
country: Italy
city: Catania
country: Italy
city: Chieti
country: Italy
city: Napoli
country: Italy
city: Pavia
country: Italy
city: Roma
country: Italy
facility: First site in
city: Roma
country: Italy
facility: Second site in
city: Trieste
country: Italy
city: Amsterdam
country: Netherlands
city: Den Haag
country: Netherlands
city: Hilversum
country: Netherlands
city: Leeuwarden
country: Netherlands
city: Rotterdam
country: Netherlands
city: Venlo
country: Netherlands
city: Zwolle
country: Netherlands
city: Elblag
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Pulawy
country: Poland
city: Torun
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Oradea
country: Romania
state: Bihor
city: Craiova
country: Romania
state: Dolj
city: Focsani
country: Romania
state: Vrancea
city: Baia Mare
country: Romania
city: Braila
country: Romania
city: Bucuresti
country: Romania
city: Cluj-Napoca
country: Romania
city: Iasi
country: Romania
city: Pitesti
country: Romania
city: Targoviste
country: Romania
city: Timisoara
country: Romania
city: Târgu-Mureş
country: Romania
city: Barnaul
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Moscow
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Tyumen
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: San Juan de Alicante
country: Spain
state: Alicante
city: Sabadell
country: Spain
state: Barcelona
city: Salt
country: Spain
state: Girona
city: Almeria
country: Spain
city: Barcelona
country: Spain
facility: First site in
city: Barcelona
country: Spain
facility: Second site in
city: Granada
country: Spain
city: Lugo
country: Spain
city: Madrid
country: Spain
facility: First site in
city: Madrid
country: Spain
facility: Second site in
city: Madrid
country: Spain
facility: Third site in
city: Ourense
country: Spain
city: Santiago de Compostela
country: Spain
city: Valencia
country: Spain
city: Vigo
country: Spain
city: Helsingborg
country: Sweden
city: Uppsala
country: Sweden
city: Cherkasy
country: Ukraine
city: Ivano-Frankivsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Odesa
country: Ukraine
city: Uzhhorod
country: Ukraine
city: Vinnytsia
country: Ukraine
city: Zaporizhzhia
country: Ukraine
city: Zhytomyr
country: Ukraine
city: Romford
country: United Kingdom
state: Essex
city: Southampton
country: United Kingdom
state: Hampshire
city: Blackpool
country: United Kingdom
state: Lancashire
city: Barnet
country: United Kingdom
city: Basildon
country: United Kingdom
city: Birmingham
country: United Kingdom
city: Bournemouth
country: United Kingdom
city: Bradford
country: United Kingdom
city: Chertsey
country: United Kingdom
city: Doncaster
country: United Kingdom
city: Dundee
country: United Kingdom
city: Harrow
country: United Kingdom
city: Leeds
country: United Kingdom
city: Leicester
country: United Kingdom
city: Liverpool
country: United Kingdom
city: Llanelli
country: United Kingdom
city: London
country: United Kingdom
city: Luton
country: United Kingdom
city: Newport
country: United Kingdom
city: Oxford
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Swansea
country: United Kingdom
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References:
citation: Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
citation: Goette A, Kwong WJ, Ezekowitz MD, Banach M, Hjortshoj SP, Zamoryakhin D, Lip GYH. Edoxaban therapy increases treatment satisfaction and reduces utilization of healthcare resources: an analysis from the EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of atrial fibrillation (ENSURE-AF) study. Europace. 2018 Dec 1;20(12):1936-1943. doi: 10.1093/europace/euy141.
citation: Goette A, Merino JL, Ezekowitz MD, Zamoryakhin D, Melino M, Jin J, Mercuri MF, Grosso MA, Fernandez V, Al-Saady N, Pelekh N, Merkely B, Zenin S, Kushnir M, Spinar J, Batushkin V, de Groot JR, Lip GY; ENSURE-AF investigators. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet. 2016 Oct 22;388(10055):1995-2003. doi: 10.1016/S0140-6736(16)31474-X. Epub 2016 Aug 30.
citation: Lip GY, Merino J, Ezekowitz M, Ellenbogen K, Zamoryakhin D, Lanz H, Jin J, Al-Saadi N, Mercuri M, Goette A. A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation: The EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study. Am Heart J. 2015 May;169(5):597-604.e5. doi: 10.1016/j.ahj.2015.02.009. Epub 2015 Feb 21.